The November 2011 Digital Edition of Pharmacy Practice News by McMahon Group

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The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition

Volume 38 • Number 11 • November 2011

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Jail time, loss of licensure questioned

The ‘Second Victims’ Of Medication Errors Begin To Gain Support

ore than three decades later, Dennis Tribble, PharmD, is still haunted by the memory of one of the worst cases of his professional life. Now the chief pharmacy officer for Baxa Corporation, Dr. Tribble was at that time a pharmacist in a hospital he prefers not to name. “I had been practicing for a number of years by that time. I failed to note that an adult dose of quinine had been prescribed for a pair of 10-year-old twins suffering from malaria. It put those kids into heart block and almost killed them,” said Dr. Tribble, his voice shaking. What support did his hospital provide? “One of my bosses sat down with me and said, ‘I think you’ve already beat yourself up a whole

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see Second Victims, page 79

in this issue Up Front

Your Letters ASHP defends actions on jailed pharmacist.

Clinical

Hem/Onc Pharmacy New prostate cancer drug data deemed practice-changing.

NEW COLUMN

Journal Scan Experts comment on latest pharmacistfocused research.

Technology

Automation A telepharmacy success story.

Profiles in persistence

Operations & Mgmt

Hard Work Pays Off: 2011 ASHP Lit Awards To Be Given at Midyear

Wicked Change

he five winners of the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation’s 2011 literature awards will be recognized during the Midyear Clinical Meeting in New Orleans. To honor their extraordinary contributions, Pharmacy Practice News spoke to each of them.

Supply Chain

Christine A. Sorkness Award for Sustained Contributions

Utility and Stability of a Generic Sodium Ferric Gluconate in Complex With Sucrose

In the mid-1970s, an internist suggested to a young assistant professor of pharmacy at the State University of New York in Buffalo that she launch one of the first pharmacist-managed anticoagulation clinics in the United States. “My initial reaction was abject fear,” recalled

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see HARD WORK, page 7

Oncology Drug Shortage Worsens; ‘Mayhem’ Cited

Kyle E. Hultgren, PharmD, on designing a framework for organizational change.

Policy

n mid-September, Melissa Dinolfo, PharmD, BCOP, director of pharmacy and clinical operations at Santa Monica, Calif.-based Premiere Oncology, did something that she’d never had to do before in her career as an oncology pharmacist: tell a treating oncologist that she could not provide a patient with her next dose of chemotherapy. The patient, a 44-year-old woman with advanced breast cancer, had “pretty well blown through all the other regimens we have,” said Dr. Dinolfo. “But she’s young, she has kids. She’s starting to dwindle, and she’s not well enough for a clinical trial but she still wants to fight.”

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Duke University’s team approach to coping with drug shortages.

Xigris Withdrawn After Study Shows No Benefit in Severe Sepsis

See page 20

Premixed Products Improve Safe Medication Practices See page 56

see DRUG SHORTAGE, page 22

rug manufacturer Eli Lilly and Co., has withdrawn drotrecogin alfa (Xigris) from the market in the wake of the release of the PROWESS-SHOCK trial, which found no statistically significant reduction in 28-day all-cause mortality in patients treated with the sepsis drug compared with placebo. The company advised that patients currently taking drotrecogin alfa should stop use, and physicians should not start new patients on the medication.

PROWESS-SHOCK was launched in 2008 as a condition for continued marketing of the drug in Europe, when the European Medicines Agency (EMA) concluded that the initial efficacy results of the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial had not been replicated in further studies. That initial trial had led to FDA approval for drotrecogin alfa in 2001.

•

see XIGRIS, page 65

New Products Cooper-Atkins releases enhanced TempTrak™ software, version 4.5.

Baxa unveils SureConnect®: Closed System

See page 78

Pharmacy Practice News • November 2011

Up Front 3

Capsules Zoledronic Acid Eases Pain From Bone Metastases

surf

NOVEMBER 2011

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Pharmacists and Anesthesiologists Partner To Improve OR Outcomes 2. Compatibility of Commonly Used Intravenous Drugs 3. Pharmacists Phone Home for MTM Service 4. Pop-up e-Reminders At Point of Care May Boost HCAHPS Scores 5. Technology Rollouts Increase Efficiency at Christiana System Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘This [colchicine dosing] algorithm is definitely something that practicing pharmacists should be aware of and should discuss with prescribers when appropriate.’

