The June 2012 Digital Edition of Pharmacy Practice News

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Volume 39 • Number 6 • June 2012

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4 0th A N N IV E RSA RY

Young Cancer Patients in this issue Front Getting More Attention Up In Brief Orlando, Fla.—In recent years, a niche of medicine has sprung up to address the needs of adolescents and young adults (AYA) with cancer. AYA oncology now has its own society and its own journal, and in March, the National Comprehensive Cancer Network (NCCN) issued its first set of AYA guidelines. The attention to AYA cancer patients—defined as those aged 15 to 39 years—is sorely needed. In the past 40 years, cancer survival rates of children and older adults has improved significantly, whereas survival rates among AYAs with cancer have barely budged. “Improvements in cancer survival among AYA patients definitely have lagged behind other sectors of the population,” said Kerry Parsons, PharmD, a pediatric oncology pharmacist at Children’s of Alabama, in Birmingham, who discussed AYA oncology at the annual meeting

•

see YOUTH CANCER, page 9

Pharmacists Employ Cost-Saving Strategies For Pricey New Drugs Orlando, Fla.—These days, cancer centers across the United States are doing everything they can to contain costs. At the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA), pharmacists presented strategies for reducing costs involved with ipilimumab (Yervoy, Bristol-Myers Squibb) and rasburicase (Elitek, Sanofi-aventis).

Cost Cutting With Ipilimumab A study by researchers from the Roswell Park Cancer Institute in Buffalo, N.Y., demonstrated that dose rounding of ipilimumab to the nearest 50 mg has the potential to result in a significant cost savings without adversely affecting patient care (abstract 9). Ipilimumab was approved in March 2011 for the treatment of metastatic melanoma at a dose of 3 mg/kg every 21 days for four doses. The drug is supplied as 50- or 200-mg single-use vials, each

•

see STRATEGIES, page 8

Anticonvulsant may help relieve cannabis dependence.

3

Policy

USP <Chapter 797> Tips for preventing contamination in sterile compounding settings.

6

Clinical

Hem/Onc Pharmacy “Dont ask, don’t tell” doesn’t work with dietary supplements.

11

Extended docetaxel infusion slashes adverse reactions.

12

Critical Care Neuromuscular blockers cut mortality in ICU.

14

Steroids speed extubation in septic shock patients.

16

Operations & Mgmt

Wicked Change Envisioning a new practice future.

28

Reimbursement Matters How to get your fair share of bundled payments.

29

Leadership in Action Conflict: the destroyer or an opportunity?

30

Educational Review

Managing Anemia in Patients With Chronic Kidney Disease See insert after page 16

Heart Failure Checklist Decreases Readmissions Physicians and pharmacists develop tool to keep HF patients healthy and at home Chicago—An inexpensive checklist used at discharge has virtually eliminated 30-day readmissions for heart failure (HF) in a Michigan hospital. At six months, the benefits of the strategy still held strong, with nearly twice as many patients staying at home after undergoing checklist-driven interventions, according to a poster study presented at the annual meeting of the American College of Cardiology. “The study has huge significance,” Abhijeet Basoor, MD, a cardiology fellow at St. Joseph Mercy Oakland Hospital, in Pontiac, and lead author of the study, told Pharmacy Practice News. “With such an inexpensive tool, you can improve quality of care and decrease readmissions.” The checklist can help hospitals achieve another important goal: steering clear of financial penalties that the Centers for Medicare & Medicaid Services (CMS) will assess on facilities that are deemed to have excessive readmission rates for HF and other conditions. The penalties are scheduled to take effect Oct. 1, 2012, according to a CMS press release.

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see READMISSION, page 23

Vancomycin Plus Piperacillin-Tazo May Trigger Acute Kidney Injury Houston—As many as 50% of patients treated with the combination of vancomycin and piperacillin-tazobactam (Zosyn, Wyeth) experience acute kidney injury, according to two studies presented at the annual meeting of the Society of Critical Care Medicine (SCCM). Piperacillintazobactam on it own also posed a safety risk, with the drug appearing to be more nephrotoxic than vancomycin. “We have been taught that vancomycin causes a lot of renal failure,” said

Thaddaus Hellwig, PharmD, an assistant professor of pharmacy practice at South Dakota State University College of Pharmacy, in Brookings, and an author of one of the studies. However, based on the new data, “maybe we should be keeping a little closer eye on patients [taking] Zosyn,” he said. Dr. Hellwig and his colleagues retrospectively studied (abstract 301) all patients aged 18 years and older who

The Book Page

New Product

Applied Biopharmaceutics & Pharmacokinetics, Sixth Edition Leon Shargel, Andrew Yu, Susanna Wu-Pong See page 31.

•

see NEPHROTOXICITY, page 13

CutisPharma offers two new compounding kits. See page 10.

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Pharmacy Practice News • June 2012

Up Front 3

Capsules

Gabapentin May Be a Potent Weed Killer

surf

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JUNE 2012

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Drug Shortages Continue To Chip Away at Patient Care 2. Medication Safety Pearls 3. Changes Are Coming For Stress Ulcer Prevention Therapy 4. Medication Errors: A Year in Review 5. Fine-Tuning ADE Alerts Helps Avoid Drug Errors Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘Envisioning a new

practice future is hard but rewarding work that involves thinking about …

a shared ownership in a better future.’ —Janice Glascock, PharmD, and Collin E. Lee, PharmD

See article, page 28

abapentin, an anticonvulsant approved by the FDA for postherpetic neuralgia and epilepsy, may have another use, according to a new study: the treatment of marijuana smokers seeking to end their cannabis dependence. In the study, self-reported cannabis use dropped significantly in patients taking gabapentin. Several objective measures, such as serum levels of cannabis metabolites, also showed that the patients had a diminishing dependence on weed, the authors reported (Neuropsychopharmacology 2012 Feb 29. doi: 10.1038/npp.2012.14. [Epub ahead of print]). The novel treatment also helped ease patients’ symptoms of withdrawal. “A lot of other drugs have been tested for their ability to decrease cannabis use and withdrawal, but this is the first to show these key effects in a controlled … study,” said lead researcher, Barbara J. Mason, co-director of the Pearson Center for Alcoholism and Addiction Research at the Scripps Research Institute, La Jolla, Calif. “The other nice thing about gabapentin is that it is already widely prescribed, so its safety is less likely to be an issue.” The 12-week randomized, placebo-controlled trial included 50 outpatients, aged 18 to 65 years, who were diagnosed with current cannabis dependence. The patients received either gabapentin (1,200 mg per day; n=25) or placebo (n=25); all patients also received abstinence-oriented counseling. Patients who took gabapentin used significantly less cannabis relative to the placebo group, as measured by the Timeline Followback Interview, a standardized self-report of grams of marijuana smoked per week (F=8.8; df=140; P=0.004). On another measure of cannabis use, D-9-tetrahydrocannabinol (THC) metabolite concentrations derived from weekly urine toxicology, patients who took gabapentin also showed significant reduction in cannabis use relative to placebo (F=12.2; df=216; P=0.001). Compared with the placebo group, the gabapentin group had significantly fewer withdrawal symptoms, as measured by the Marijuana Withdrawal Checklist (F=35.7; df=137; P<0.001), the Beck Depression Inventory II (F=15.3; df=611; P=0.009), and the Pittsburgh Sleep Quality Index (F=17.0; df=150; P<0.001). The gabapentin group scored significantly greater improvement on measures of executive function, three subtests from the DelisKaplan Executive Function System (t=–2.4; df=15; P=0.029). On the Marijuana Problems Scale, a measure of negative consequences associated with cannabis dependence, gabapentin, but not placebo, showed significant reductions (gabapentin change score, 3.4; 95% confidence interval, 0.8-6.0; P=0.02). Gabapentin was well tolerated and did not have significant side effects. Coupled with the efficacy data, gabapentin “may offer the most promising treatment for cannabis withdrawal and dependence studied to date,” the authors stated. The gabapentin results are encouraging, the researchers added, given the fact that there are no medications for cannabis dependence approved by the FDA. Morever, the problem of cannabis dependence is a significant one: Marijuana is the world’s most widely used illicit drug, and patients seeking treatment for primary cannabis dependence represent 25% of substance use admissions worldwide. —George Ochoa

EDITORIAL BOARD

Michele McMahon Velle, MAX Graphics/Creative Director

Administration

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

Robert Adamson, PharmD, Livingston, NJ

James O’Neill, Senior Systems Manager

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

Volume 39 • Number 6 • June 2012 • pharmacypracticenews.com

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

Dan Radebaugh, Director of Production and Technical Operations

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

Internal Medicine

EDITORIAL STAFF

Marty Barbieri, Production Manager

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

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

David Bronstein, Editorial Director davidb@mcmahonmed.com

Brandy Wilson, Circulation Coordinator

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

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Cardiology

Oncology

C. Michael White, PharmD, Storrs, CT

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

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors

CNS/Psychiatry

Robert Ignoffo, PharmD, San Francisco, CA

Charles F. Caley, PharmD, Storrs, CT

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

Biotechnology Indu Lew, PharmD, Livingston, NJ

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

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

Cathy Rosenbaum, PharmD, Cincinnati, OH Critical Care

Pediatrics

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

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

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

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

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

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Technology

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

ART/PRODUCTION STAFF

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9LVLW www.RECOTHROM.com

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RECOTHROM is a registered trademark of ZymoGenetics, Inc. ‹ =\PR*HQHWLFV ,QF $OO ULJKWV UHVHUYHG 57

7KURPELQ PDGH ZLWK D WZLVW RECOTHROM is human thrombin produced using recombinant DNA technology ² ,Q D JHQHWLFDOO\ PRGLĂ€HG &+2 &KLQHVH KDPVWHU RYDU\ FHOO OLQH Q 1RW GHULYHG IURP FDWWOH RU KXPDQ SODVPD Q &RQYHQLHQW DQG HDV\ WR XVH ² 5(&27+520 &RQYHQLHQFH .LWV DOORZ IRU TXLFN DQG HDV\ UHFRQVWLWXWLRQ Q )OH[LEOH SURGXFW OLQH ZLWK PXOWLSOH DSSOLFDWLRQ PHWKRGV ² 0D\ EH DSSOLHG GLUHFWO\ RU LQ FRQMXQFWLRQ ZLWK DEVRUEDEOH JHODWLQ VSRQJH 863

INDICATION RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical. IMPORTANT SAFETY INFORMATION Contraindications ‡ Topical use only – DO NOT INJECT directly into the circulatory system ‡ Do not use for the treatment of massive or brisk arterial bleeding ‡ Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions ‡ Potential risk of thrombosis if absorbed systemically ‡ In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction Adverse Reactions ‡ 7KH VHULRXV DGYHUVH HYHQW WKDW RFFXUUHG LQ • Q RI SDWLHQWV H[SRVHG WR 5(&27+520 LQ FRPSOHWHG FOLQLFDO WULDOV ZDV DWULDO žEULOODWLRQ 7KH PRVW FRPPRQ DGYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV 1 ZHUH LQFLVLRQ VLWH SDLQ SURFHGXUDO SDLQ DQG QDXVHD $GYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV were consistent with those commonly observed in surgical patients Please see Brief Summary of Full Prescribing Information on following page.

6 Policy

Pharmacy Practice News • June 2012

USP Chapter <797>

Abide by Guidelines To Prevent Infection in Sterile Compounding

I

nfection outbreaks caused by sterile compounding errors have been an ongoing problem, starting with a case in Nebraska in 1990 to more recent ones in Alabama and Tennessee in 2011. The U.S. Pharmacopeia (USP) Chapter <797> was designed to minimize such outbreaks, but it can only be effective when its requirements are strictly followed, and that is not always the case, according to an expert speaking at a

webinar sponsored by Wolters Kluwer Health, provider of the USP compliance software Simplifi 797. USP <797>, which applies to preadministration manipulations of compounded sterile preparations and to all compounding personnel and facilities, was introduced in its first iteration in 2004 and in a revised form in 2008. (The next revision is in process and is slated for completion in 2013.)

Immunogenicity The potential development of antibodies to RECOTHROM has been evaluated in multiple clinical trials. These pre-specified evaluations were performed in order to characterize the immunogenicity of RECOTHROM and the neutralizing potential of any detected antibodies. In completed clinical studies 5 of 552 (0.9%) patients exposed to RECOTHROM with both baseline and post-treatment antibody specimens available developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human thrombin.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION RECOTHROM® Thrombin, topical (Recombinant) Rx Only The following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant). CONTRAINDICATIONS Do not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding. Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM, or hamster proteins. WARNINGS AND PRECAUTIONS Potential risk of thrombosis if absorbed systemically. In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction. ADVERSE REACTIONS The serious adverse event that occurred in ≥ 1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial fibrillation. The most common adverse events in patients exposed to RECOTHROM in clinical trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%). Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials have been performed with RECOTHROM applied with absorbable gelatin sponge (Phase 2, Phase 3, and Phase 3b studies) and applied with a spray applicator (Phase 2 study). Adverse events reported in clinical trials were consistent with those commonly observed in surgical patients. Clinical Trials of RECOTHROM Used in Conjunction with Gelatin Sponge Among the 411 patients treated with study drug in the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, all but 2 patients (1 patient/treatment group) reported adverse events. Most events were moderate in severity and had a similar incidence in the RECOTHROM and bovine thrombin treatment groups. The most common adverse events were incision site pain (63% for both treatment groups), procedural pain (RECOTHROM 29%; bovine thrombin 34%), and nausea (RECOTHROM 28%; bovine thrombin 35%). Serious adverse events were reported by 18% of patients treated with RECOTHROM and 22% with bovine thrombin. Adverse events of interest were pre-specified, based on the thrombin mechanism of action, use of absorbable gelatin sponge, USP, historical reporting in association with cross-reacting antibodies to bovine thrombin product, and results from Phase 2 clinical trials of RECOTHROM applied with absorbable gelatin sponge. The incidences of these pre-specified adverse events were similar between treatment groups (see Table 1). Table 1. Events of Interest in the RECOTHROM Phase 3 Study AE Category* Patients with any event category Bleeding Cardiac Hypersensitivity Nausea + vomiting Other infection Post-operative wound infection Thromboembolic

RECOTHROM (N=205) n (%) 124 (60%) 27 (13%) 41 (20%) 30 (15%) 68 (33%) 26 (13%) 19 (9%) 12 (6%)

Although the <797> guidelines have been in place and there are many levels of oversight governing compounding and dispensing activities—the FDA, state boards of pharmacy, pharmacists and pharmacy technicians—cases of noncompliance do occur, noted webinar presenter Keith H. St. John, MS, CIC, director of clinical epidemiology at Wolters Kluwer Health, in Bellevue, Wash. Because technicians and other pharmacy

Thrombin-JMI (N=206) n (%) 136 (66%) 24 (12%) 38 (18%) 37 (18%) 83 (40%) 31 (15%) 22 (11%) 10 (5%)

†

Adverse events were included in event categories based on a blinded review of the investigator verbatim and coded terms. † THROMBIN-JMI® Thrombin, Topical (Bovine). *

In an open-label, single-group Phase 3b study, 209 patients with documented or highly likely prior exposure to bovine thrombin within the previous 3 years were treated with RECOTHROM when undergoing surgeries (spinal or peripheral arterial bypass or arteriovenous graft formation for hemodialysis access). The most common adverse events were incision site pain (45%), procedural pain (39%), and nausea (27%). Similar to the Phase 3 study, serious adverse events were reported by 22% of patients treated with RECOTHROM. Clinical Trials of RECOTHROM Applied with Spray Applicator In an open-label, single-group, Phase 2 study in burn patients, 72 patients were treated with RECOTHROM applied with a spray applicator at the burn wound excision site prior to autologous skin grafting. This study included both adults (≥ 17 years of age, n=68) and pediatric patients ≤ 16 years of age (n=4). The most common adverse events in the adult and pediatric age groups included procedural pain (35%), pruritis (25%), and constipation (19%).