brief course of the bisphosphonate zoledronic acid (Zometa, Novartis) significantly decreased the pain associated with bone metastases, according to a study presented at the European Multidisciplinary Cancer Congress, held recently in Berlin (abstract 3062). Patients with multiple myeloma and solid tumors experienced a decline of more than 50% in pain scores within four days of beginning treatment with zoledronic acid. The greatest analgesic effect occurred in patients with elevated serum C-telopeptide (CTX), a marker of bone turnover. “In symptomatic bone metastases with significant pain refractory to standard analgesics and radiotherapy, loading-dose zoledronic acid represents a simple and nontoxic treatment to obtain significant pain relief in a very short time,” wrote study author Filip Geurs, MD, of Regionaal Ziekenhuis Sint-Maria in Halle, Belgium, in a poster presentation. Clinical trials have yielded mixed results on the potential of bisphosphonates to relieve pain from bone metastases (J Clin Oncol 2004;22:3587-3592), but there is little evidence on the efficacy of zoledronic acid in particular. That is why the study examined the impact of zoledronic acid on pain associated with bone metastases in patients with multiple myeloma or solid tumors. All 20 patients in the study had diffuse metastatic disease and severe pain (visual analog scale [VAS] score >4) and were treated with a loading dose (4 mg) of zoledronic acid on four consecutive days. The investigators reported that at baseline, patients’ CTX values averaged 896 pg/dL and their mean pretreatment pain score was 7.95 on the 10-point VAS. By the fourth day of treatment, the mean CTX level had declined to 227.5 pg/dL (P<0.001), and VAS scores averaged 3.39 (P<0.001). The drug was also well tolerated. Patients with substantially elevated CTX at baseline (>800 pg/dL) derived the most pain relief from treatment with zoledronic acid. Three patients with normal baseline levels of CTX had no analgesic effect with zoledronic acid, which also failed to reduce their CTX levels. Patients who responded to treatment, however, experienced an average decline in serum levels of the biomarker of 62% from baseline. “Bone metastases often are associated with unbearable and persistent pain that often does not respond to standard pain therapy regimens including opiates,” said Jennifer Goldman-Levine, PharmD, professor of pharmacy practice, Massachusetts College of Pharmacy and Health Sciences, in Boston. “Bisphosphonates have antiresorptive effects that reduce bone cancer pain. This study adds to the growing literature support of zoledronic acid to decrease pain in patients with bone metastasis. Pain management options are needed to hopefully improve functionality, quality of life and survival in these patients.” —PPN Staff

—Geoffrey C. Wall, PharmD

See article, page 64

CORRECTION: In the educational review “Sedation in the ICU: Shifts and Strategies,” which appeared in our July 2011 issue, there were several errors. Please go to pharmacypracticenews.com (“Supplements” menu bar) to see the corrected version.

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Volume 38 • Number 11 • November 2011 • pharmacypracticenews.com

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Where does your topical thrombin come from?

Graphics are for illustrative purposes only. Not intended to depict actual manufacturing process or application method. Thrombin products are for topical use only.

INDICATION

IMPORTANT SAFETY INFORMATION FOR RECOTHROM

5(&27+520 7KURPELQ WRSLFDO 5HFRPELQDQW 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 WHFKQLTXHV VXFK DV VXWXUH OLJDWXUH RU FDXWHU\ LV LQHIIHFWLYH RU LPSUDFWLFDO

Contraindications Â&#x2021; 7RSLFDO XVH RQO\ Â˛ '2 127 ,1-(&7 GLUHFWO\ into the circulatory system Â&#x2021; 'R QRW XVH IRU WKH WUHDWPHQW RI PDVVLYH RU brisk arterial bleeding or in patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins

References: 1. RECOTHROM [package insert]. Seattle, WA: ZymoGenetics, Inc. 2. Evithrom [package insert]. Somerville, NJ: Ethicon, Inc. 3. Thrombin-JMI [package insert]. Bristol, TN: King Pharmaceuticals, Inc. RECOTHROM is a registered trademark of ZymoGenetics, Inc. ÂŠ2011 ZymoGenetics, Inc. All rights reserved. RT396-01, July 2011

Warnings and Precautions Â&#x2021; 3RWHQWLDO ULVN RI WKURPERVLV LI DEVRUEHG systemically Â&#x2021; ,Q SDWLHQWV ZLWK NQRZQ K\SHUVHQVLWLYLW\ WR VQDNH proteins, there may be potential for allergic reaction