In the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, the development of specific anti-product antibodies was evaluated in both treatment groups. Blood samples were collected at baseline and at day 29 for 97% of the patients in both treatment groups. For patients randomized to RECOTHROM, the samples were analyzed by ELISA for antibodies to RECOTHROM, Chinese hamster ovary (CHO) host cell protein, and pro-thrombin activator (used in the conversion of single chain precursor to active RECOTHROM). For patients randomized to bovine thrombin, the samples were analyzed by ELISA for antibodies to bovine thrombin product. At baseline 1.5% of patients (n=3/198) in the RECOTHROM group had positive anti-product antibody titers compared with 5% of patients in the bovine thrombin group (n=10/200). Of the patients who had detectable anti-product antibodies at baseline, 0 of 3 in the RECOTHROM group and 8 of 10 in the bovine thrombin group exhibited ≥ 1.0 titer unit (≥ 10-fold) increases in antibody levels after study treatment. Treatment with RECOTHROM applied with absorbable gelatin sponge resulted in a statistically significantly lower incidence of specific anti-product antibody development. Three of 198 (1.5%; 95% CI, 0 to 4%) of the patients in the RECOTHROM arm developed specific anti-thrombin product antibodies (1 patient also developed anti-CHO host cell protein antibodies). No patients developed antibodies to pro-thrombin activator. Forty-three of 200 patients (22%; 95% CI, 16 to 28%) in the bovine thrombin arm developed specific antibodies to bovine thrombin product. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. In the open-label, single group, Phase 3b study in patients with a high likelihood of prior bovine thrombin exposure undergoing spinal, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies at baseline prior to treatment with RECOTHROM. Following treatment, none of the 200 evaluable patients (patients for whom specimens were available for antibody testing at baseline and post-RECOTHROM treatment) developed antibodies to RECOTHROM. In the randomized, double-blind, controlled Phase 2 studies of RECOTHROM compared to placebo (RECOTHROM excipients reconstituted with 0.9% sodium chloride, USP) applied in conjunction with absorbable gelatin sponge, which were performed across a range of surgical settings (spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the incidence of antibody development to RECOTHROM was 1.2% in the RECOTHROM group (n=1/83) compared to 2.4% (n=1/41) in the placebo group. In the open-label, single group Phase 2 study of RECOTHROM applied with the spray applicator to excised burn wounds, 1 patient developed antibodies following treatment (1.6%, n=1/62). The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with results from studies of other products due to differences in assay methodology, patient populations, and other underlying factors. To report SUSPECTED ADVERSE REACTIONS, contact ZymoGenetics, Inc. at 1-888-784-7662, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Drug interactions have not been formally studied. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with RECOTHROM. It is also not known whether RECOTHROM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RECOTHROM should be given to a pregnant woman only if clearly needed. Pediatric Use Of the 72 patients undergoing burn wound excision and grafting treated with RECOTHROM applied with the spray applicator in the open-label, single group, Phase 2 study, 4 were pediatric patients. All were age 12 to 16 years. The safety and effectiveness of RECOTHROM in all pediatric age groups have not been fully established. Geriatric Use Of the total number of patients in Phase 2 and Phase 3 clinical studies of RECOTHROM with absorbable gelatin sponge, 38% were 65 years old and over, while 16% were 75 years old and over. No substantive differences in safety or effectiveness were observed between these patients and younger patients, 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.

staff are “directly involved in compounding and dispensing activities … we need to empower [them] to speak up when things are not done according to standard operating procedures,” said Mr. St. John. According to Eric S. Kastango, MBA, RPh, FASHP, there are particular requirements of <797> that tend to be problem areas for noncompliance. Mr. Kastango is president and CEO of the consulting company Clinical IQ, LLC, in Florham Park, N.J., and was not affiliated with the webinar. Aspects of <797> that often are overlooked in pharmacies include “adherence to proper garbing and hand hygiene, the use of sterile gloves, sterile alcohol, proper disinfection of components and disinfection of injection ports and vial septums.”

Infection Control Requirements Reviewing some specific infection control requirements in <797>, Mr. St. John said, “The goal is to reduce the bioburden in compounding areas.” The chapter outlines specific frequency requirements. For example, there should be daily cleaning/disinfection of ISO Class 5 surfaces and equipment, work surfaces near the ISO Class 5 area, floors and shipping containers. A major aim is to keep the environment free of particulates. “Dust particles can carry microbes, [which] then can eventually end up in the sterile compounding area if there’s a breach in aseptic technique, and, of course, that will eventually lead to contamination,” said Mr. St. John. “We’re trying to reduce downstream contamination risk by minimizing particulates and having the environment as clean as possible.” Primary engineering controls, such as a hood or glovebox, protect the direct compounding area from contamination. “Pharmacists and infection preventionists may appropriately have a partnership in evaluating [these] instruments,” said Mr. St. John. “You have to do a critical evaluation of what’s best for your pharmacy.” Personnel most often are the source of microbial contamination in aseptic processing. Compounding personnel need to wear hairnets, beard covers and face masks, as well as gowns, gloves and shoe covers, said Mr. St. John. “Hand hygiene is paramount for safety in preparing medications,” he added, noting that Chapter <797> includes specific information about how hands should be cleaned, including washing with soap and water up to the elbows and using an alcohol-based surgical hand scrub with persistent antimicrobial activity.

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Environmental Sampling

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RT022-06, January 2011

Pharmacy Practice News • June 2012

Policy 7

USP Chapter <797> If pharmacy wants to improve its <797> compliance…[an observer] should ‘sit in the work area and watch what people are doing; observe people. … Visually audit whether people are following procedures.’ —Eric S. Kastango, MBA, RPh, FASHP

that you tailor this to your specific situation. More important than just filling out checklists is to have a way to analyze the results and provide feedback to staff on compliance.” said Mr. St. John. Mr. Kastango concluded, “You have to make sure people understand [infection control procedures] and that that understanding translates correctly into behaviors in the clean room.” —George Ochoa Mr. Kastango and Mr. St. John reported no relevant financial conflicts of interest.

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sections in the chapter.” The Centers for Disease Control and Prevention (CDC) does not advocate routine microbial environmental culturing (sampling) of inanimate surfaces in the absence of an outbreak, whereas the FDA requires sterile processing operations in manufacturing facilities to perform daily monitoring of viable air, surface and glove fingertip samples. In its current version, <797> moved away from the FDA’s position and toward the CDC’s—but still requires some routine sampling. As far as the anticipated revision goes, Mr. St. John said, “the verdict is still out on this.” Aseptic technique in sterile compounding requires understanding of “first-air,” the air exiting the high-efficiency particulate air (HEPA) filter, which is virtually free of particulate contaminants, said Mr. St. John. All critical manipulations must occur in the first-air zone. A written quality assurance procedure is necessary and important for training and assessing competency, according to Mr. St. John. It is “unacceptable” to have no written procedures, he said. “This is an area where you have to have processes and checks.” Additionally, he said, “There needs to be a primary oversight person [who] looks at the overall process.” If a pharmacy wants to improve its <797> compliance, said Mr. Kastango, those who work there “should understand where they are relative to compliance—do a gap analysis.” Additionally, he said, “They should go to gemba,” using the Japanese term for going to the workplace and seeing what is done. An observer should “sit in the work area and watch what people are doing; observe people. … Visually audit whether people are following procedures.” A consulting company, such as Mr.

Kastango’s, can be of assistance. As a consultant to hospital pharmacies, he said, “I help them design <797>-compliant clean rooms, and help them to develop policies and procedures.” He also does audits when pharmacies want a thirdparty view. Checklists can be useful for monitoring and improving performance. The infection preventionist and the pharmacist can partner to develop checklists. <797> has examples of checklists, but, “it’s very important

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8

Hem/Onc Pharmacy

Pharmacy Practice News • June 2012

In Focus

STRATEGIES continued from page 1

containing 10 or 40 mL, respectively, of a 5-mg/mL sterile solution. Prescribing directions advise that partially used vials should be discarded after 24 hours. The acquisition cost of the drug is $120/mg. “When we looked at this drug before it came out, we thought that if we are going to use exact doses in these patients according to their actual body weight, we are going to have a significant amount of drug waste,” said Anthony Jarkowski III, PharmD, BCOP, clinical pharmacy specialist at Roswell Park, who led the study. “You can bill for drug waste, but currently we don’t do that at our site, so our physicians agreed that dose rounding would be a good idea.” In the study, ipilimumab was dosed at 3 mg/kg according to the package directions, but the exact total milligram dose was rounded to the nearest 50 mg, with 1 to 24 mg rounded down to the nearest 100-mg integer and 25 to 49 mg rounded to nearest 50-mg integer. Waste was defined as the amount of drug that would have been discarded if the actual calculated dose had been used in the treatment regimen instead of the rounded dose. Overall, 22 patients received at least one dose. At the time of the analysis, 20 patients had completed therapy and two were still receiving therapy. Clinicians rounded down in nine patients and up in 12; one patient did not require rounding. Of the 20 patients who completed therapy, 11 received all four doses of therapy and nine received fewer than four doses. The researchers determined that patients received an average of 2.86 doses, and the maximum potential cost savings for the 22 patients was $155,400. “We had one response and one

‘You can bill for drug waste, but curently we don’t do that at our site, so our physicians agreed that dose rounding [of ipilimumab] would be a good idea.’ —Anthony Jarkowski III, PharmD rounding. “A few people came by and said ‘I’m going to take this back to my director at my institution and tell him we should be doing this,’” he said. Other pharmacists noted that their institutions “are billing for drug waste, but that can get a little complicated with the documentation,” he added. Niesha Griffith, MS, RPh, director of pharmacy and infusion services at The Arthur G. James Cancer Hospital, The

‘Although this is not necessarily a new ... strategy, [Dr. Chan] is to be commended for helping her organization identify cost-savings opportunities.’ —Neisha Griffith, MS, RPh patient with stable disease,” said Dr. Jarkowski. He noted that these results were in the range of those seen in the literature, as were the grade 3/4 adverse events, which occurred in approximately 20% of the patients. Dr. Jarkowski noted that some pharmacists who visited his poster at the meeting said they also were rounding doses of ipilimumab at their institution, and others said they intended to change their policy to implement

Ohio State University, in Columbus, is one pharmacist who saw the poster and said her hospital will be adopting the practice. “I think this is a great idea,” she said, noting that dose rounding is an effective cost containment strategy for many oncology drugs. “We don’t use as much ipilimumab here because we only have two physicians who treat melanoma, and only one of them does so full time. Regardless, this is a fantastic idea and we are

going to implement it.” Ms. Griffith pointed out that many institutions have electronic order entry systems that can be programmed to do the rounding. “For now,” she said, “we are going to do it manually, but I am going to ask for a build that includes the rounding parameters.”

Reeling in Rasburicase Costs In another study (abstract 7), researchers from the University of Michigan College of Pharmacy, in Ann Arbor, showed that use of a single, fixed dose of rasburicase resulted in a significant cost savings and normalized uric acid levels within 24 hours in patients who received the drug to prevent or treat tumor lysis syndrome. Rasburicase is approved for the treatment of hyperuricemia at a weightbased dose of 0.2 mg/kg per dose. Because several studies have shown that a single, fixed dose can be effective, the Michigan researchers set out to determine how often patients who receive a single fixed dose require at least one additional dose within five days of the initial dose and to determine the cost savings associated with a single fixed dose. “Most of the literature that we identified used a variety of doses, 1.5 mg all the way up to 7.5 mg,”

said Melinda Tran, PharmD, hematology/oncology specialty pharmacy resident at the University of Michigan Hospitals and Health Centers, who led the study. In 2009, the University of Michigan Hospitals and Health Centers implemented a fixed 6-mg rasburicase dose for adults, based on the literature (Pharmacotherapy 2006;26:806-812). They implemented two fixed doses for children, depending on weight. Children weighing less than 30 kg received 1.5 mg of rasburicase and those weighing more than 30 kg received 3 mg. Patients in the study primarily had leukemia, lymphoma and multiple myeloma. Reviewing the charts of adult patients seen one year before and one year after fixed dosing was implemented and pediatric patients seen 1.5 years before and after implementation, they compared 40 adult patients and eight children in the weight-based group with 74 adults and 11 children in the fixed-dose group. No significant difference was identified between patients who received a weight-based dose and those who received a fixed dose with respect to additional doses required or average number of doses used. The fixed-dose regimen provided an approximate annual cost avoidance of $227,400. As has been found in other studies, the fixed dose was effective at normalizing uric acid levels in adults and children, with one exception. Among the pediatric patients with Burkitt’s lymphoma, those “in the weight-based group didn’t require additional doses and they normalized uric acid in 24 hours” but “three of the four patients in the fixed-dose group required additional dosing within five days and also didn’t seem to normalize uric acid within 24 hours,” noted Dr. Tran. “This is hypothesis generating and perhaps we need to increase the dose.” According to Ms. Griffith, using fixed-dose rasburicase is a good cost containment strategy and her institution has been using a fixed dose of 4.5 mg for several years and has studied this strategy. “Our study and other studies have shown that doses of 4.5 mg and even lower can be effective,” said Ms. Griffith. “I think most institutions have already gone to using a fixed dose. Although this is not necessarily a new cost containment strategy, [Dr. Tran] is to be commended for helping her organization identify cost-savings opportunities.” —Kate O’Rourke

Drs. Tran and Jarkowski reported no relevant financial conflicts of interest. Dr. Griffith serves on the advisory board of Sanofi-aventis.

Hem/Onc Pharmacy 9

Pharmacy Practice News • June 2012

In Focus

YOUTH CANCER continued from page 1

of the Hematology/Oncology Pharmacy Association. According to the American Cancer Society, 70,000 AYAs are diagnosed with invasive cancer each year in the United States. (For a breakdown of cancer types, see Table 1.) Some of those malignancies are associated with a poorer prognosis due to either more aggressive or unique biology features, including breast cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin’s lymphoma and acute leukemia, according to Leonard Sender, MD, founder of the Society for Adolescent and Young Adult Oncology (SAYAO), and director of the combined adolescent and young adult cancer program at Children’s Hospital of Orange County and University of California, Irvine. Dr. Sender added that AYAs often do better on more rigorous pediatric protocols than adult protocols, but many doctors are not aware of this. A 2007 study on AYA cancer trends offers some sobering statistics on just how wide the survival gap has become in this vulnerable patient population. Fourteen cancer types in AYA patients have five-year survival rates that are significantly lower than rates in younger patients, the authors reported (CA Cancer J Clin 57;242-255). Of those, six cancer types have survival rates that are worse than those in both younger and older patients. Moreover, “cancer kills more 20- to 30-year-olds than any other disease except depression-induced suicide,” the authors noted. “Yet cancer in young adults has been under-recognized and frequently not considered” by clinicians who often come into contact with these patients—“including oncologists.”

Major Culprit: Clinical Trials Access According to Dr. Parsons, the factor most responsible for this lack of progress in AYA oncology is inadequate access to clinical trials. “During the period of 1997 and 2003, approximately 70% of children with cancer were enrolled in an NCI [National Cancer Institute]-sponsored clinical trial,” she said. Unfortunately, “this level of clinical trial participation drops dramatically as you span into the AYA age range and falls to less than 2% [for patients] between 20 and 39 years of age.” The new NCCN AYA guidelines strongly advise that this group of patients be placed in clinical trials and referred to cancer centers with experience in this patient population. Dr. Parsons said that a 20-year-old Marine with osteosarcoma was recently referred to her hospital because it has been gaining a reputation as a center with AYA expertise. Her hospital was able to

Table 1. Most Common Cancers in AYAs In the United States

Cancer Type

Incidence Per 100,000 Patients Aged 15-39 Years

Females Breast cancer

20.4

Thyroid cancer

14.6

Melanoma

9.5

Cervix and uterine cancer

9.1

Hodgkin’s lymphoma

3.7

Colorectal cancer

3.4

Males Gonadal germ cell tumors

10.1

Melanoma

5.5

Non Hodgkin’s lymphoma

4.7

Colorectal cancer

3.6

Thyroid cancer

2.9

Source: SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008, based on November 2010 SEER

‘The AYAs represent a unique enough cancer diagnosis that argues for the emergence of AYA oncology as a specialty practice in medicine.’

place him in a clinical trial. “We don’t need a fancy facility to care for these patients,” she said. “In my practice at the University of Alabama, we don’t necessarily have a formal program, although we are moving that way, but over the past few years, we have had a lot more phone calls and discussions between our physicians and our pharmacy colleagues about managing AYA patients.” In partic-

—Kerry Parsons, PharmD ular, Dr. Parsons pointed out that strides are being made in getting AYAs into clinical trials for sarcoma. The percentage of AYA patients enrolled in NCI clinical trials for sarcoma was 5% during 1998 and 1999 and 19% during 2004 and 2005, she said.

Table 2. Highlights From the NCCN Adolescent And Young Adult Oncology Guidelines AYA patients usually are more tolerant of intensive therapies than older patients. Monitoring of cumulative dosing for certain medications (anthracylines, epipodophyllotoxins, cisplatin, ifosfamide) associated with irreversible organ damage may be essential when certain lifetime exposure is encountered. Fertility preservation should be an essential part in the management of AYAs with cancer. AYA patients with cognitive dysfunction or other psychiatric symptoms (e.g., depression or anxiety) should be referred to a mental health provider and community-based resources serving AYA patients. All AYAs should have a survivorship care plan. AYAs with cancer need long-term follow-up care for monitoring and treatment of late effects long after completion of treatment. This can include screening for pulmonary, thyroid, cardiovascular and audiologic issues; breast, colorectal, and bladder cancer; acute myeloid leukemia; myelodysplasia; and kidney disease. Source: www.nccn.org

In addition to inadequate research opportunities, poor access to health care, delayed diagnosis and treatment and poor adherence to treatment regimens also play a role in the survival rates of AYAs not improving over the years. Dr. Parsons noted that a 2010 Gallup poll identified AYAs as the most underinsured age group.

Signs of Progress All is not dire, however, in the field of AYA cancer. Since 2006, the NCI has collaborated with the Lance Armstrong Foundation and published a series of reports on AYAs with cancer to bolster awareness. In 2010, Dr. Sender helped found the SAYAO. In 2011, the quarterly Journal of Adolescent and Young Adult Oncology was launched. The latest big development in this growing field was the release in March of the NCCN’s AYA oncology guidelines (Table 2). The guidelines aim to help improve the diagnosis, treatment and survivorship care of AYAs. (The NCCN Guidelines for AYA Oncology and other NCCN guidelines are available free of charge at NCCN.org.) According to Dr. Parsons, pharmacists can do their part by paying particular

•

see YOUTH CANCER, page 10

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Hem/Onc Pharmacy

Pharmacy Practice News • June 2012

In Focus

YOUTH CANCER continued from page 9

attention to toxicity and dosing considerations in this population because of different pharmacokinetics. The oral clearance of dexamethasone and methotrexate, for example, is twofold greater for young children compared with adolescents, and there is an inverse relationship in AYAs between age and clearance of etoposide and busulfan. Pharmacists should be aware that when using dactinomycin, the area under the curve is

‘You need to know that the term young adult needs to be put into a [Pubmed] search when you have a leukemia or a sarcoma.’ lower in adolescents than in young children, she said. Through acute lymphoblastic leukemia (ALL) clinical trials run by the Children’s Oncology Group, researchers have found that patients between the ages of 16 and 30 years experience higher rates of certain toxicities com-

—Leonard Sender, MD pared with children aged 1 to 15; these include hyperglycemia (22% vs. 15.4%), hyperbilirubinemia (6.7% vs. 3.7%), oral mucositis during interim maintenance therapy (18.5% vs. 11.3%) and peripheral neuropathy (11.5% vs. 7.4%) (Blood, ASH Annual Meeting abstracts, 2011 118: Abstract 1510). Osteonecrosis is far

more prevalent in ALL patients 10 years or older than in patients younger than age 10 (19.6% vs. 3.1%) (J Clin Oncol 29:2011: Abstract 9504).

Survivorship Issues Need To Be Heeded AYAs have specific survivorship issues that need attention, including financial pressures, psychosocial issues and medical concerns such as fertility. According to Dr. Sender, psychological distress is significantly greater in AYAs compared with younger children and older patients with cancer. Thus, health care workers need to focus on managing the psychosocial issues of this particular group of patients. The NCCN AYA guidelines echo the need for specific attention to psychosocial issues. Dr. Parsons stressed that there still is a need to increase the overall awareness among the medical community as well as the lay community about the specific needs of AYA patients. “The AYAs represent a unique enough cancer diagnosis that argues for the emergence of AYA oncology as a specialty practice in medicine,” she said. Dr. Sender agrees and said practitioners can dive into the subject matter using online resources. “With Google and PubMed, you can bring yourself up to speed pretty quickly, if you know [how] to look for it. You need to know that the term young adult needs to be put into a search when you have a leukemia or a sarcoma,” he said. Expressing hope that the growing awareness of AYA oncology will spur health care providers to specialize in the niche, he added, “There is a really rewarding career in doing young adult medicine.” —Kate O’Rourke

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Hem/Onc Pharmacy 11

Pharmacy Practice News • June 2012

In Focus

Undisclosed Supplement Use Poses Threat to Cancer Patients Orlando, Fla.—Almost one-third of cancer patients taking supplements did not have them listed on their medication history or had only a partial list of what they were taking, according to a study presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA; poster T05). “It is very important that we specifically ask patients whether they are taking supplements,” said Christan Thomas, PharmD, who led the study when she was a pharmacy student at Gatton College of Pharmacy, East Tennessee State University, in Johnson City. “Consumers need to disclose supplement use to their pharmacists so they can manage those interactions and side effects.” In 2011, researchers at the Regional Cancer Center in Johnson City interviewed 99 cancer patients who had been seen at the center and explicitly asked them about supplement use. They then compared these results with the drug information in the patient charts. The researchers found that 27% of patients taking supplements either had no supplements listed on their medication histories or had only a partial list. The most commonly reported supplements were a multivitamin (54%), vitamin B12 (22%), potassium (22%), fish oil (20%), iron (17%), calcium plus vitamin D (17%), vitamin D alone (14%) and calcium alone (8%). Other supplements included red yeast rice and vitamin E. No potential chemotherapy–supplement interactions were specifically identified in the study population, but several supplements reportedly taken by patients have been shown to have adverse effects in cancer patients, the researchers noted. If taken in high doses, fish oil, for example, can reduce platelet aggregation and increase risk for bleeding. Calcium and iron can cause constipation, which is often already a problem with cancer patients on opioids. Red yeast rice and vitamin E can increase liver enzymes and cause fatigue and weakness. Dr. Thomas believes that although a reminder to ask about supplements was at the top of the patient history form, nurses or other health care professionals just forgot to ask and patients didn’t connect the dots. “I think a lot of patients don’t consider supplements to be drugs because they are natural and you can get them over the counter,” said Dr. Thomas.

A More Holistic Approach Cathy Rosenbaum, PharmD, MBA, RPh, clinical effectiveness and safety officer at Bethesda North Hospital, in Cincinnati, said that disclosure of supplement use to health care professionals is not the only problem: Overuse of supplements, without the advice and

consent of a physician, also is a concern. A better approach to achieving holistic health, she noted, would be to adopt an optimal nutrition plan that embraces the use of locally grown, organic whole foods—“as much as one can afford,” noted Dr. Rosenbaum, who also is the founder and CEO of Rx Integrative Solutions, a private consulting practice in holistic medicine located in Cincinnati. “For cancer patients trying to use

vitamins, minerals and protein supplements who are having difficulty eating due to side effects from chemotherapy, nutrition in the form of a smoothie might be a more appropriate solution,” she added. According to the National Center for Health Statistics, more than half of all Americans use some kind of vitamin or supplement (NCHS Data Brief 2011;61:18). A recent study of cancer patients

in the Veterans Administration medical system found that 25% of patients who were using supplements did not tell their physicians about them (J Altern Complement Med 2004;10:560-564). —Kate O’Rourke

Drs. Thomas and Rosenbaum reported no relevant financial conflicts of interest.

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Pharmacy Practice News • June 2012

In Focus

Doublet Regimen Tested for Salvage Therapy in NSCLC Orlando, Fla.—A doublet regimen of mitomycin C and irinotecan can provoke roughly a 20% response rate when it is used as salvage therapy in patients with advanced non-small cell lung cancer (NSCLC), according to a study from Texas researchers. “I think it’s a reasonable regimen to use in patients seeking aggressive therapy,” said Shreya A. Shah, PharmD, oncology pharmacy resident at the University of Texas MD Anderson Cancer Center, Houston, who presented the retrospective study at the annual meeting of the Hematology/Oncology Pharmacy Association (poster T13). She pointed out, however, that patients should be closely monitored for toxicities. No evidence-based recommendations exist for patients with advanced NSCLC who have progressed after third-line regimens. Studies examining the combination of mitomycin C and irinotecan in the salvage setting of NSCLC are scarce but indicate that the regimen may have activity (Oncologist 2006;11:655-665). To examine the regimen in their patient

population, Dr. Shah and her colleagues conducted a retrospective chart review of all patients with advanced NSCLC who had received at least one cycle of mitomycin C and irinotecan as salvage therapy at MD Anderson between January 2005 and October 2011. In the 31 patients identified, the median performance status was 1 and the median number of regimens previously used was three (range, one to six). All patients had received a prior platinum-based doublet. Patients received a median of one doublet therapy cycle, at a median dose of 7 mg/m2 of mitomycin C and 140 mg/m2 of irinotecan, with 17 patients receiving one cycle, 10 patients receiving two cycles and seven patients receiving three to five cycles. Overall, 23% of patients responded to therapy. The median time-to-treatment failure was 2.4 weeks; median survival time was 23.7 weeks; and overall survival at six months was 45%. Grade 3/4 toxicities included neutropenia (19%), thrombocytopenia (16%) and anemia (7%). “About 50% of patients had stable disease or improvement, but about half of

the patients [47%] discontinued therapy,” said Dr. Shah. She noted that although the response rate (including stability of disease) and the toxicity rate seen in the study was similar to that seen with other regimens used in the second- and thirdline setting with advanced NSCLC, the discontinuation rate was higher. Other regimens have been associated with discontinuation rates between 5% and 11% due to medication-related toxicity, but their study captured drug discontinuations from any cause, she said. “It’s aggressive in the salvage setting to use a doublet in non-small cell lung cancer,” Dr. Shah said. “Usually after thirdline therapy, options include monotherapy, clinical trial or best supportive care. It seems like patients respond to this doublet regimen but may face additional toxicity compared with monotherapy.” Cindy O’Bryant, PharmD, BCOP, an associate professor in the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora, said the doublet regimen was

not something she would routinely use in this patient population but that she would consider it for patients with good performance status who wanted more intensive treatment. She pointed out, however, that the “number and severity of toxicities leading to discontinuation make it very unlikely that patients who even get a benefit will be able to stay on therapy. Finding the type of patient who is able to tolerate [it] is difficult, as most, by this time, have poor performance status.” Single-agent therapy is a more realistic and tolerable treatment option and would possibly improve a patient’s quality of life, Dr. O’Bryant added. “With the current improvements in identifying treatments based on molecular subtypes, which this study does not note, there may be better more personalized treatment options for patients.” —Kate O’Rourke Drs. Shah and O’Bryant reported no relevant financial conflicts of interest.

Extended Docetaxel Infusion Reduces Adverse Reactions Orlando, Fla.—Using a slow-accelerated, extended infusion of docetaxel is feasible and significantly reduces infusion reactions, according to a study conducted at the University of Texas MD Anderson Cancer Center, in Houston. Although the strategy required a bigger investment in time and effort from nurses, it reduced the rate of reactions to less than 1%. Prior to the study, when infusions were given over a flat onehour time period, the docetaxel infusion reaction rate at MD Anderson was 3%. “We were tired of the infusion reactions we were having. The doctors were tired of being called in, and patients, of course, don’t want the reactions either,” said Thomas Rogers, PharmD, presenting the results at the annual meeting of the Hematology/Oncology Pharmacy Association (poster PP23). The study, conducted between February and October 2011, included all docetaxel-naive outpatients and those who had reacted in the past. It excluded outpatients who had not had reactions and inpatients. Forty percent of the patients had breast cancer, 25% had lung cancer, 15% had head and neck cancer and 20% had other types of cancers. After an initial rate of 300 mL per hour for 15 mL to clear the line, patients received a slow-accelerated and extended administration of docetaxel, explained Dr. Rogers, pharmacy clinical coordinator at MD Anderson. A

Table 1. Titration Schedule I (February 2011-August 25, 2011) Change

Rate, mL/h

Time, min

Clear line

300

1

10

2

Table 2. Titration Schedule II (August 26, 2011- October 2011)

Volume, mL

Change

Rate, mL/h

Time, min

3

15

5

0.8

20

5

3

40

4

Clear line

300

3

15

1

40

5

3.3

1.7

2

80

5

6.7

5

3.3

3

120

10

20

80

5

6.7

4

200

Remaining

5

120

10

20

Until complete

6

200

Until complete

Remaining

standard 20-mg dose of dexamethasone was given to all patients. During the first half of the study, the investigators started off on a very slow infusion (schedule I; Table 1). When that was successful, they increased the rate slightly (schedule II; Table 2). A 295mL bag took roughly 114 minutes to infuse in titration during schedule I and 98 minutes in titration schedule II. Overall, 524 infusions were given to 69 patients and only one reaction occurred (0.19%). This constituted a reduction of 94% in infusion reactions over the onehour standard infusion. Dr. Rogers said that MD Anderson now books two hours of chair time for patients receiving docetaxel infusions and the institution is in the process

of formally making the slow infusion using titration schedule II its standard of care. Dr. Rogers said other institutions should consider adopting the practice, but he warned that some nurses might push back. “Nurses have to go back three or four times to adjust the pump rate,” he said. “People have been complaining about the extra time it takes to do this.” Sara Kim, PharmD, oncology pharmacy clinical coordinator at the Mount Sinai Medical Center, in New York City, noted that the study did show the value of the slowed infusion but was limited in not providing baseline patient characteristics, including median age, as well as details on the malignancies. Dr. Kim noted that Mount Sinai also was using a slow-titration approach for

Volume, mL

docetaxel therapy. “We infuse taxanes, paclitaxel and docetaxel—at 25 mL per hour initially—and titrate upward based on tolerability. Docetaxel is typically diluted in a 250-mL NS bag,” she said. “A few years ago, we had a cluster of docetaxel-associated infusion-related reactions—rash, acute and severe back pain during infusion—at our center, particularly in breast cancer patients. Since that time, we routinely premedicate patients with diphenhy­ dramine and an H2 antagonist, in addition to a steroid, prior to docetaxel administration, and the rate of infusion-related reactions appears to have been reduced with this strategy.” —Kate O’Rourke Drs. Rogers and Kim reported no relevant financial conflicts of interest.

Pharmacy Practice News • June 2012

Clinical 13

Infectious Disease Table. Nephrotoxicity Rates

NEPHROTOXICITY continued from page 1

were admitted to Sanford and received vancomycin and/or piperacillin-tazobactam during two 90-day periods. In one period, piperacillin-tazobactam was given in a conventional infusion of 30 minutes and in the other it was provided as an extended infusion over four hours. Roughly 300 patients received vancomycin alone and the other four study groups included approximately 100 patients each. Acute kidney injury was defined as 50% or greater increase in baseline serum creatinine or an increase from baseline serum creatinine of at least 0.5 mg/dL. Overall, rates of acute kidney injury were lower among those treated with vancomycin alone (4.9%) than in all other study groups: piperacillin-tazobactam conventional infusion (13.5%), piperacillin-tazobactam extended infusion (8.4%), combination vancomycin and conventional piperacillin-tazobactam (20.2%) and combination vancomycin and extended piperacillin-tazobactam (16.8%). A statistically significant difference was found when comparing acute kidney injury in the vancomycin-alone group to that in the groups receiving piperacillin-tazobactam alone in either infusion as well as to that in either combination therapy group (Table). The incidence of acute kidney injury was less with the extended fourhour infusion compared with the conventional infusion, but the difference was not statistically significant.

mon in patients receiving vancomycin/piperacillintazobactam than in patients Vancomycin alone 4.9% receiving vancomycin alone Piperacillin-tazobactam 11.1%; P=0.0241 vs (49.3% vs. 8.9%; P<0.001). alone (either infusion) vancomycin alone Patients who developed acute kidney injury had Combination therapy 18.6%; P<0.001 vs vancomycin alone higher median vancomycin levels compared with patients without acute kidnephrotoxic antibiotics compared with ney injury (19.9 vs. 13.9 mg/L; P=0.015). the vancomycin/piperacillin-tazobactam Dr. Min said that it is not clear group (P=0.02). “whether it is the combination that Acute kidney injury was more com- is causing the nephrotoxicity that we Regimen

Incidence of Acute Kidney Injury

observed or we are just seeing the nephrotoxicity from Zosyn,” but the rates are higher than what is reported in the Zosyn package insert. She said anecdotal information had led pharmacists to think that the combination of vancomycin and piperacillintazobactam might be fairly nephrotoxic, but the study provides confirmation. —Kate O’Rourke Drs. Hellwig and Min reported no relevant financial conflicts of interest.

In SICU, Similar Findings A second retrospective study of surgical intensive care unit patients admitted to the University of California, San Diego (UCSD) Medical Center between January and December 2008 showed a similar finding (abstract 714). Presenting the study at the SCCM meeting, Emily Min, PharmD, a postgraduate year 2 critical care pharmacy resident at the medical center, said that patients who received therapy with vancomycin and piperacillin-tazobactam, vancomycin alone, or piperacillin-tazobactam alone were eligible for the study. Acute kidney injury was defined as an increase in serum creatinine of at least 0.3 mg/dL or a 1.5-fold increase in serum creatinine from baseline at any time during antibiotic therapy. Patients receiving antibiotic therapy for less than 48 hours and those on renal replacement therapy at baseline were excluded. The group receiving piperacillin-tazobactam alone was not included in the final study analysis because of the small sample size (n=10). Baseline characteristics in the vancomycin/piperacillin-tazobactam group (n=73) and the vancomycin monotherapy group (n=67) were well balanced. A greater proportion of patients in the vancomycin group received other

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14 Clinical

Pharmacy Practice News • June 2012

Critical Care In acute respiratory distress syndrome…

Meta-analysis Supports Early Use of Neuromuscular Blockers Houston—Administration of neuromuscular blockers (NMBs) decreases mortality among ICU patients with acute respiratory distress syndrome (ARDS), according to a recent meta-analysis of three studies presented at the recent annual meeting of the Society of Critical Care Medicine (SCCM; abstract 686). “I think with this meta-analysis, we can feel a bit more comfortable saying that there is probably a mortality improvement if you use neuromuscular agents in severe ARDS in the first 48 hours, but we still need a larger sample size to be able to say that with full force,” said Pablo Moreno Franco, MD, a critical care fellow at Mayo Clinic in Rochester, Minn., who presented the study at the SCCM meeting. Over the past decade, most ICUs have moved away from the early, routine administration of continuous infusions of NMBs in ARDS patients because of their association with prolonged muscle weakness and the lack of a large rigorous study demonstrating benefit. In 2010, however, evidence began to emerge supporting early use of NMBs. Evidence from the ACURASYS (ARDS et Curarisation Systematique) trial in France by Papazian et al showed that 90-day mortality in patients with ARDS was almost 10% lower in patients receiving cisatracurium besylate (Nimbex, Abbott) than in patients receiving placebo (31.6% vs. 40.7%; P=0.08), but the difference in ICU mortality did not reach statistical significance (N Engl J Med 2010;363:1107-1116). The beneficial effect of cistracurium was limited to the two-thirds of patients presenting with the severest form of ARDS, based on arterial blood oxygen values. Based on these findings, the French researchers recommended using NMBs for patients with severe hypoxemia, in the first day or two of disease and for a short duration (<48 hours). For their meta-analysis, researchers at Mayo Clinic searched several medical databases from their inception to 2011 and identified 873 studies discussing NMBs and ARDS. They then sorted the studies to identify trials that reported mortality among ARDS patients aged 18 years and older who were admitted to the ICU and randomized to either receive or not to receive NMBs. Only three studies met the criteria, one of which was the 2010 NEJM study. The other two were much smaller studies also conducted by the same French group (Crit Care Med 2006;34:27492757; Crit Care Med 2004;32:113-119). Of the 431 patients in the three studies, 223 (51.7%) received NMBs. The investigators identified a statistically

significant decrease in ICU mortality in the NMB group (31.4% vs. 44.7%; odds ratio, 0.56; 95% confidence interval, 0.38-0.84). Using a chi-square test for heterogeneity, they found no significant heterogeneity among the studies. The authors concluded that clinicians can be more liberal with early use of NMBs in patients with severe ARDS.