RECOTHROM is recombinant human thrombin RECOTHROM is human thrombin produced via recombinant DNA technology using a genetically PRGLĂ&#x20AC;HG &KLQHVH KDPVWHU RYDU\ &+2 FHOO OLQH1 Other thrombins are derived from human or bovine plasma2,3 â&#x20AC;&#x201C; In a phase 3 study comparing RECOTHROM to bovine thrombin, the overall incidence of adverse events was similar between treatment groups â&#x20AC;&#x201C; RECOTHROM has not been compared to human plasma-derived thrombin in clinical trials

Know your thrombin inside and out Visit RECOTHROM.com

Adverse Reactions Â&#x2021; 7KH VHULRXV DGYHUVH HYHQW WKDW RFFXUUHG LQ Â&#x2022; Q RI SDWLHQWV H[SRVHG WR 5(&27+520 LQ FRPSOHWHG FOLQLFDO WULDOV ZDV DWULDO Ă&#x20AC;EULOODWLRQ 7KH most common adverse events reported in these trials 1 ZHUH LQFLVLRQ VLWH SDLQ SURFHGXUDO SDLQ DQG QDXVHD $GYHUVH HYHQWV UHSRUWHG LQ these trials were consistent with those commonly observed in surgical patients Please see Brief Summary of full Prescribing Information on following page.

6 Up Front

Pharmacy Practice News • November 2011

Your Letters

ASHP Defends Its Actions on Behalf of Jailed Pharmacist

To the Editor: he American Society of Health-System Pharmacists (ASHP) would like to correct some misstatements of fact in Mr. Poikonen’s assessment of its work relating to the case of Eric Cropp (“Five Questions for ...,” Pharmacy Practice News, October 2011, page 28), the Ohio pharmacist who was jailed following a medication error at his hospital.

First, ASHP has a long history of advocating for patient safety measures and opposes the criminalization of medical errors. In the case of Eric Cropp, ASHP worked with its affiliate, the Ohio Society of Health-System Pharmacists (OSHP), as well as other pharmacy leaders in the state of Ohio, providing assistance in their assessment and response to the Cropp case. ASHP also worked

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%)

with OSHP to advocate against legislation that would make not reporting medication errors a criminal act. Further, ASHP supported OSHP’s work with the Ohio State Board of Pharmacy on patient safety practices that reflect ASHP policy and best practices, including rules related to pharmacy technicians. ASHP also recently helped develop and endorse a statement by the National Coordinating Council for Medication Error Reporting

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. For Full Prescribing Information, access www.RECOTHROM.com Manufactured for ZymoGenetics, Inc. RT022-06, January 2011

and Prevention opposing the criminalization of errors in health care, and we are advocating that the National Association of Boards of Pharmacy endorse the statement as a means to encourage all state boards of pharmacy to adopt it into state pharmacy practice acts. Second, Mr. Poikonen is incorrect in his statement that the profession of pharmacy is the only profession that has faced these issues. Sadly, in several states, other health professionals have also been convicted of felonies related to medical error. ASHP continues to be a staunch advocate for improving the medication-use system and an effective medication error-reporting process. ASHP’s longstanding work and member-developed professional policy on patient safety and error-reporting systems has been singled out by the Institute of Medicine in its report To Err is Human as evidence of the society’s exceptional efforts to create failsafe medication-use systems. Fear of blame and retaliation can greatly inhibit error reporting and the advances in safety that can be achieved by sharing information about errors. ASHP and its members will continue our efforts to create medication-use systems that are harm-free for patients and emphasize a just-culture approach to human error. Henri R. Manasse Jr., PhD, ScD ASHP Executive Vice President and CEO

Where’s the Data on ‘Medical’ Marjuana? To the Editor: e: “Pharmacists’ Role in Medical Marijuana Remains a Bit Hazy” (Pharmacy Practice News, June 2011, page 1), despite the growing number of states that have “legalized” medical marijuana, there is not very much data to support it as a superior treatment alternative to traditional therapies. Additionally, everyone seems to overlook the fact that marijuana is illegal under federal law and no state can enact a law that makes it legal. The federal government has chosen not to actively do anything in these cases, but the fact remains that medical marijuana is not legal despite these state laws. As licensed pharmacists, we are expected to adhere to all applicable state and federal laws. In light of the fact that it remains an illegal substance under federal law, we should neither condone nor encourage the use of medical marijuana. Joe Stephanak, RPh

Mohrsville, Pa.