John Devlin, PharmD, FCCM, an associate professor in the Department of Pharmacy Practice at Northeastern University, and a scientist in the Division of Pulmonary, Critical Care and Sleep Medicine at Tufts Medical Center, in Boston, said that when conducting a meta-analysis, “one has to be careful, from a methodological perspective, of combining the

results of additional small, potentially heterogeneous studies (not designed to look at an outcome such as ICU mortality), to one large randomized control trial in an effort to provide additional power needed to shift the 95% confidence interval for the outcome of interest in the larger study to significance.” In addition to noting that ventila-

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

Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2011 American Regent, Inc. VEN040 • Rev. 12/2011 • venofer.com

Pharmacy Practice News • June 2012

Clinical 15

Critical Care tion and sedation practices may have been different between the 2010 and the 2004/2006 studies, Dr. Devlin also pointed out that the 2010 NEJM study had methodologic factors that may have potentially weakened the conclusions that were made. Given that nonparalyzed patients can trigger the ventilator and paralyzed patients cannot, treatment allocation may not have been truly blinded among clinicians, Dr. Devlin said. The NEJM study also failed to formalize either the identification or management of ventilator dyssynchrony and relied on

a clinical evaluation (which might not be possible in a patient in the ICU or a patient who is delirious) rather than standard electromyographic procedures. At a session on refractory hypoxemia at the recent SCCM meeting, attendees were asked how often they used NMBs and there appeared to be a wide range of usage patterns.

For example, Dr. Devlin said, “At Tufts Medical Center, the publication of the 2010 NEJM study has not influenced clinical practice in our ICUs. Although neuromuscular blockers are certainly administered on an ‘as-needed’ basis for short periods among patients with severe ARDS who are difficult to ventilate, we do not routinely start a continuous neuromuscular blocker early in their care.” For his part, Dr. Franco said that he

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

Please see brief Prescribing Information on adjacent page.

and his colleagues “do not believe our meta-analysis should be used to propose a practice change but to review available evidence and contrast the study designs, and to then raise new research questions.” He noted that “peer review studies coming out of the pipeline with bigger sample sizes are necessary” to provide more solid conclusions about the role of early use of NMBs. —Kate O’Rourke Drs. Franco and Devlin reported no relevant financial conflicts of interest.

16 Clinical

Pharmacy Practice News • June 2012

Critical care

Steroids for Sepsis Topped List of Controversies at SCCM Session Houston—If there was a treatment that was inexpensive, relatively safe, doubles the rate of extubations in patients with acute respiratory distress syndrome (ARDS) and does not increase mortality, how many doctors would use it? Gianfranco Umberto Meduri, MD, professor of medicine at the Memphis VA Medical Center in Memphis, Tenn., posed this question to the audience at the recent Society of Critical Care Medi-

cine (SCCM) annual meeting. He was referring to using corticosteroids in septic shock and ARDS, and many in the audience raised their hands. Speaking at a session on ongoing sepsis controversies, Dr. Meduri said the evidence is strong that corticosteroids improve several patient-centered outcomes in patients with septic shock. However, the evidence is mixed regarding mortality reduction. The biolog-

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Venofer safely and effectively. See full prescribing information for Venofer. Initial U.S. Approval: 2000 RECENT MAJOR CHANGES Warnings and Precautions 6/2011 INDICATIONS AND USAGE Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). DOSAGE AND ADMINISTRATION Administer Venofer intravenously either by slow injection or by infusion. CKD patients on hemodialysis: 100 mg undiluted slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl, over a period of at least 15 minutes. CKD patients not on dialysis: 200 mg undiluted slow IV injection over 2 to 5 minutes. • CKD patients receiving peritoneal dialysis: infuse 300 mg over 1.5 hours given on two occasions 14 days apart followed by a single infusion 14 days later of 400 mg given over 2.5 hours. Dilute each Venofer dose in a maximum volume of 250 mL of 0.9% NaCl. DOSAGE FORMS AND STRENGTHS • 10 mL single use vial / 200 mg elemental iron (20 mg/mL) • 5 mL single use vial / 100 mg elemental iron (20 mg/mL) • 2.5 mL single use vial / 50 mg elemental iron (20 mg/mL) CONTRAINDICATIONS • Known hypersensitivity to Venofer WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Hypotension:Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer. • Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload. ADVERSE REACTIONS • The most common adverse reactions (≥ 2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness,hypotension,pruritus,pain in extremity,arthralgia,back pain,muscle cramp,injection site reactions,chest pain,and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION 2 DOSAGE AND ADMINISTRATION Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs. 2.1 Adult Patients with CKD on dialysis Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session.Venofer should be administered early during the dialysis session. 2.2 Adult Patients CKD not on dialysis Administer Venofer 200 mg undiluted as a slow IV injection undiluted over 2 to 5 minutes on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on day 1 and day 14. 2.3 Adult Patients with CKD receiving peritoneal dialysis Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion. 5.2 Hypotension Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension following administration of Venofer may be related to the rate of administration and/or total dose administered. 5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing. 6 ADVERSE REACTIONS Venofer injection may cause serious hypersensitivity reactions and hypotension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. 6.1 Adverse Reactions in Clinical Studies The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse events reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks. Table 1. Treatment-Emergent Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator Adverse Reactions (Preferred Term) Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

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

78.8

76.3

73.4

72.0

65.2

0

2.2

0.7

0

0

0.4

0

0

2.7

0

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

ic rationale for the treatment is solid: Systemic inflammation is the hallmark of sepsis and corticosteroids modulate the immune response to sepsis through genomic and non-genomic effects. In almost half of patients with septic shock, cytokines suppress cortisol production or access to tissues, inducing corticosteroid insufficiency. Research has shown that unfavorable outcomes in sepsis and ARDS are related

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

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

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

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

0

0

0

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

0

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

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

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

IN2340BS, Rev. 6/2011

to the degree of inflammatory response at the onset and during the course of the disease (Chest 1995;107:1062-1073). Furthermore, findings from large data­ sets indicate that systemic inflammation extends beyond clinical resolution of acute illness and has a significant negative affect on long-term outcome (Am J Respir Crit Care Med 2008;177:12421247). For this reason, Dr. Meduri said, corticosteroid treatment should be directed at achieving biological and not clinical resolution and followed by slow tapering (six to nine days) to avoid rebound inflammation. Among the evidence Dr. Meduri presented supporting the use of steroids in ARDS patients, was a 2009 review concluding that prolonged low- to moderate-dose glucocorticoid therapy promotes the down-regulation of inflammatory cytokine transcription at the cellular level (Chest 2009;136:16311643). This review incorporated eight controlled studies (five randomized) in patients with ARDS (most sepsisinduced) that all reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, mechanical ventilation-free days (weighted mean difference, 6.58 days; 95% confidence interval [CI], 2.93-10.23; P<0.001) and intensive care unit (ICU)-free days (weighted mean difference, 7.02 days; 95% CI, 3.20-10.85; P<0.001). This is a sizable response not observed with any other investigated intervention in ARDS, said Dr. Meduri. In the aggregate (n=628), the eight studies found a substantial reduction in mortality for all patients (relative risk [RR], 0.75; 95% CI, 0.63-0.89; P<0.001) and for those treated before day 14 (RR, 0.71; 95% CI, 0.590.85; P<0.001). The most recent data comes from a study in early ARDS patients that found that administration of methylprednisolone was associated with improvement in important biomarkers of inflammation and coagulation and clinical outcomes compared with placebo (Crit Care Med 2012;40:495-501).

In Septic Shock, Mortality Data Mixed Turning to septic shock, Dr. Meduri pointed out that a meta-analysis of 12 trials investigating prolonged lowdose corticosteroids reported a significant reduction in 28-day mortality (37.5% vs. 44%; P=0.02), organ dysfunction and duration of ICU stay (JAMA 2009;301:2362-2375). The CORTICUS (Corticosteroid Therapy of Septic Shock) study, however, showed no mortality benefit, despite a reduction in the duration of vasopressor use (N Engl J Med

Pharmacy Practice News • June 2012

Clinical 17

Cardiology

Center Cuts Ventilation Time for CABG Patients Protocol improves outcomes, and likely bottom line

P

rolonged ventilation is linked to pneumonia and other serious complications, but is early extubation safe in the intensive care setting? One institution’s experience with a fast-tracking protocol for patients on mechanical ventilation after coronary artery bypass graft (CABG) surgery suggests that departments can significantly reduce ventilation times without sacrificing outcomes. Ravi S. Tripathi, MD, an assistant professor of critical care medicine at Ohio State University Medical Center, in Columbus, said he and his colleagues decided to start the protocol when they noticed the median time on mechanical ventilation for the 68 CABG patients in the first quarter of 2010 was 12.8 hours—far above the national average of 7.9 hours. After initiating the protocol, Ohio State’s figure for the 58 CABGs performed in the first quarter of 2011 fell to 7.2 hours. The incidence of prolonged ventilation—the patient’s breathing tube still in place 24 hours after arrival to the intensive care unit (ICU)—also declined, from 27.8% to 8.6%.

Roadblocks to Early Extubation “The biggest hurdle was getting everyone on the same page and showing them it was possible to extubate earlier,” Dr. Tripathi said. “They thought we needed to let patients rest. But we

2008;358:111-124). This large randomized Phase III study carried weight because it studied 500—mostly surgical—patients comparing hydrocortisone or placebo every six hours for five days followed by a six-day taper. In a 2010 review, several sepsis experts concluded that despite the disappointment of the CORTICUS trial, the evidence suggests a modest to high probability (80%-98%) of efficacy for low-dose steroids with respect to both mortality and shock reversal (Crit Care 2010;14: R134). A new analysis of the CORTICUS dataset found reductions in organ dysfunction scores for hydrocortisone-treated patients from day 0 to day 7 compared with placebotreated patients (P=0.0027) (Intensive Care Med 2011;37:1765-1772). This was driven by reductions in cardiovascular organ dysfunction/failure (P=0.0005) and liver failure (P<0.0001) in the hydrocortisone-treated patients. At the SCCM meeting, researchers from the University of Manitoba presented a retrospective, multicenter propensity-matched cohort study, in which

presented them data showing it’s better for patients if we keep things moving.” Along with unstandardized extubation practices, the other roadblock to decreasing ventilation time was use of non–goal-directed sedation and analgesia. “Before the study, we provided five different medications postoperatively, and the doctors and nurses could pick and choose which to use,” Dr. Tripathi said. “Unfortunately, some were using all of the medications.” Now the medical staff chooses from IV hydromorphone and hydrocodone tablets, while the blood pressure medications available are sodium nitroprusside and hydralazine.

ICU Pharmacist’s Take Simon Lam, PharmD, a medical ICU clinical specialist at The Cleveland Clinic in Ohio, agreed that “one of the biggest roadblocks” to early extubation is the use of non–goal-directed sedation and analgesia. “Despite large randomized trials demonstrating the benefits of a sedation protocol, survey results demonstrate that its [rate of ] use in the United States and Canada is 64% and 29%, respectively,” he noted. “Furthermore, among centers with a sedation protocol, routine evaluations should be undertaken to determine the adherence rates to the protocols.” When a similar evaluation was performed at his institution, Dr. Lam noted,

the adherence rate to the daily awakening portion of the sedation protocol was only 41%. “Each medical institution should be vigilant in maintaining the understanding and implementation of its sedation protocol among the clinical staff,” he said.

Other Approaches for Reducing Time on Ventilation Several strategies can be used to further decrease ventilation time. “Some centers extubate cardiac surgery patients in the operating room prior to going to the ICU,” said Elizabeth A. Martinez, MD, an associate professor of anesthesia, critical care and pain medicine at Massachusetts General Hospital, in Boston. “However, this practice requires a robust system that is prepared to manage patients both intraoperatively and postoperatively in a manner that makes it safe to extubate them in the OR.” Jeanine Wiener-Kronish, MD, anesthetist-in-chief at Mass General, agreed. “Not every patient can be fast-tracked,” she said. The elderly, smokers, patients with lung disease or complications from surgery may not be good candidates for early extubation. Regardless of which strategy for early extubation is used, the payoff is generally very positive. In the Ohio State study, re-intubation of patients decreased from 11.8% to 3.4%, and the incidence of postoperative pneumonia decreased from 5.9% to

‘We have known for a long time that when you give steroids to someone in shock, they resolve their shock more quickly.’ —Judith Jacobi, PharmD half of the 3,676 patients were treated with low-dose corticosteroid therapy within 48 hours of documented septic shock and half were not (abstract 389). The investigators did not identify any significant differences in 30-day mortality among the three lowest APACHE II quartiles. In the highest quartile, the use of low-dose corticosteroids was associated with a significantly lower 30-day mortality (50% vs. 55.8%; HR, 0.81; 95% CI 0.68-0.97). According to Dr. Meduri, there is strong evidence that prolonged glucocorticoid therapy down-regulates systemic inflammation and is consistently associated with large and significant improvements in patient-centered

outcomes. Moderate to strong evidence exists that the use of prolonged glucocorticoids is not associated with increased risk for nosocomial infections and is associated with a reduction in post-traumatic stress disorder. There is weak evidence, he said, that prolonged use of glucocorticoid therapy is associated with decreased mortality. “The risk–benefit ratio supports the use of prolonged treatment [with steroids] with slow tapering in unresponsive pressor-dependent shock, early severe ARDS and unresolving ARDS,” Dr. Meduri said, noting large and significant reductions in vasopressor duration, multisystem organ failure and dura-

‘One of the biggest roadblocks’ to early extubation is the use of non-goal directed sedation and analgesia. —Simon Lam, PharmD 1.7% with the lower ventilation rates. “Early extubation speeds up the recovery process,” Dr. Tripathi explained. “Having a breathing tube in place takes away the patients’ ability to cough and clear throat secretions. That’s why the pneumonia rates decreased with early extubation.” The next step is to conduct a cost analysis, Dr. Tripathi said. “Less ventilation time probably saves money because of the lower pneumonia and e-intubation rates, along with shorter hospital stays.” —Dana Hawkins-Simons Drs. Lam, Tripathi, and Wiener-Kronish reported no relevant financial conflicts of interest.

tion of ICU stay. “The risk of treatment is limited to hyperglycemia that is decreased with infusion and neuromuscular weakness that is decreased by avoiding neuromuscular paralysis.” Judith Jacobi, PharmD, a critical care pharmacist at Indiana University Health Methodist Hospital, in Indianapolis, who attended Dr. Meduri’s presentation at SCCM, said she uses corticosteroids in her patients in septic shock. “We have known for a long time that when you give steroids to someone in shock, they resolve their shock more quickly. The CORTICUS trial concluded there is no impact of steroid replacement on mortality [in septic shock patients],” she said. “I suspect that the apparent conflict has led to differing practice patterns.” She said she does not use steroids in her ARDS patients, adding, “That needs to be confirmed in a large-scale, multicenter clinical trial.” —Kate O’Rourke Drs. Meduri and Jacobi reported no relevant financial conflicts of interest.

PREMIXED AMIODARONE. Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: s

Known hypersensitivity to any of the components of NEXTERONE, including iodine

s

Cardiogenic shock

s

Marked sinus bradycardia

s

Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available

s NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

s Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported

in 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion.

s In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

s Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. s The most common adverse reactions leading to discontinuation (1-2%) of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock.

s Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. s Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular ďŹ brillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: s +NOWN HYPERSENSITIVITY TO ANY OF THE COMPONENTS OF .%84%2/.% 0REMIXED )NJECTION INCLUDING iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage BLEEDING FEVER ARTHRALGIAS JOINT PAINS EOSINOPHILIA ABNORMAL BLOOD COUNTS URTICARIA HIVES thrombotic thrombocytopenic purpura, or severe periarteritis (inammation around blood vessels). s #ARDIOGENIC SHOCK s -ARKED SINUS BRADYCARDIA s 3ECOND OR THIRD DEGREE ATRIO VENTRICULAR !6 BLOCK UNLESS A FUNCTIONING PACEMAKER IS AVAILABLE 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and beneďŹ ts of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically signiďŹ cant hypotension during infusions was seen most often in the ďŹ rst several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difďŹ cult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical deďŹ brillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically signiďŹ cant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular conuent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. )N PATIENTS WITH LIFE THREATENING ARRHYTHMIAS THE POTENTIAL RISK OF HEPATIC INJURY SHOULD BE WEIGHED against the potential beneďŹ t of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE FOR EVIDENCE OF PROGRESSIVE HEPATIC INJURY )N SUCH CASES CONSIDER REDUCING THE RATE OF ADMINISTRATION or withdrawing NEXTERONE.

5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when uoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information]. Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias. 5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity 4HERE HAVE BEEN POSTMARKETING REPORTS OF ACUTE ONSET DAYS TO WEEKS PULMONARY INJURY IN PATIENTS treated with intravenous amiodarone. Findings have included pulmonary inďŹ ltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary ďŹ brosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone). 5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone. 5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information]. Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

Table 4 lists the most common (incidence *2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

The institution of antithyroid drugs, Ƶ-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients. 5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics. 5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone. 5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics. 6 ADVERSE REACTIONS 6.1 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.

CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole Fever

Body as a whole 24 (2.9%)

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia

Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

Cardiovascular 41 (4.0%) 21 (2.0%) 26 (2.5%) 123 (12.0%) 30 (2.9%) Digestive System 29 (2.8%) 43 (4.2%)

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%)

Digestive System Liver function tests normal Nausea

Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever Cardiovascular: hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri Pancreatic: pancreatitis

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

Renal: renal impairment, renal insufficiency, acute renal failure

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Vascular: vasculitis

Respiratory: bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and /or mass, pleuritis Thyroid: thyroid nodules/thyroid cancer

Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

Sourced from: 07-19-65-459 Rev. November 2010

22 Clinical

Pharmacy Practice News • June 2012

Infectious Disease

Some Hospitals Slow To Embrace Fidaxomicin F

idaxomicin, the first new antibiotic to be approved for Clostridium difficile infection in the last 30 years, holds at least one key advantage over standard first-line therapy with oral vancomycin: a reduced rate of C. difficile recurrence. But the high cost of the new agent has left some hospitals reluctant to add it to their formularies—at least not without substantial restrictions. In a recent listserv survey conducted by a member of the University HealthSystem Consortium (UHC), of the 33 responding hospitals that had evaluated fidaxomicin (Dificid, Optimer Pharmaceuticals, Inc.) for formulary inclusion, only 11 institutions had added the oral drug to their formularies. Moreover, all of those hospitals had placed restrictions on its use, most typically permitting ordering or approval only by an infectious-disease physician. (UHC is an alliance representing approximately 90% of the nation’s nonprofit academic medical centers.) In Detroit, both Henry Ford Hospital and Detroit Medical Center rejected the drug for formulary status. “In fact, our prescribers have not submitted a request for its addition,” said Rachel Chambers, PharmD, BCPS, antimicrobial stewardship pharmacist at Henry Ford. “Based on cost and clinical efficacy data, the only niche our prescribers have noted is for the rare individual with severe C. difficile and a true vancomycin allergy.” Detroit Medical Center took a more in-depth look at fidaxomicin. “We did not feel the data was convincing enough to put it as first-line therapy,” said clinical pharmacist Jason Pogue, PharmD. Although Dr. Pogue acknowledged that recurrence rates with fidaxomicin were lower in recent clinical studies, “since the drug has yet to actually be studied for refractory/relapsing disease, the decision was made not to add it for that scenario.”

Cost Is a Factor—But To What Degree? Including cost in the formulary calculus for fidaxomicin is not surprising, given the gap in pricing between fidaxomicin and vancomycin. In hospitals, vancomycin often is compounded as an oral suspension using generic IV formulations, at a cost of about $100. In comparison, a 10-day course of treatment with fidaxomicin has a price tag of approximately $2,800, as confirmed by Kurt Hartman, Optimer’s general counsel, chief compliance officer and senior vice president of access. (A middle-ofthe-road option, vancomycin capsules [Vancocin, Viropharma Inc.] costs about half as much as a course of fidaxomicin.) But the higher up-front cost of fidaxomicin may tell only part of the story, according to two new studies presented

at the 2011 Midyear Clinical Meeting of the American Society of Health-System Pharmacists. In fact, the pharmacoeconomics studies—both by a team of scientists at Washington State University supported by Optimer—suggested that the cost of fidaxomicin might be warranted from a system-wide perspective. Using pooled data from two randomized clinical trials that were included in the FDA approval process, the researchers determined that the number needed to treat to achieve sustained clinical response was 7.1. In most primary and all secondary case scenarios of C. difficile, the researchers found that the estimated value of fidaxomicin (the “warranted price”) exceeded its wholesale acquisition cost (WAC). For example, in secondary cases of C. difficile (mean attributable length of stay, 2.9 days; mean attributable cost, $15,759), the value (price) of fidaxomicin versus IV vancomycin used orally was $772 per day, significantly exceeding the daily WAC of $280 for fidaxomicin. In most scenarios, this excess value-forcost ratio held true. But in primary cases of C. difficile, when measured against IV vancomycin used orally, the value (price) of fidaxomicin was $223 per day, less than its actual WAC. Do these data justify the higher upfront expense of fidaxomicin? “I don’t believe that $2,800 is too high a price to pay—if it were for therapy of refractory cases, and if there were a way to determine who those patients are likely to be,” said Robert Rapp, PharmD, professor of pharmacy emeritus in the College of Pharmacy at the University of Kentucky, Lexington. “That said, I believe it is too much for every patient with confirmed or suspected C. diff to receive it. Therefore, we need a risk stratification strategy to ensure we are choosing the patients most likely to respond. But we do not have that as of yet.” Dr. Pogue said that his hospital “did look a bit at the cost models, but there are too many unknown variables—does a patient with a relapse get readmitted? Do they come back to the same hospital? Are they treated as outpatients?” Without that type of additional information, it is difficult “to feel overly confident with the [pharmacoeconomic] numbers.”

The Case for an Added Edge In Recurrent Disease The data on recurrences largely came out of a Phase III study in The New England Journal of Medicine (2011;364:422431). Significantly fewer patients in the fidaxomicin arm of the study experienced recurrence of a C. difficile infection (defined as diarrhea and a positive stooltoxin test within four weeks of treatment completion), than with patients treated

with vancomycin. This was documented in the modified intent-to-treat analysis (15.4% vs. 25.3%; P=0.005), as well as in the per-protocol analysis (13.3% vs. 24%; P=0.004). However, when analyzed based on the type of C. difficile strain present, a somewhat different picture emerged. In patients with nonvirulent strains, recurrences were as low as 7.8% in fidaxomicin-treated patients compared with 25.5% in those given vancomycin (P=0.001). In contrast, in patients with the virulent NAP1/BI/027 strain, recurrence rates were similar for fidaxomicin and vancomycin (24.4% vs. 23.6%, respectively; P<0.001). Given those results, should the type of C. difficile strain affect patient selection for fidaxomicin therapy? In theory, yes, some experts suggest. But there are roadblocks to that approach. “Our current PCR [polymerase chain reaction] testing does not make that distinction,” said one Midwest infectiousdisease pharmacist who asked not to be quoted by name due to the sensitivity of the formulary decision-making process. “And we felt that the drug hasn’t really been studied in the patients we’d most like to use it in, which would be those who have had multiple recurrences or are at greatest risk for recurrence. There’s just no data in that population.” Sherry Gorbach, MD, chief scientific officer and senior vice president for research and development at Optimer, acknowledged those data limitations. But Dr. Gorbach pointed out that the data gap applies to all drugs on the market for C. difficile. “There are no data from any drug on treatment of multiple recurrences,” he said. “There just is a complete absence of clinical trials in this area. In a way, the pharmacists and the doctors are all flying by opinion. But we feel there is a value proposition here that shouldn’t be overlooked. Even a few days in hospital [with a C. difficile recurrence] more than make up for the differences in drug cost.”

Annals Study A recent review article in Annals of Internal Medicine (2011;155:839-847) offered some insights into how fidaxomicin stacks up against other treatments. The researchers included 11 studies in their review, and concluded that “initial cure rates did not statistically significantly differ for fidaxomicin, vancomycin, and metronidazole.” However, the authors did underscore the fact that recurrent disease “was less frequent with fidaxomicin (15%) than with vancomycin (25%).” But the authors were circumspect on the question of whether that difference should affect choice of therapy. “Multiple factors,” they noted, “will

‘We feel there is a value proposition here that shouldn’t be overlooked. Even a few days in hospital [with a C. difficile recurrence] more than make up for the differences in drug cost.’ —Sherry Gorbach, MD probably influence use [of fidaxomicin], including the willingness of providers to prescribe a new medication, safety data as use becomes more widespread, local patterns of incidence and recurrence of C. difficile infection, and costs (including both drug costs and those associated with [recurrences]).” Certainly, the question of recurrences was a polarizing one for the FDA advisory panel that reviewed fidaxomicin for approval. Although all 13 panel members voted unanimously to approve the drug, it split 6-6 (with one abstention) over whether the reduction in recurrence risk was significant. (When the FDA did okay the drug, the approval did not include an indication for recurrent infection.)

Varying Payer Policies Debates over recurrences and cost may continue, but on the payer side, Optimer said it is pleased with fidaxomicin uptake so far. As of May 2012, about 94% of all commercial lives in the United States have formulary payer access, according to the company. “We believe this speaks to a value proposition that we have been able to communicate with payers,” Mr. Hartman said. “They see all costs, not just hospital and not just drug costs, but also long-term care and readmission.” —Gina Shaw and Rosemary Frei Dr. Pogue disclosed that he has served on speakers bureau, advisory boards or served as a consultant to Merck, Pfizer, Cubist, Forest and Astellas. Dr. Rapp is a consultant to, and is on the speaker’s bureau for, Pfizer. Dr. Chambers reported no relevant financial conflicts of interest.

Pharmacy Practice News • June 2012

Clinical 23

Cardiology

READMISSION continued from page 1

A Mix of Medications And Interventions The checklist, developed by Dr. Basoor with input from pharmacists on review boards at St. Joseph’s, consists of one page with three sections: medications; interventions and counseling; and follow-up services. The medications include β-blockers, angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), diuretics, digoxin, aldosterone antagonist, nitrates, warfarin, aspirin and lipidlowering agents. The medications are listed on a “pick-and-choose” basis to remind clinicians about prescribing the drugs or titrating them up. “Treatment must be individualized,” Dr. Basoor stressed. The interventions included general risk modification education, HF monitoring and smoking cessation counseling. Follow-up services included cardiology and primary care and cardiac rehabilitation. In the randomized controlled trial (abstract E1026), 96 patients with congestive HF were equally assigned to either the checklist group or a control group. The results showed that significantly higher proportions of patients were on ACE inhibitors/ARBs in the checklist group than in the control group (40 of 48 vs. 23 of 48; P<0.001). Moreover, up-titration for β-blockers and/or ACE inhibitors/ARBs was significantly more common in the checklist group (21 of 48 vs. 4 of 48; P<0.001). The checklist group fared significantly better with respect to both 30-day readmissions (1 of 45 vs. 9 of 46, after excluding deaths; P=0.02) and six-month readmissions (11 of 48 vs. 20 of 48; P=0.045). The study was small, Dr. Basoor acknowledged, but “we found significant results.” (A paper based on the poster study is currently under review.)

Checklist Lauded For Its ‘Simplicity’ Cam Patterson, MD, MBA, chief of the Division of Cardiology at University of North Carolina, Chapel Hill, who was not a study author, applauded the checklist strategy for its basic approach to HF management. “There are many ideas about how we can keep our [HF] patients out of the hospital, but most of them are cost-intensive,” Dr. Patterson said. “The beauty of the checklist developed by Dr. Basoor and his colleagues is its simplicity. This is a cheap tool that, if validated in larger populations, could be highly beneficial to health care providers and their patients.” A challenge of the checklist, he added, “is that it requires tight teamwork among physicians, nurses and pharmacists to ensure that each of the checklist issues [is] fully addressed.”

Cynthia Jackevicius, PharmD, BCPS (AQ Cardiology), also offered kudos to Dr. Basoor and his colleagues for their checklist-based interventions—especially given the opportunities it creates for hospital pharmacists. “The pharmacist is in an ideal position to play a leading role in implementing this type of checklist for [HF] patients,” she said. “Many of the criteria are medication-related or lifestyle modification—areas where pharmacists often have roles in both the inpatient and outpatient settings,” noted Dr. Jackevicius, director of Residency & Fellowship

Training in the Department of Pharmacy Practice & Administration at Western University of Health Sciences College of Pharmacy, in Pomona, Calif.

Other HF Efforts Given the looming CMS payments tied to hospital readmissions, it’s not surprising that many other health systems are working closely with patients at multiple points of care. At Novant Health, in Winston-Salem, N.C., for example, pharmacists working in the Safe Med program call patients within the first week after

discharge and counsel them about their medications, noted Terri B. Cardwell, RPh, PharmD, MHA, who directs the program. Targeted patients include those aged 65 years and older and those taking multiple medications. Many are HF patients. “If the patient is on a diuretic medication, we might explain that it’s not just for when [their] ankles are swollen,” Dr. Cardwell said. “That’s a common misconception. They’re supposed to take it regularly. … If they don’t understand why they’re taking a medication, we explain why.”

•

see READMISSION, page 25

LEVETERACITAM INJECTION, USP

Rx Only

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

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

15 14 13 7

9 13 8 6

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

3

2

15 9 4 4 3 3 2 2 2 2 2

8 4 2 2 1 1 1 1 1 1 0

Pharyngitis Rhinitis Cough Increased Sinusitis Special Senses

6 4 2 2

4 3 1 1

Diplopia

2

1

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

5

3

Pharyngitis Influenza

7 5

0 2

Neck pain Nervous system disorders

8

2

Somnolence Psychiatric disorders

12

2

Depression

5

2

Musculoskeletal and connective tissue disorders

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

8

7

Fatigue Infections and infestations

10

8

Nasopharyngitis Psychiatric disorders

14

5

Irritability Mood swings

6 5

2 1

General disorders and administration site conditions

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

AR126 Iss. Date 1/2012

Pharmacy Practice News • June 2012

Clinical 25

Cardiology

Low-cost Strategy Boosts Compliance With ACS Guidelines Chicago—A sequence of simple and inexpensive quality improvement interventions significantly increased physician adherence to evidence-based therapies for acute coronary syndrome (ACS) in a cluster randomized trial. The multipronged strategy, consisting of a color-coded label on the patient’s chart indicating severity of chest pain, a color-coded patient bracelet, an interventions checklist, educational materials and care coordination by a nurse case manager, increased physician use of all recommended therapies by 18%, Otavio Berwanger, MD, PhD, reported at the annual meeting of the American College of Cardiology. Results of the trial—BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndrome)—also were published online in the Journal of the American Medical Association (2012 Mar 25. [Epub ahead of print]). “We have very good guidelines. The problem is physicians don’t apply these guidelines in practice,” said Dr. Berwanger, director of the Research Institute HCor at the Cardiac Hospital of Sao Paolo, Brazil, in a press briefing. “There are important gaps between what the guidelines recommend and what is done in practice, regardless of how easily [the interventions are] given.” These gaps become a particular problem in low- and middle-income countries, which carry the largest ACS burden, he said. Dr. Berwanger and his colleagues randomized 34 public hospitals in major urban areas of Brazil on a 1:1 ratio to a quality intervention and a control arm. Public hospitals serve about 70% of the country’s population. The hospitals in this study represented a broad range of ACS care capabilities, and the two study groups were well matched. One or two nurses at each hospital in the intervention arm coordinated patient care and checked with physicians when they noticed that a protocol had not been followed. “The case manager here was

READMISSION continued from page 23

Rick Couldry, MS, RPh, director of pharmacy at the University of Kansas Hospital, in Kansas City, said the case for having pharmacists directly involved in efforts to reduce HF readmissions is a strong one. “When a pharmacist is involved with the discharge of a patient, providing counseling and review of medications, there is evidence the risk for readmission is reduced,” Dr. Couldry

anticoagulation during the first 24 hours; aspirin, β-blockers, statins and angiotensin-converting enzyme inhibitors at discharge), using the same “all-or-none” approach; and overall composite adherence scores. Among the 801 eligible patients (69.7%), those in the intervention group (50.3%) were significantly more likely to receive all acute and discharge medications than those in the control group (31.9%). Clinical outcomes trended in favor of the quality improvement intervention, but the study was not large enough to accurately assess the strategy’s effects on cardiovascular events, Dr. Berwanger said; larger studies will be needed to measure clinical impact. “It’s never simple to design interventions for changing behavior,” but the interventions used in this study are simple in the sense that they do not require expensive technology, he said. “We wanted to be simple to make it applicable to various scenarios.”

‘It’s never simple to design interventions for changing behavior. We wanted it to be simple

A Pharmacist’s Take

to make it applicable to

probably the most important part of our intervention,” Dr. Berwanger said. Hospitals in the control arm practiced care as usual without any quality improvement interventions, he noted. Physicians in the intervention group also received reminders in the form of a checklist based on Brazilian Society of Cardiology guidelines for ACS, which are basically the same as those of the American College of Cardiology and the American Heart Association. The checklist included an algorithm enabling physicians to stratify patients based on presentation, electrocardiogram results and cardiac enzyme levels, and indicated appropriate evidencebased therapies. The algorithm divided

patients into three colorcoded risk categories: red for ST segment elevation myocardial infarction (MI); yellow for non–ST-segment elevation ACS; and green for patients with a normal electrocardiogram and enzymes. Data were collected on 1,150 patients during the six-month trial. The primary end point was 100% adherence to recommended therapies (aspirin; clopidogrel; anticoagulation with enoxaparin, unfractionated heparin or fondaparinux; and statins) during the first 24 hours in patients without contraindications using the “all-or-none” approach. This end point was reached for 49.5% of patients in the control group and 67.9% of patients in the intervention group who were eligible for treatment (923 of 1,150 or 80.3%). Secondary end points included adherence to all eligible evidence-based therapies at admission and within one week of discharge among patients without contraindications (aspirin, clopidogrel and

said. His hospital is developing a “tactical approach to reduce readmissions” for HF patients. On the inpatient side, all HF patients are to be on one floor, with pharmacists being part of their health care team. On the outpatient side, the focus will be on helping to keep patients out of the hospital. Although CMS payment policies are a factor, Mr. Couldry said, the real driver is that “it’s the right thing to do for our patients.” St. Joseph’s Dr. Basoor echoed the importance of patient care in any type

of HF quality improvement program. Focusing on ACE inhibitor therapy is a good place to start, he pointed out, because the drugs are underused and underdosed, despite published treatment guidelines and studies underscoring the benefits of the drugs in HF patients. Indeed, “ACE inhibitors are recommended and should be used for almost all heart failure patients,” Dr. Basoor said. Unfortunately, without regular patient contact, it is difficult to ensure that

various scenarios.’ —Otavio Berwanger, MD, PhD

C. Michael White, PharmD, director of the University of Connecticut/Hartford Hospital Evidence-Based Outcomes Center, said that it is unclear whether these interventions would have the same effect in the United States, where performance measures for MI are already in place. In the United States, he noted, the problems are more likely to be under-dosing of patients with ACS medications and patient adherence following discharge. “Pharmacists have been instrumental in getting patients on these medications but also in getting them up closer to therapeutic dosages,” he said. In addition, “While 30-day utilization of these drugs after MI might be high, the long-term use of these medications is poor without consistent evaluation and feedback. This is another place where pharmacist care is valuable.” —Susan Birk Drs. Berwanger and White reported no relevant financial conflicts of interest.

any class of drugs for HF patients is used optimally, he noted. Thus, “intervention and counseling should be considered for every patient,” with follow-up visits “recommended within seven days of discharge either with primary care or cardiologist.” —George Ochoa Mr. Couldry and Drs. Basoor, Cardwell, Jackevicius and Patterson reported no relevant financial conflicts of interest.