Pharmacy Practice News • November 2011

Up Front 7

Awards

HARD WORK continued from page 1

Christine A. Sorkness, PharmD, winner of this year’s ASHP Literature Award for Sustained Contributions to the Literature of Pharmacy Practice. “The internist, Faith Davis, had just come to Buffalo from Baltimore, where they had an anticoagulation clinic managed mainly by internists and cardiologists. She said,

Coumadin clinic is,’” said H. William Kelly, PharmD, professor emeritus of pediatrics at the University of New Mexico in Albuquerque. “I told her, ‘You’re a principal investigator in AsthmaNet. You don’t have time for that.’ She replied, ‘I love the patients. I started the program and I feel obligated to it. It’s just something I love to do.’ That’s Chris in a nutshell. She’s an incredibly devoted researcher and clinician.”

‘Most people’s careers are a bit of serendipity and luck. You can rise to the occasion or not. It’s been a wonderful ride.’ —Christine A. Sorkness, PharmD ‘We really need to do the same thing here. And it makes more sense for it to be pharmacy-managed.’ I said, ‘That’s fine, but I don’t know how to do it.’ She said, ‘No problem, I’ll train you.’ She dedicated the time to give me the clinical skills, and it just blossomed.” In 1979, when Dr. Sorkness joined the University of Wisconsin (UW) faculty, she opened another pharmacist-managed anticoagulation clinic at the Veterans Hospital in Madison. Thirty-two years later, having blossomed into one of the country’s leading investigators of asthma pharmacotherapy, Dr. Sorkness remains one of the anticoagulation clinic’s senior clinicians and continues her weekly schedule there. “It’s been one of the best things I have ever done in my life,” said Dr. Sorkness, now professor of pharmacy and medicine at UW. “There are still some people in my anticoagulation clinic who I have taken care of since 1979. It’s really the best part of my week.” How she finds the time for the clinic is something that mystifies colleagues. Nationally influential in research contributing to the development of asthma treatment guidelines, Dr. Sorkness has published more than 100 articles on asthma pharmacotherapy. She is coprincipal investigator at the Madison site of the National Heart, Lung, and Blood Institute AsthmaNet; co-principal investigator of the National Center on Minority Health and Health Disparities Center of Excellence grant to establish the UW Collaborative Center for Health Equity (CCHE) and associate director of CCHE; and a co-investigator with the National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium. A few years ago, a longtime research collaborator on one of Dr. Sorkness’ many studies was trying to plan a conference call with her. “She said, ‘I can’t do it on Thursday afternoon; that’s when my

As the ASHP Foundation stated in announcing her award, “The Asthma Control Test that [Dr. Sorkness] and her colleagues developed has become a standard in research and clinical practice. Several of her publications have been noted by the American Thoracic Society as one of the top five asthma articles in the years of their publication.” Dr. Sorkness credited her UW colleagues William W. Busse, MD, and Robert F. Lemanske Jr., MD, as collaborators in many of the studies in which she has participated. She also acknowledged the opportunity provided by Mark K. Drezner, MD, to become a key partner with the UW Clinical and Translational Science Award grant, as senior associate executive director of the Institute for Clinical and Translational Research. And yet Dr. Sorkness might never have gotten into asthma research or research administration, or even left Buffalo, had it not been for a 1977 blizzard that was so bad she and colleagues were snowed in at the medical center in Buffalo for a week. A fellow pharmacist there, Ronald Sorkness, received a call that week from the dean of UW’s School of Pharmacy, to ask if he would be interested in interviewing for a position there. He looked out the window, where the snow was blowing directly up, not down, and said, “Yeah.” Not until he left did he and Christine Sczupak begin dating. In 1979 she married Ron and joined the UW faculty. Commenting on her pioneering work in two unrelated areas where she had no prior training, anticoagulation clinics and asthma research, she said, “When you accept a faculty position, it’s because you want to press the envelope. You have an obligation to do it—but do it responsibly. Most people’s careers are a bit of serendipity and luck. You can rise to the occasion or not. It’s been a wonderful ride.”