26 Clinical

Pharmacy Practice News • June 2012

Cardiology

Bariatric Surgery Beats Drug Therapy for Obese Diabetics Chicago—Obese patients with poorly controlled type 2 diabetes achieved markedly better glycemic control with a combination of bariatric surgery and medical therapy than with medical therapy alone, according to the results of the STAMPEDE trial, a randomized study of 150 patients. STAMPEDE (Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently) is one of the first studies to suggest that a surgical approach may be superior to a polypharmacy approach to treating the disease in obese patients, according to lead investigator Philip R. Schauer, MD, who presented the findings at the annual meeting of the American College of Cardiology (ACC). The study, which was also published online in The New England Journal of Medicine (http:// www.nejm.org/doi/pdf/10.1056/NEJMoa1200225), was sponsored by Ethicon Endo-Surgery, with support from LifeScan, the Cleveland Clinic and the National Institutes of Health. The patients in the study were 66% female, with a mean age of 49 years and a mean hemoglobin A1c of 9.2% at baseline. Many of the patients had major diabetes-related coexisting illnesses, including retinopathy and nephropathy, or end-organ damage. Patients either underwent medical therapy alone, or were treated with medical therapy combined with either sleeve gastrectomy or gastric bypass surgery. The primary end point of the study— a glycated hemoglobin level of 6% or less at 12 months—was reached by five of 42 patients who received medical therapy alone (12%), compared with 18 of 49 patients who underwent sleeve gastrectomy (37%; P=0.008) and 21 of 50 patients who underwent gastric bypass surgery (42%; P=0.002), reported Dr. Schauer, a professor of surgery and director of the Cleveland Clinic’s Bariatric and Metabolic Institute. Additionally, although the two surgery groups did not differ with respect to the primary end point, 28% of sleeve gastrectomy patients who achieved the end point required one or more glucose-lowering medications, whereas none of the gas-

tric bypass patients required medication to achieve the end point. “That’s as close to a definition of remission as you can get,” Dr. Schauer said in a press briefing during the ACC meeting. At 12 months, 38% of patients in the medical therapy group were using insulin compared with 8% in the sleeve

quite dramatically—about 80% in the surgical group compared with about a 30% reduction in the medical group,” said Dr. Schauer, who noted that a fouryear follow-up study is planned to assess long-term safety and efficacy. Dr. Schauer noted that the study shows there is another modality besides

‘There are complications to these surgeries, and they’re pretty severe. So patients need to be screened appropriately....’

—Tanna Cooper, PharmD

Table. Weight Loss and BMI Changes for Surgery Versus Medical Therapy Alone Study Arm

BMI Changesa

Gastric bypass group

−27.5±7.3%

37 to 26.8 kg/m2

Sleeve gastrectomy group

−24.7±6.6%

36.1 to 27.2 kg/m2

Medical therapy group a

Weight Lossa

5.2±7.7%

36.3 to 34.4 kg/m2

P<0.001 for each surgery group compared with medical therapy

BMI, body mass index

gastrectomy group and 4% in the gastric bypass group (P<0.001). At baseline, 86% and 78% of patients in the gastric bypass and sleeve gastrectomy groups required lipid-lowering drugs, but at 12 months, use declined to 27% and 39%, respectively, versus 92% for the medical therapy-alone group (P<0.001). Patients in the gastric bypass and sleeve gastrectomy groups lost significantly more weight and had significantly greater decreases in body mass index (BMI) over time than did the medical therapy group (Table). “Other markers of cardiovascular risk, such as C-reactive protein, decreased

medical therapy that can get “patients with uncontrolled diabetes into good control,” he said. “We do know the consequences of poorly controlled diabetes, both in terms of increased rates of microvascular complications, retinopathy, nephropathy, neuropathy and a higher risk for cardiovascular events. So this provides another therapy to help the physician to manage this chronic disease. Diabetes is a progressive disease, and even with fairly good medical control, most patients go on to become refractory to medical therapy and ultimately will develop one of these major complications.”

Tanna Cooper, PharmD, BCPS, clinical pharmacy specialist for medical/surgical intensive care and the digestive diseases service line at the Medical University of South Carolina, in Charleston, noted that one-third of patients in the study had a BMI at baseline of less than 35 kg/m2. “We typically only do [gastric bypass] surgery on patients with a BMI of 35 or greater,” she said. Although there were no deaths in this study, “there are complications to these surgeries,” she added, “… and they’re pretty severe. So patients need to be screened appropriately for what would be the best option for them.” Because the most significant changes usually occur within the first year following surgery, “it will be really interesting to see what they find in the four-year follow-up.” Rick A. Nishimura, MD, a professor of medicine at Mayo Clinic in Rochester, Minn., also stressed the importance of a comprehensive evaluation and careful patient selection. “These great results are coming from these very comprehensive centers that evaluate the patients with an endocrinologist, a psychiatrist, a nutritionist,” he said. “When people start gaining a lot of weight, sometimes it’s for other reasons, and we don’t want to just jump in on an operation. So they have to have extensive evaluation beforehand.” Dr. Schauer noted that rigorous standards are in place for bariatric surgery centers, which must qualify as a center of excellence to receive Medicare reimbursement. “They have to demonstrate that they have all of these processes in place, and they also have to report outcomes to meet standards in terms of morbidity and mortality,” he said, stressing that patients should be referred “to one of these centers of excellence.” —Susan Birk Dr. Schauer and the STAMPEDE co-investigators have received consulting honoraria from Bard-Davol, Barosense, Carefusion, Covidien, Ethicon Endo-Surgery, Gore, Orexigen, RemedyMD, Stryker Endoscopy, Surgiquest and Vivus. Drs. Cooper and Nishimura reported no relevant financial conflicts of interest.

Vorapaxar Reduces Ischemic Events but Boosts Risk for Bleeding Chicago—Adding the investigational antiplatelet agent vorapaxar to standard therapy for patients with stable atherosclerosis reduces the risk for cardiovascular death and ischemic events but increases the risk for moderate or severe bleeding and intracranial hemorrhage (ICH), according to a large randomized

trial presented at the annual meeting of the American College of Cardiology. “This is the first proof we have that we can improve antiplatelet treatment on top of aspirin in patients who have had a previous heart attack,” said investigator David A. Morrow, MD, MPH, of Brigham & Women’s Hospital, in

Boston, during a press briefing at the meeting. But, he acknowledged that there are safety concerns with the drug, particularly in patients with a history of stroke, and said that vorapaxar is not appropriate for all patients with atherosclerosis. “Just like [with] any other potent platelet blocker that we

use, we need to select patients where we think there’s an appropriate balance of the potential benefits versus the risk.” In January 2011, the study’s data and safety monitoring board recommended discontinuing vorapaxar in patients with a history of stroke due to an elevated incidence of ICH.

Pharmacy Practice News • June 2012

Clinical 27

Cardiology Merck Research Laboratories funded the study—TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50)—which was published on April 12 in The New England Journal of Medicine. During the trial, researchers at 1,032 sites in 32 countries randomized 26,449 patients with a history of myocardial infarction (MI), ischemic stroke or peripheral arterial disease to receive vorapaxar 2.5 mg daily or placebo. Patients also received aspirin or a thienopyridine or both. Patients were followed for a median of 30 months. At three years, the primary end point—death from cardiovascular causes, MI or stroke—had occurred in 1,028 patients in the vorapaxar group (9.3%) and 1,176 patients in the placebo group (10.5%) (hazard ratio [HR] for vorapaxar, 0.87; 95% confidence interval [CI], 0.80-0.94; P<0.001). The drug yielded a 20% reduction in the combined end point of cardiovascular death, MI and stroke among the nearly 18,000 patients who entered the study with a history of MI. An analysis of the data indicated that the most favorable balance of benefits versus risks was among patients with no history of stroke and a body weight of at least 60 kg. However, the incidence of moderate or severe bleeding was significantly greater among all patients who received vorapaxar (4.2% vs. 2.5% among those who received placebo; HR, 1.66; 95% CI, 1.43-1.93; P<0.001). Notably, patients who received the drug had an increased risk for ICH (1.0% vs. 0.5% in the placebo group; P<0.001). The incidence of ICH was most noticeable among patients with a history of stroke (2.4% vs. 0.9%; P<0.001 in the drug and placebo groups, respectively).

‘Vorapaxar is not ready for prime time. Given these findings, I would not anticipate [FDA approval].’ —C. Michael White, PharmD post-MI patients over 60 kg, comparing aspirin plus clopidogrel [Plavix,

Bristol-Myers Squibb] plus vorapaxar versus aspirin plus prasugrel [Effient,

Lilly] or ticagrelor [Brilinta, AstraZeneca]. These FDA-approved antiplatelet agents already have been shown to stand up favorably against clopidogrel without CYP [cytochrome P450] 2C19 testing to select optimal patients.” —Susan Birk Dr. Morrow has received research support and consulting fees from Merck and other manufacturers of antiplatelet and anticoagulant therapies. Dr. White reported no relevant financial conflicts of interest.

Unique Mechanism of Action Despite the safety issues, Dr. Morrow said that vorapaxar could offer a valuable additional treatment for patients with a history of MI because of its unique mechanism of action. The drug selectively inhibits the platelet activator thrombin through the antagonism of protease-activated receptor (PAR)-1. “It’s really been unclear to this point whether blocking this pathway would turn out to be advantageous for our patients, and we see now that it reduces clotting events,” he said. According to C. Michael White, PharmD, director of the University of Connecticut/Hartford Hospital Evidence-Based Practice Center, “vorapaxar is not ready for prime time. Given these findings, I would not anticipate the FDA approving vorapaxar without additional study. What is really needed is a trial specifically in

TM

28 Operations & Management

Pharmacy Practice News • June 2012

Wicked Change

Envisioning a New Practice Future

P

Janice Glascock, PharmD

Collin E. Lee, PharmD, BCPS

Assistant Director   of Pharmacy Emory Hospitals Atlanta, Georgia

Drug Information   Pharmacist Emory Hospitals Atlanta, Georgia

harmacists at Emory Hospitals have embarked on a program to advance departmental leadership skills, with a goal of making challenging and critical changes to Emory’s pharmacy practice model. To facilitate this effort, in April 2011, four Emory pharmacists enrolled in an ASHP Foundation Pharmacy Leadership Academy (PLA) Capstone course, “Developing Leader Skills.” Although combined we had more than 100 years of pharmacy experience (65 years at Emory), we recognized that, as leadership expert John Kotter has said, “Despite the increasing importance of leadership to business success, the on-thejob experiences of most people actually seem to undermine the development of attributes needed for leadership.” We recognized that pharmacy school did not teach how to lead people effectively or how to improve our individual leadership skills in the same dedicated way that clinical skills are maintained. Additionally, we realized that over time we become a part of the established “status quo” culture and become blind to our weaknesses. Unless leaders have a clear plan for growth and recognize that progress is “becoming superior to your previous self,” on-the-job experiences may not challenge us to look and act outside of our comfort zones. The PLA Capstone program enlightened and inspired us while opening our eyes to both potential opportunities and challenges we face. Unlike the technological changes Emory has instituted during the past several years, this practice model change would be driven by our pharmacy leadership. Our traditional “buy-in” approach was not working, probably because it did not include broad leadership and end-user involvement in developing, thinking and planning the model at the outset. As former Merck chairman Henri Lipmanowitz noted, in complex situations, ownership—rather than buy-in—is more likely to generate superior results. We realized we would have to align ourselves with a vision that could carry us through conflict and change to move forward. We would likely need to identify and abandon some of what we had held sacred, and even model a new culture. Thus, we determined that to create an environment in which creativity and innovation would thrive, we needed two things: a renewed

vision and a leadership training program to help us identify, model and coach the behaviors necessary for change to occur. In an article in Harvard Business Review, Kotter recommends eight steps to bring about transformational change; three of the steps include the word “vision”: 1) create the vision, 2) communicate the vision, and 3) empower others to act on the vision. In August 2011, we pulled a group of pharmacists, technicians and leaders together to revamp our vision statement. To engage attendees in our goal and set the tone for the need for change, all attendees were asked to interview two individuals with the following questions prior to the meeting: 1) Describe one service goal you would like to see the department or your team undertake, and 2) Describe one change in the departmental culture you would like to see the department embrace. The group met for five hours, spending much of the time on working with tools that assisted us in shifting from using our ever-present logic- and linearoriented left-side brains to our intuitive-, random- and possibility-oriented right-side brains. We exposed ourselves to the vulnerability and difficulty of working as a collaborative team without clear expectations or communications. We shared comments from the interviews, brainstormed our best ideas and wrote stories about how we would envision our pharmacy in 2015. We listed visual, powerful adjectives that we would like to include in our statement. We created the following vision statement: “Optimizing the medication management of every patient, every day, within a collaborative culture.” Then, we decided to divide our vision statement into three different target sections for action. The first section, “Optimizing medication management,” was the most obvious and familiar part for our pharmacists. As part of our newly transformed pharmacy practice model, staff is now required to attend codes, complete self-assessment modules, participate in educational seminars and conduct clinical projects. Emory also has provided

financial incentive for board certification. Our department has set a goal that challenges all of our clinical specialists to be board-certified pharmacotherapy specialists by January 2014, and we are seeing other pharmacists on staff take on this challenge as well. The second section of the vision statement, “every patient, every day,” relies on both 1) defining what care every patient should receive every day and the pharmacist skill sets needed to provide that care and 2) pharmacy managers creating staffing schedules that have our people in the right places at the right times. We must examine the value of what we do, challenge the “sacred” and be as efficient and effective as possible when we make our choices. For example, streamlining processes for kinetics and anticoagulation—clinical programs that have been in place for years—requires LEAN/Microsystems skill sets. This is an area we are just beginning to gain experience with and serves as an opportunity for growth for our leaders and staff. In the meantime, as we progress toward obtaining helpful and accurate workload data, staff has begun piloting a medication trigger tool that identifies patient care activities that hold high clinical value. Finally, this care must be accomplished “within a collaborative culture.” We outlined a training plan, with a goal that pharmacy leaders would attend a series of training sessions and learn to apply key leadership principles through communication, collaboration and change management. Thus, the final section of our vision statement, “within a collaborative culture” is a focus of this leadership training class. In our first leadership session, the pharmacy leadership group completed a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis on our progress advancing the pharmacy practice model at Emory, and identified opportunities for improvement in: • Using the ASHP Pharmacy Practice Model Initiative (PPMI) recommendations • Connecting the pharmacy practice model to our vision • Better defining the pharmacy practice model with clearer expectations • Exploring performance review feedback opportunities and consistency among leadership • Identifying LEAN/Microsystems opportunities that could free up more time

Wicked Change focuses on leadership development and change management. Content for the column is coordinated by Sharon Murphy Enright, BSPharm, MBA, president of EnvisionChange, LLC, Richmond, Va. Ms. Enright welcomes your feedback at wickedchange@gmail.com.

• Developing better feedback mechanisms and coaching structure related to clinical skills delivery. In the future, our team members need to recognize, as Henri Lipmanowitz has noted, that pride is a serious enemy of self-improvement.3 We will need to create environments conducive to the collective advancement of knowledge and skills, and to place ourselves in learning roles that are crucial for growth. Ownership “requires giving people space and time for self-discovery,” thus the leadership training must be engaging and interactive but with clear expectations, so that we do not lose momentum. In our first 3 leadership sessions, we have established an environment in which leaders are both engaged and enthused about available opportunities. Our leadership team attends the sessions with the optimism needed to bring about the changes. Our next step involves asking our leaders to bring real examples of how they have applied, or have been challenged to apply, the principles we have read about and discussed at our sessions to create the foundation for tangible change. This will lead to our taking ownership for our own development as well as that of our team, thus advancing us toward the collaborative culture we seek. Envisioning a new practice future is hard but rewarding work that involves thinking about what is, thinking differently about what could be, and building a new sense of collaborative trust and a shared ownership in a better future. Author biographies available at www.pharmacypracticenews.com

References 1. Kotter J. What leaders really do. Harvard Bus Rev. 1990;68(3):103-111. 2. Maxwell JC. The 17 Essential Qualities of a Team Player: Becoming the Kind of Person Every Team Wants. Nashville, TN: Thomas Nelson; 2002. 3. Lipmanowitz H. Buy-in versus ownership. Clinical Microsystems: 2011. http://clinicalmicrosystem.org/toolkits/getting_started/Buyin. Accessed May 7, 2012. 4. Kotter J. Leading change, why transformation efforts fail. Harvard Bus Rev. 1995;73(2):59-67.