Marie A. Smith Award for Innovation in Pharmacy Practice In 2009, among the more than 500 health care professionals at the first National Medical Home Summit in Philadelphia, the only pharmacist in attendance was Marie A. Smith, PharmD. “On the train ride back home, I was feeling dissatisfied with, and challenged by, the fact that I had been the only pharmacist there,” said Dr. Smith, the Henry A. Palmer Professor in Community Pharmacy Practice and assistant dean for practice and public policy partnerships at the University of Connecticut (UC) School of Pharmacy, in Storrs. “That was the impetus for me to start writing about what I thought the role of a pharmacist was in this new model of the medical home.” Her resulting paper, “Why Pharmacists Belong in the Medical Home,” published in the May 2010 issue of Health Affairs (5:906-913), has won the ASHP Foundation’s Award for Innovation in Pharmacy Practice.

States and abroad about how useful the paper was as they’re going through the process of trying to justify the expansion of their pharmacy services.” The fact that her papers have appeared outside of the pharmacy literature mean they influence others in the health care profession, said Robert L. McCarthy, PhD, dean and professor of UC’s School of Pharmacy. “Her work is changing the way we practice pharmacy,” he said. “We’re not surprised but we’re really thrilled that she has been honored with this award.” Dr. Smith began her career in the 1970s, working as a clinical pharmacist at a walk-in clinic associated with the University of Tennessee in Memphis. Since

‘All of my co-authors are very accomplished in their own right. It brought a level of national leadership to the subject [of the medical home].’ —Marie A. Smith, PharmD To co-author the paper, she carefully chose three other leading health care professionals: David W. Bates, MD, chief of general medicine at Brigham and Women’s Hospital in Boston; Thomas Bodenheimer, MD, adjunct professor of family and community medicine at the University of California, San Francisco; and Paul D. Cleary, PhD, dean of the School of Public Health at Yale, New Haven, Conn. “The paper was interdisciplinary and cross-institutional,” she said. “All of my co-authors are very accomplished in their own right. It brought a level of national leadership to the subject.” In making their case for the role of pharmacists in the medical home, they noted that pharmacists “perform comprehensive therapy reviews of prescribed and self-care medications, resolve medication-related problems, optimize complex regimens, design adherence programs and recommend cost-effective therapies.” They recommended that these roles be evaluated in medical home demonstration projects. “It’s an honor and very humbling to find out you’re being recognized by your peers,” Dr. Smith said. “What also touched me was hearing from other pharmacists both in the United

then she has authored dozens of papers and worked as an administrator at more than 10 schools of pharmacy around the country, as well as serving on the national staff of ASHP. “Some of my siblings asked me to stop moving, because they had no more room in their address books,” she said with a laugh. “I do like change. I guess I really think of myself as a change agent. I even

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see HARD WORK, page 10

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10 Up Front

Pharmacy Practice News • November 2011

Awards

HARD WORK continued from page 7

did a fellowship in change management at Johns Hopkins.” She insisted, however, that her roaming days are over until she is ready to semi-retire and play golf—lots and lots of golf.

Rhonda M. Cooper-DeHoff Drug Therapy Research Award So devoted to research is Rhonda M. Cooper-DeHoff, PharmD, MS, that she now has only one patient to whom she delivers clinical pharmacy care: her cat Orion. “He has congenital heart disease,” said Dr. Cooper-DeHoff. “I have to give him atenolol twice a day.”

7, 2010, edition of the Journal of the American Medical Association (304:6168). The observational study examined the outcomes of the 6,400 of the initial 22,576 participants who were at least 50 years old and had both diabetes and CAD. Those whose blood pressure was treated intensively, to less than 130 mm Hg in accordance with current guidelines, were actually found to have a small but significantly higher risk for all-cause mortality than those with less intensive blood pressure lowering (treated to between 130 and <140 mm Hg) at longterm follow-up, with an adjusted hazard ratio of 1.15 (95% confidence interval, 1.01-1.32; P=0.03). “Not only did lowering blood pressure aggressively not lower risk in

‘Maybe we need to focus on other comorbidities [in patients with diabetes] like dyslipidemia and obesity, rather than focusing so much on blood pressure.’ —Rhonda M. Cooper-DeHoff, PharmD, MS