Pharmacy Practice News • June 2012

Policy 29

Reimbursement Matters

Bundled Payments: How Do I Get My Share? H

ealthcare care reform is presenting new challenges and opportunities, with an important emphasis on quality. However, at the same time, the insurance component of healthcare is undergoing one of the biggest changes, and several new payment models are moving forward as demonstration projects. Many of the initiatives focus on bundled payments. Indeed, the concept of bundled payments is growing by leaps and bounds, leaving pharmacy wondering how the department will be reimbursed for the products they supply, the services they provide and the clinical components of their practice. As providers and payers strategize as to what to put into their bundles, pharmacy departments should be working with those same finance teams to determine how the bundled payment will be unbundled once it reaches the facility. In parsing those figures, it is important to determine how much of the bundled reimbursement will be allocated to the pharmacy department, both for product supplied and for key services, including the clinical component.

only a very few medications falling into a separately payable list, with even these usually being reserved for dialysis patients with non-dialysis-related conditions requiring therapy. Again pharmacy stumbled with accurate billing to identify true cost in looking after these patients and failed to develop a mechanism to receive the amount owed them for the actual medications, the services and the clinical compo-

Impact on OPPS Payments Bundled payments impacted the rest of the Medicare outpatient scene (the outpatient prospective payment system, or OPPS) with the arrival of separately

Bonnie Kirschenbaum, MS, FASHP

payable drugs and biologics based on reimbursement for actual dose calculated. Those payment determinations were made using the Center for Medicare &

•

see PAYMENTS, page 30

®

Now Available... Optimizing the Selection and Use of Topical Hemostats To participate in this FREE CE/CME activity, visit

A History of Bundling Bundled payments are not a new concept; they made an early appearance with the inception of Medicare’s inpatient prospective payment system (IPPS) using diagnostic-related groups (DRGs). Separate payment for drugs and biologics was no longer a part of Medicare’s inpatient reimbursement, and as a result, the hospital received a lump-sum payment for all of the expenses associated with the admission based on the DRG classification assigned to the case. The amount paid out by Medicare was calculated annually using a multitude of expenses factored in, including all drugs and biologics the patient received. Over the years, pharmacy departments have stumbled with accurate billing, and some unfortunately fell into the habit of neglecting to bill for many products being used. Either the finance department lost site of the importance of accurate and complete billing or the pharmacy department just didn’t want to be bothered. Unfortunately, those lackluster billing practices have had a negative impact on appropriate reimbursement. If you don’t specify what was used, it doesn’t get included in the cost of care, creating an artificially low estimate. Bundled payments next made an appearance in the ancillary areas of the hospital and impacted Medicare patients in outpatient areas, including ambulatory surgery and radiology. Next came outpatient dialysis, with

nent of pharmacy practice. And once again, the Medicare payments shrank and were deemed to be an inaccurate reflection of the true cost of looking after these patients.

“Reimbursement Matters” is a tool for maintaining your health-system’s fiscal health. Please e-mail the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Release Date: April 1, 2012

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

Faculty

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

Medical Writer

Mary Culpepper

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

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30 Operations & Management

Pharmacy Practice News • June 2012

Leadership in Action

Conflict: The Destroyer or the Opportunity? C onflict is inevitable in life; if there are human beings interacting, there is bound to be conflict. These struggles can be triggered by misunderstanding or poor communication. They also may arise from differences in values, goals, expectations, interests or opinions. If we turn to the leadership literature for clues about how to deal with these situations, we can see that there are constructive—and destructive—ways to respond to conflict. Understanding these responses, and choosing the ones that actually preserve relationships, can go a long way toward improving your personal and professional life.

‘Staging’ Conflict Responses There are three basic ways that people respond to conflict. On the extreme end of the spectrum, people either run from conflict, or they go on the attack. Neither of these responses is probably the best in most circumstances and only lead to an escalation to a worse situation. The best response is the middleground approach—one of peacemaking, as described by Ken Sande in his book, “The Peace Maker” (Baker Books, 2004). Let’s look at each of these responses in more detail. Escape response. There are three types of escape responses. The first is denial, in which we pretend a conflict doesn’t exist. In these situations, both parties or even an entire department know there is a problem but no one is willing to confront it. It is the proverbial “elephant in the room” that makes people feel they are walking on eggshells, and it can hurt productivity and hinder communication. Another response is that of flight, running away from the person or situation. It could be as simple as avoiding someone in the workplace or as drastic as leaving a job. Usually this response only postpones the inevitable and eats away on the inside, sometimes destroying a person’s self-confidence and effectiveness. Sometimes flight may be a good temporary solution to let “hot emotions”

PAYMENTS continued from page 29

Medicaid Services (CMS) assigned billing units (as opposed to the vial of the product) totaling greater than a fixed sum per day. In 2012 the differentiating daily cost is $75. Drugs and biologics costing more than $75/day are separately payable. Those costing less than $75/day are not separately reimbursed; instead, they are bundled into the visit payment to the facility. The facility also is paid for the drug being administered according to a scale that takes into consideration the

cool down. In rare cases, however, when people lose all hope of resolving a conflict, they may choose the third and obviously most dangerous escape response— suicide. I remember a legal case involving a pharmaceutical company in which an employee actually committed suicide as a form of escape rather than face the consequences of some illegal activities. Attack response. Some people respond to conflict by attacking. This can come from people trying to control others through intimidation, wanting to get their own way. The assaults may be verbal, directed against another person, or they can be indirect, where the aggressor assaults the reputation of another person

This is a private decision that one makes without involving others. When an offense is not something that can be overlooked, then the ideal is to reconcile the relationship. This usually will involve an apology from one or both of the parties, a recognition that some corrective action needs to take place to prevent similar situations from occurring, and an agreement to move forward. This takes place in private between the two parties. Sometimes the two clashing parties may need to negotiate a go-forward position. This may involve the mending of the relationship with an agreement on how the situation will be avoided in the future. A clarification of expectations

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

Ernest R. Anderson Jr., MS, RPh

initiatives. This binding decision is then implemented by all parties. Accountability, the last of the six types of peacemaking responses outlined by Sande, is an important component of conflict resolution. As leaders, it is our responsibility to hold people accountable to decisions that have been made to resolve a conflict. By truly resolving conflicts and restoring relations, all parties can move forward to develop trusting relationships that breed cooperation and productivity.

As leaders we need to be an example to others of how

Addressing the Issue

to manage conflict in a productive way. behind his or her back. In the professional workplace, assault usually does not involve physical violence, although it could if tempers flare. It also is possible that conflicts may result in litigation as a form of attack. Although this usually does not occur in the professional workplace between individuals, I have seen it between companies. This points to the importance of having solid contractual agreements with our vendors. Peacemaking response. Sande outlines six peacemaking responses. The first is to overlook an offense. Sometimes the offense is so minor that it is not worth getting mad or irritated; it’s better to just overlook it. I often tell people not to empower the weaknesses of others. It will improve your sense of well-being rather than be irritated at someone who may not even know they have offended you. Some disputes are just not worth it.

and responsibilities in the workplace can be helpful in such cases. Again, this is done in private without involving others. In some instances, if two individuals in conflict cannot resolve their issue in private, then outside mediation may be necessary. In the workplace, I first recommend that conflicting individuals try to resolve their issue in private. If that is not effective, then I may need to jump in as mediator. Arbitration is another useful peacemaking tool cited by Sande, and it’s a role I am often asked to play when there are differing opinions about how to accomplish an important task. In our health system, this multiplicity of views is evident in our efforts to standardize processes and procedures across multiple facilities. After looking at the options from a quality, safety and cost perspective, I often find myself making a decision on how we will move forward to achieve these

As we look at these six possible peacemaking responses, the first three are done privately without outside intervention. The last three responses involve outside intervention to help resolve the conflict. In all cases, the outcome is intended to address the issues, resolve the conflict and move on. This does not mean that there will not be conflicts in the future; if we look at our own lives, whether in the workplace or personally, we know that conflicts reoccur. The goal is to learn from these clashes and hopefully avoid similar conflicts in the future. Conflict can and should be a growth opportunity. One way to understand conflict is to realize that it often comes down to a choice—that is, how we respond to these clashes? Do we run in flight? Do we attack? Or can we learn to approach conflict in a healthy way aimed at resolution and reconciliation? As leaders, we need to be an example to others of how to manage conflict in a productive manner. Indeed, when we help others resolve conflict, we are fulfilling our role as servant leaders. Think about the possibilities in both the workplace and in our private lives if we can put these practices into place. Correct conflict resolution is hard work, but is worth the effort.

complexity of the drug and the length of the administration. Again, pharmacy has stumbled and in most cases has failed both to accurately bill for these products or to recoup the cost of products and services in internal facility transfer. (The facility is being paid for the visit to the facility and for medication administration, and the cost of pharmacy products and services is included in this payment.) Is it too late to address these flawed reimbursement practices? Not at all! Here’s some action steps that you can start taking now, working in concert with your billing department:

• Ensure accurate and complete billing of all drugs and biologics as well as all supplies used. • Audit the crosswalks or software used to convert the dose of product administered to CMS-assigned billing units. Fix any problems discovered. Commercial software products are available to help with this. • Audit medication administration billing to determine its accuracy. If poor documentation is a culprit, fix the problem. • Create a mechanism with finance for internal transfer of the share

of payment being received for bundled payments, including the pharmacy overhead as well as the product cost. • Ambulatory care should be an important focus. IT solutions such as computerized prescriber order entry, electronic health records and definitely any system that supports documentation must extend their reaches into these areas. The online version of this article offers you an opportunity to comment and to share your thoughts on the blog. Let’s hear from you!!

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4

Emergency Cardiovascular Pharmacotherapy: A Point-of-Care Guide

Barbara S. Wiggins ASHP, 2012 The purpose of this text is to provide instruction as well as to serve as a reference to assist pharmacists and other health care practitioners to become optimal members of a code team. This point-of-care reference offers information on the various treatment modalities used to manage patients with various cardiovascular emergencies.

5

Fine Particles in Medicine and Pharmacy

Egon Matijevic Springer, June 16, 2011 Pharmaceutical manufacture is very exacting—for example, drugs must be uniform in size, shape, efficacy, bioavailability and safety. The presence of different polymorphs in drug production is a serious problem, since different polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density and flow properties. This book discusses particle size, shape and composition and how they determine the choice of polymorph of a drug.

6

Fundamentals of Pharmacognosy and Phytotherapy, Second Edition

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

7

Handbook on Injectable Drugs: 16th Edition

Lawrence A. Trissel ASHP, October 27 , 2010 All 349 monographs have been updated in this edition, including six new monographs. For each monograph, compatibility, stability, storage and preparation data have been referenced and presented.

8

The APhA Complete Review for Pharmacy, Ninth Edition

American Pharmacists Association APhA, January 15, 2012

Preparing for the NAPLEX® by reviewing all of the material from each pharmacy school course would be overwhelming. A far better approach would be to study only the information most relevant to the exam, summarized in abbreviated bullet format—and that’s what this book contains. PPN0612

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Managing Anemia in Patients

With Chronic Kidney Disease AMY E. LODOLCE, PHARMD, BCPS Assistant Director

COURTNEY KRUEGER, PHARMD, BCPS Clinical Assistant Professor Drug Information Group University of Illinois at Chicago College of Pharmacy Chicago, Illinois

C

hronic kidney disease (CKD), which is increasing sing in prevalence, results in significant morbidity, mortality, and health care costs in the United States.1 According to data

collected from the National Health and Nutrition Examination Survey (1999 to 2004), 11.5% of adults (more women than men) have evidence of CKD.2,3 These estimates rise in patients with diabetes and hypertension, with more than 35% of adults with diabetes and more than 20% of those with hypertension suffering from CKD.

According to the National Kidney Foundation (NKF), the presence of kidney disease should be established and assigned a level according to the NKF Kidney Disease Outcomes Quality Initiative (KDOQI) classification, which is summarized in Table 1.1 Diagnosis is established by the presence of structural or functional abnormalities with or without decreased glomerular filtration rate (GFR) or a GFR less than 60 mL per

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minute per 1.73 m2 with or without kidney damage, for a period of at least 3 months.

Causes and Consequences Of Anemia and Iron Deficiency Anemia, defined in the KDOQI guidelines as a hemoglobin less than 13.5 g/dL in adult men and less than 12 g/dL in adult women, is a common complication of

P H A R M AC Y P R AC I C E N E WS • J U N E 2 0 1 2

1

Table 1. KDOQI Classification Of CKD GFR (mL/min/1.73 m2)

Stage 1

≼90

2

60-89

3

30-59

4

15-29

5

<15 or receiving dialysis

CKD, chronic kidney disease; GFR, glomerular filtration rate; KDOQI, Kidney Disease Outcomes Quality Initiative Based on reference 1.

CKD. Its prevalence increases with increasing stage of CKD, such that nearly all patients with stage 5 CKD are affected.4 Anemia leads to impaired quality of life (QoL) and is a risk factor for early death among patients with CKD.5 Symptoms associated with anemia include fatigue, depression, decreased exercise tolerance, dyspnea, and symptoms of cardiac dysfunction. The primary cause of anemia in such patients is deficiency of erythropoietin as a result of impaired production in the kidney. Erythropoietin is involved in increasing the production of reticulocytes, restoring normal red blood cell mass, and correcting hypoxia in the tissues. Iron deficiency also plays a role in anemia of CKD in that patients have reduced iron intake, impaired intestinal absorption of iron, blood loss (among dialysis patients), and an increase in iron requirements when erythropoiesis-stimulating agents (ESAs) are given.5 Patients with CKD may have absolute iron deficiency due to little or no stored iron, or functional iron deficiency, which occurs when erythropoiesis increases due to ESA use.5,6 Ferritin concentration and transferrin saturation are indices commonly used to evaluate iron stores and assess for iron-deficiency anemia.4,6 Ferritin is an indirect measure of iron stores, whereas transferrin is the carrier protein for iron.7 In the KDOQI guidelines, the goal serum ferritin level is greater than 100 ng/mL (>200 ng/mL in patients undergoing dialysis), and the target transferrin saturation is greater than 20%.4

Treatment Approaches Iron therapy and ESAs are the mainstay anemia treatment in patients with CKD.4 The latest guidelines from the KDOQI were published in 2006, with an update relating to target hemoglobin levels published in 2007 in response to literature regarding ESA therapy (see below).8 According to the guidelines, clinicians must be careful in their selection of the target hemoglobin level and the level at which ESA therapy is initiated, considering risks and benefits of ESA therapy. Potential benefits of therapy include a reduced need for transfusion and improved QoL, whereas risks

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include the potential for cardiac events and mortality. Although selection of the target hemoglobin should be individualized, the guidelines suggest a target of 11 to 12 mg/dL for patients with CKD (both dialysis and non-dialysis).

IRON THERAPY Patients with CKD frequently experience iron deficiency, especially those with end-stage renal disease (ESRD) who are receiving hemodialysis.5 Hemodialysis results in losses of 6 to 7 mg of iron per day of dialysis, which is compounded by physiologic losses and loss from periodic venipuncture.6 It is estimated that patients receiving hemodialysis can have annual iron losses that exceed 1.5 to 3 g, which exceeds total body stores.5,6 Iron is available in oral or parenteral dosage forms. Oral iron is relatively inexpensive and easy to administer; however, there are some limitations to its use.9 Gastrointestinal (GI) adverse events (AEs) such as constipation, dyspepsia, bloating, nausea, diarrhea, and heartburn may affect up to 20% of patients. These GI effects can be minimized if iron supplements are taken with food, but the presence of food will decrease iron absorption. Other factors that can decrease absorption are the use of phosphate binders or acid suppressive therapy, as well as the presence of hepcidin (produced by the liver during inflammation).10 Frequent dosing requirements (often 3 times per day) that can result in poor adherence also can limit the use of oral iron. Furthermore, the use of ESAs can increase the demand for iron beyond the amount that can be given orally. Rozen-Zvi et al conducted a systematic review and meta-analysis to compare IV and oral iron supplementation for the treatment of anemia in patients with stage 3 to 5 CKD.11 Thirteen randomized controlled trials comparing oral iron with IV iron were included in the analysis. The primary outcome of interest was the absolute hemoglobin level or change in hemoglobin from baseline after 2 to 3 months of therapy. There were a variety of secondary outcomes including allcause mortality, cardiovascular morbidity and mortality, bacterial infections, need for renal replacement therapy, iron indices, ESA dose, hospitalizations, QoL, and need for transfusion. Efficacy analyses were conducted separately for patients who were receiving dialysis and those who were not. The results revealed that the hemoglobin level was significantly increased among patients on dialysis (n=7 trials) who received IV iron therapy compared with those who received oral iron therapy (weighted mean

Table 2. Summary of IV Iron Preparations Preparation

Usual Adult Dose

Administration

Notes

Iron dextran (Infed, Watson; Dexferrum, American Regent)

Total dose (mL)=0.0442 × (desired hemoglobin – observed hemoglobin) × lean body weight (kg) + (0.26 × lean body weight); small doses (such as 50-100 mg), given regularly until response

Given undiluted by slow IV injection (≤50 mg/min)

• Due to the potential for anaphylaxis, a test dose is required prior to the first therapeutic dose. • Resuscitative medication and personnel should be available each time iron dextran is administered.

Sodium ferric gluconate (Ferrlecit, Sanofi-aventis; Nulecit, Watson)

Hemodialysis recipients: 125 mg IV (expressed as elemental iron); most patients will require a minimum dose of 1,000 mg elemental iron over 8 dialysis sessions

May be diluted and given by slow IV infusion over 1 h or given undiluted by slow IV injection at a rate up to 12.5 mg/min at end of dialysis

• Has been associated with hypotension and flushing; reducing the dose and infusing the drug over 4 h has been shown to reduce these effects.

Iron sucrose (Venofer, American Regent)

Hemodialysis recipients: 100 mg at each consecutive dialysis session for a total cumulative dose of 1,000 mg Non-dialysis chronic kidney disease: 200 mg on 5 different occasions within 14 d

Given undiluted by slow IV injection at a rate ≤20 mg/min (over 2-5 min); may also be given by IV infusion directly into the dialysis line over ≥15 min after dilution in normal saline.

• Slow injection is necessary to reduce the risk for hypotension.

Ferumoxytol (Feraheme, Amag)

510 mg IV × 1 dose, followed by 510 mg IV 3-8 d later

Given undiluted at a rate ≤1 mL (30 mg)/sec

• Regimen may be repeated after 1 mo if needed. • This preparation is relatively well tolerated and may be given rapidly. • There are no published comparative studies with other IV iron preparations.

ESAs, erythropoiesis-stimulating agents Based on references 4, 10, and 12-14.

difference [WMD], 0.83 mg/dL; 95% confidence interval [CI], 0.09-1.57).11 Furthermore, the ESA dose decreased significantly (WMD, –28.21 units/kg per week; 95% CI, –42.12 to –14.3) and ferritin levels significantly increased (WMD, 172.34 ng/mL; 95% CI, 111.31233.38) in patients treated with IV iron. No changes were found with regard to transferrin saturation, and data were not available for QoL. In patients with CKD not receiving dialysis, a small increase in hemoglobin associated with IV iron therapy was noted (WMD, 0.31 g/dL; 95% CI, 0.09-0.53); however, the authors judged this change to be clinically unimportant. Ferritin levels (WMD, 213.35 ng/mL; 95% CI, 56.5-370.2) and transferrin saturation (WMD, 9.45%; 95% CI, 1.9%-17.1%) were significantly increased in the IV iron group. QoL was reported in a single trial, and IV iron was associated with an improvement among patients not receiving dialysis. Safety was reported for the combined population, and there were no differences in all-cause mortality, serious AEs, or need for transfusion between the oral and IV iron therapy groups.11 Hospitalization rate was reported in a single paper, with no differences found between groups. No data were available for cardiovascular morbidity and mortality and bacterial infections.

There was no difference in the need for renal replacement therapy among patients who were not receiving dialysis initially. The authors concluded that IV iron therapy was more effective than oral iron therapy for improving hemoglobin levels in patients receiving dialysis, but they noted that the effect among those not receiving dialysis was small and clinically unimportant. Either oral or IV iron therapy may be used for initial management of patients not receiving dialysis and those receiving peritoneal dialysis, but IV iron therapy is recommended strongly for patients undergoing hemodialysis.4 The KDOQI guidelines do not recommend any particular preparation of IV iron, and these products generally are considered equivalent on a milligram-per-milligram basis (Table 2).4,10,12-14 Although iron dextran regimens have been administered safely, it is important to consider that with the information available today on the safety profile of sodium ferric gluconate and iron sucrose, many clinicians would consider these newer agents as first-line therapy.7

ESA THERAPY Epoetin alfa (Epogen, Amgen; Procrit, Janssen) and darbepoetin alfa (Aranesp, Amgen) are effective in

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raising hemoglobin,4 but their use e y has come under increased scrutiny in recent years. In March 2007, the FDA required that a boxed warning be added to the ESA product labels and that updates be made in the “warnings” and “dosage and administration” sections.15 cIn June 2011, the FDA again recommended updating of the label; these changes are summarized in Table 3.16 In addition to the labeling changes, nges, as of escribed under February 2010, ESAs also are prescribed a risk evaluation and mitigation strategy (REMS).17 Components of the REMS include a medication guide for all patients (approved in 2008) and a prescribing program for patients receiving the drugs for cancerassociated anemia. The ESA labeling changes specific for CKD were based largely on results from 2 trials published in 2006—CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) and CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta).18,19 In the CHOIR trial, patients with CKD not receiving dialysis were randomized to epoetin alfa to achieve a target hemoglobin of 13.5 g/dL (n=715) or 11.3 g/dL (n=717).18 The primary end point was the time to the composite of death, myocardial infarction (MI), hospitalization for congestive heart failure (CHF), or stroke. The data and safety monitoring board stopped the trial early when they realized that it was unlikely that the high-hemoglobin group was going to show a benefit. The median study duration was 16 months. The primary end point occurred in more patients in the high-hemoglobin group (125 vs 97; hazard ratio [HR], 1.34; 95% CI, 1.03-1.74; P=0.03). The results were driven by a higher incidence of death and CHF hospitalization in the high-hemoglobin group. No differences were found in QoL between groups, and more patients in the high-hemoglobin group reported at least 1 AE (376 of 686 [54.8%] vs 334 of 688 [48.5%]; P=0.02). The authors concluded that a target hemoglobin of 13.5 g/dL was associated with greater risk for harm and no improvements in QoL compared with a target of 11.3 g/dL. A secondary analysis of data from CHOIR found that significantly more patients randomized to the high-hemoglobin group were unable to achieve target hemoglobin concentrations and required high doses of epoetin alfa.20 Patients who were able to achieve hemoglobin targets (in both groups) had

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better o outcomes than those who could not. Furth Furthermore, no increased risk was found with high-hemoglobin targets in patients who achieved their randomized target. The CREATE trial randomized patients with C CKD (GFR, 15-35 mL/min per 1.73 m2) to epo epoetin beta (not available in the United State States) to target hemoglobin levels of 13 to 15 g/dL (n=301) or 10.5 to 11.5 g/dL 19 (n= The primary end point was (n=302). tim to first cardiovascular event (comtime po posite of sudden death, MI, acute heart fa failure, stroke, transient ischemic attack, an angina resulting in hospitalization, complic plication of peripheral vascular disease, or arrhythmia requiring hospitalization). There was no significant difference between groups in incidence of the primary end point (HR, 0.78; 95% CI, 0.531.14; P=0.20). QoL improved significantly with target hemoglobin levels of 13 to 15 g/dL. Overall, there were no significant differences in AEs between groups, but the incidences of headache and hypertensive episodes were higher in the 13- to 15-g/dL group. The authors concluded that complete correction of hemoglobin level did not lead to a reduction in the risk for cardiac events. A third pivotal trial was published after the ESA labeling changes. TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) differed from CHOIR and CREATE in that it was a randomized, double-blind, placebo-controlled trial. 21 Patients with CKD and type 2 diabetes were randomized to darbepoetin alfa to achieve a hemoglobin level of 13 g/dL (n=2,012), or placebo (n=2,026) with rescue darbepoetin alfa if the hemoglobin fell below 9 g/dL. The primary end points were the composite of death or a cardiovascular event (nonfatal MI, CHF, stroke, or hospitalization for myocardial ischemia) or the composite of time to death or ESRD. There were no significant differences between groups in terms of death or a cardiovascular event (HR, 1.05; 95% CI, 0.94-1.17; P=0.41) or for death or ESRD (HR, 1.06; 95% CI, 0.951.19; P=0.29). Fatal or nonfatal stroke occurred in almost twice as many patients assigned to darbepoetin (101 vs 53; HR, 1.92; 95% CI, 1.38-2.68; P<0.001). Transfusions were significantly more common in placebo recipients (496 vs 297; P<0.001). No clinically important differences in QoL were reported between the groups. The authors concluded that the use of darbepoetin in patients with type 2 diabetes and CKD was not associated with improvements in the primary

Table 3. Summary of ESA Labeling Changes

end point of death or cardiovascular events, or death or development of ESRD. However, they pointed out that such therapy was associated with an increased incidence of stroke, and they concluded the risk associated with therapy outweighed potential benefits for many patients. Results from CHOIR, CREATE, and TREAT reveal that ESA therapy may be associated with harm in patients with CKD, and that targeting high-hemoglobin levels does not appear to be beneficial. Unanswered questions remain, however, with respect to a precise hemoglobin target and optimal dosing of ESAs. The KDOQI guidelines have not been updated to reflect information in the TREAT trial; however, the CHOIR and CREATE papers were among those considered when the hemoglobin target was reduced to 11 to 12 g/dL.4,8 Therefore, there is still a place in therapy for ESAs to treat anemia in patients with CKD. Subcutaneous therapy is recommended for patients who are not receiving dialysis, whereas IV therapy is suggested for those receiving hemodialysis, based on convenience of administration.4 Frequency of administration and dose are left to the discretion of the prescriber and should be based on the clinical condition of the patient. Red blood cell transfusions are an option for the treatment of anemia in patients with CKD; however, their use should be judicious because patients may develop antibodies that may affect a kidney transplant. There is no defined hemoglobin level at which transfusion is recommended. Peginesatide (OMONTYS, Affymax/Takeda), a new ESA, was approved by the FDA in March 2012 for anemia in patients receiving dialysis.22,23 Although peginesatide stimulates the erythropoietin receptor, it is not structurally similar to erythropoietin.24 Two clinical trials (EMERALD 1 and 2) support the noninferiority of peginesatide to epoetin alfa or beta; however, complete publication of these trials is lacking at this time.23,24 One advantage of peginesatide is its once-monthly dosage regimen; the initial dose is 0.04 mg/kg IV or subcutaneously once monthly. Detailed dosage recommendations for converting patients from epoetin or darbepoetin are provided in the package labeling.23 Initial data indicate that peginesatide has reasonable efficacy and safety; however, post-marketing studies evaluating cardiovascular safety have been required by the FDA.25,26 The 2 clinical trials evaluating peginesatide for anemia in non-dialysis CKD patients (PEARL 1 and 2) found an increased risk for cardiovascular events; thus, peginesatide should not be used for patients who are not receiving dialysis.24

Section

Key Label Information Related to CKD

Boxed warning

•

•

• Dosing

• • •

ESAs increase the risk for death, serious cardiac events, and stroke when the target hemoglobin is >11 g/dL. No trial has determined an ESA dose or target hemoglobin level that does not increase risk. Use the lowest ESA dose to avoid the need for RBC transfusions. Monitor hemoglobin levels at least weekly until stable. Consider initiating ESAs when the hemoglobin is <10 g/dL. Use patient-specific dosing with the lowest dose possible to avoid RBC transfusions.

CKD, chronic kidney disease; ESAs, erythropoiesis-stimulating agents; RBC, red blood cell Based on reference 16.

Medication Management In Patients With CKD Dialysis patients take an average of 11 medications, and are believed to have the highest pill burden of all chronically ill patients.27 The use of a large number of medications can result in reduced adherence to the medication regimen and decreased QoL.27-29 In addition to a high pill burden, drug-related problems occur in dialysis patients at a high rate. A 2005 study found a rate of 4 drug-related problems per dialysis patient.30,31 Improvements in patient education and continuity of care may help reduce drug-related problems in dialysis or CKD patients. Pai and colleagues randomized 104 hemodialysis patients to in-depth pharmaceutical care or usual care over the course of 2 years.32 Patients receiving pharmaceutical care underwent a program of drug therapy review that included patient education, health care provider education, and compilation of a drug profile, as well as a review of the medical and laboratory records with a pharmacist every 8 weeks. At the end of the study period, patients in the pharmaceutical care group had fewer hospitalizations and a 14% reduction in the number of medications they used. The investigators identified and resolved 530 drug-related problems in this group. This study suggests that detailed patient education and proactive pharmacist intervention not only reduces the pill burden in dialysis patients but also promotes appropriate medication use and improves medical outcomes. The continuity of care for patients with CKD often is interrupted by hospitalization. Hospitalized CKD patients have alterations in anemia management and decreased hemoglobin levels.33 Other drug-related

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complications also can occur due to problems with continuity of care. In fact, Ong and colleagues found that 65% of drug-related problems in patients with CKD were the result of incomplete medical information transfer between health care settings.34 Thus, improved medication reconciliation during care transitions has the potential to dramatically reduce drug-related problems in patients with CKD. St. Peter recently developed recommendations for the dialysis medication reconciliation team.31 Within 12 to 24 hours of admission the inpatient team should be provided with a list of current medications, discontinued medications, drug allergies, and adverse reactions, as well as any other relevant information. At discharge, the dialysis medication reconciliation team should be responsible for obtaining the list of discharge medications. The list must be reviewed in detail for discontinued medications, dosage changes, or new medications; the rationale for any medication changes should be documented.

Conclusion Appropriate management of anemia in patients with CKD requires iron supplementation and ESA therapy. IV iron therapy is recommended for patients receiving hemodialysis; however, oral iron supplementation may be appropriate for non-dialysis patients or those receiving peritoneal dialysis. The KDOQI guidelines suggest a target hemoglobin level of 11 to 12 g/dL in patients receiving ESA therapy; however, package labels for ESA agents no longer recommend a target hemoglobin range for ESA therapy. Medication management for patients with CKDassociated anemia is an important role for pharmacists. Patients with CKD often have complicated medication regimens and frequent hospitalizations, making patient education and medication reconciliation key components of successful pharmacotherapy.

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References 1.

National Kidney Foundation. Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. http://www.kidney. org/professionals/KDOQI/guidelines_ckd/toc.htm. Accessed May 10, 2012.

2. Centers for Disease Control and Prevention. National CKD Fact Sheet 2010. http://www.cdc.gov/diabetes/pubs/factsheets/kidney.htm. Accessed May 10, 2012. 3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health: National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). Kidney and Urologic Diseases Statistics for the United States. http://kidney. niddk.nih.gov/kudiseases/pubs/kustats/. Accessed May 10, 2012. 4. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(5 suppl 3):s11-s145. 5. Hayat A. Safety issues with IV iron products in the management of anemia in chronic kidney disease. Clin Med Res. 2008;6(3-4):93-102. 6. Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic kidney disease. Nat Rev Nephrol. 2010;6(12):699-710. 7. Hudson JQ. Chapter 53. Chronic Kidney Disease: Management of Complications. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey ML, eds. Pharmacotherapy: A Pathophysiologic Approach, 8th ed. http://www.accesspharmacy.com.proxy.cc.uic. edu/content.aspx?aid=7981679. Accessed April 25, 2012. 8. NKF KDOQI guidelines. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update on hemoglobin target. http://www.kidney.org/professionals/KDOQI/guidelines_anemiaUP/index.htm. Accessed May 10 2012. 9. Macdougall IC. Iron supplementation in the non-dialysis CKD (ND-CKD) patient: oral or intravenous? Curr Med Res Opin. 2010;26(2):473-482. 10. Schwenk MH. Ferumoxytol: a new IV iron preparation for the treatment of iron deficiency anemia in patients with chronic kidney disease. Pharmacotherapy. 2010;30(1):70-79.

11. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg O, Gafter U. IV versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis. Am J Kidney Dis. 2008;52(5):897-906.

23. OMONTYS [package insert]. Palo Alto, CA: Affymax; 2012.

12. McEvoy GK, ed. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2012.

25. Affymax and Takeda announce FDA approval of OMONTYS (peginesatide) injection for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. http://www.omontys.com/download/OMONTYS%20PDUFA%20 Approval%20Release.pdf. Accessed May 10, 2012.

13. Venofer [package insert]. Shirley, NY: American Regent; 2011. 14. Feraheme [package insert]. Lexington, MA: AMAG Pharmaceuticals; 2012. 15. US Food and Drug Administration. Information for healthcare professionals: erythropoiesis stimulating agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)] (3/2007). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126485.htm. Accessed May 10, 2012. 16. US Food and Drug Administration. FDA drug safety communication: modified dosing recommendations to improve the safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease. http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Accessed May 10, 2012. 17. US Food and Drug Administration. Information on erythropoiesis-stimulating agents (ESA) epoetin alfa (marketed as Procrit, Epogen) darbepoetin alfa (marketed as Aranesp). http://www. fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109375.htm. Accessed May 10, 2012. 18. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098. 19. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with CKD and anemia. N Engl J Med. 2006;355(20):2071-2084.

24. Macdougall IC. New anemia therapies: translating novel strategies from bench to bedside. Am J Kidney Dis. 2012;59(3):444-451.

26. Locatelli F, Fishbase S, Macdougall IC, et al. Safety results from two phase 3 studies of peginesatide treatment for anemia in hemodialysis (HD) patients. J Am Soc Nephrol. 2011;22. Abstract 477. 27. Chiu YW, Teitelbaum I, Misra M, de Leon EM, Advise T, Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol. 2009;4(6):1089-1096. 28. Browne T, Merighi JR. Barriers to adult hemodialysis patients’ self-management of oral medications. Am J Kidney Dis. 2010;56(3):547-557. 29. Mason NA. Polypharmacy and medication-related complications in the chronic kidney disease patient. Curr Opin Nephrol Hypertens. 2011;20(5):492-497. 30. Manley HJ, Cannella CA, Bailie GR, St. Peter WL. Medicationrelated problems in ambulatory hemodialysis patients: a pooled analysis. Am J Kidney Dis. 2005;46(4):669-680. 31. St. Peter WL. Improving medication safety in chronic kidney disease patients on dialysis through medication reconciliation. Adv Chronic Kidney Dis. 2010;17(5):413-419.

20. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alfa dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791-798.

32. Pai AB, Boyd A, Depczynski J, Chavez IM, Khan N, Manley H. Reduced drug use and hospitalization rates in patients undergoing hemodialysis who received pharmaceutical care: a 2-year randomized, controlled study. Pharmacotherapy. 2009;29(12):1433-1440.

21. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032.

33. Heung M, Mueller BA, Segal JH. Optimizing anemia management in hospitalized patients with end-stage renal disease. Ann Pharmacother. 2009;43(2):276-282.

22. US Food and Drug Administration. FDA approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. cfm?fuseaction=Search.DrugDetails. Accessed April 25, 2012.

34. Ong SW, Fernandes OA, Cesta A, Bajcar JM. Drug-related problems on hospital admission: relationship to medication information transfer. Ann Pharmacother. 2006;40(3):408-413.

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Presents

The Summer issue of

Bridging the gap between the hospital and post-discharge care

In This Issue Ask the Expert

4

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

Volume 1 • Number 2 • Spring 2012

Reports from the PBMI conference

Cost Containment In Specialty Pharmacy

Q&A

5

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

Practice Profile

6

The Apothecary Shops applies a personal touch to disease management.

Operations & Mgmt

11

New study underscores savings potential of alternate-site infusions.

Clinical

18

Anti-EGFRs linked to increased risk for thromboembolic events.

Disease State Spotlight

21

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

Excelera Eyes Market Growth For Hospitals

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

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

see CONTAINMENT, page 10

see INTERACTIONS, page 17

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

Do MTX Drug Interactions Fall Below Radar?

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Each issue will provide essential clinical and business information for stakeholders in specialty pharmacies, home infusion providers, insurers and managed care organizations.

see EXCELERA, page 8

Breadth of problem is ‘scary’

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

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

Bridging the gap between the hospital and post-discharge care

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