There is strange coincidence in the fact that her cat requires a blood pressure medication: She served for more than a decade as an investigator of INVEST (International Verapamil SR Trandolapril Study), which evaluated hypertension treatments in elderly patients with coronary artery disease (CAD); is a co-investigator on two National Institutes of Health (NIH) grants evaluating pharmacogenetic associations in hypertension; and is the principal investigator for the NIH-funded study, Metabolic Effects of Antihypertensive Drugs. It was for a subgroup analysis of the INVEST population that she won the ASHP Foundation’s Drug Therapy Research Award. The paper, for which she was first author, appeared in the July

patients with diabetes,” she said, “but it actually increased their risk. That’s an important finding. We as pharmacists spend so much time focusing on numbers and trying to achieve guidelinerecommended blood pressure control in patients with diabetes, which is very difficult. Maybe we need to focus on other comorbidities like dyslipidemia and obesity, rather than focusing so much on blood pressure.” Dr. Cooper-DeHoff’s role in INVEST began in the late 1990s, when she served as director of the pharmacy coordinating center. “I was responsible for making sure that all the study medications were distributed to all of the 22,576 patients in 14 different countries,” she said. Since the treatment phase of the study ended in 2003, she has co-authored many of the 50 or so publications that have come out of INVEST. After completing her residency at the University of California, San Francisco, School of Pharmacy in 1987, Dr. Cooper-DeHoff took a job at Shands Hospital in Gainesville, as the coordinator of the Invesigational Drug Service. After about 13 years, she took a faculty position in the Division of Cardiovascular Medicine at the University of Florida College of Medicine when she began her association with INVEST. Dr. Cooper-DeHoff now has a dual appointment as an associate professor there and with

the College of Pharmacy’s Department of Pharmacotherapy and Translational Research. “You could tell right from the very beginning that she was extremely competent,” said Randy C. Hatton, PharmD, FCCP, BCPS, director of the Drug Information and Pharmacy Resource Center at Shands, the university’s affiliated hospital. “She started the investigational drug service here. She took something that did not exist and turned it into something exemplary. Then she turned herself into an NIH-funded researcher due to her innate ability, willpower and hard work. But I’m kind of biased. I’ve known Rhonda for more than 20 years and she’s a good friend of mine.” If truth be told, however, Orion is not her only cat, nor her only loved one. She and her husband of 15 years, Bob DeHoff, also have an older cat, Pilgrim. “Those are my babies,” she said, without quite specifying whether she included Bob in that group.

Marie Chisholm-Burns Pharmacy Practice Research Award What excuse did Marie ChisholmBurns, PharmD, MPH, cook up to explain why she pushed back a scheduled telephone call by a half hour? “I’ve just been appointed dean of the University of Tennessee College of Pharmacy,” she said. “That’s why I was late—I was on a conference call with the people from the great state of Tennessee.”

ously published studies examining the effects of pharmacist-provided direct patient care on therapeutic, safety and humanistic outcomes. The study, published in the October 2010 edition of Medical Care (48:923-933), found favorable benefits across patient outcomes, health care settings and disease states. “It’s not just an award for me or my 11 co-authors—it’s really an award for the profession of pharmacy,” she said. “The research was all about the impact we make on direct patient care. We pharmacists may see the benefits of our clinical care as already proved, but it’s still not always understood outside our profession. Most of the time, pharmacists still don’t get reimbursed for clinical care. The thing we have to do is show this evidence to other people.” The daughter of a mechanic father and stay-at-home mother, neither of whom graduated from high school, Dr. Chisholm-Burns said she had the values of education and hard work instilled in her from an early age by her “honest, humble, hard-working and great parents. Watching them being such hard workers, I applied that to my schoolwork,” said Dr. Chisholm-Burns, who noted with pride that her mother obtained a GED later in life. “I had a job at a Pizza Hut when I was 16 years old. Man, that was hard. I knew right then I had to go to college.” While working her way through college and pharmacy school, she said, “Never in my wildest dreams did I ever think I would be doing the things

‘It’s not just an award for me or my 11 co-authors—it’s really an award for the profession of pharmacy.’ —Marie Chisholm-Burns, PharmD, MPH Oh, sure: the old I-was-on-the-phonewith-the-University-of-Tennessee-tobecome-their-new-dean-of-the-college-of-pharmacy line. How predictable. Actually, for the 43-year-old woman who grew up poor in Hempstead, Long Island, N.Y., and was already serving as professor and head of the Department of Pharmacy Practice and Science at the University of Arizona College of Pharmacy, Tucson, when named the winner of ASHP’s 2011 Pharmacy Practice Research Award, it was no more surprising than anything else about her meteoric rise through the profession. Co-author of more than 230 publications, with some $8 million in funding for studies she oversees from the NIH and other sources, Dr. Chisholm-Burns won the ASHP award for a systematic review and meta-analysis of 298 previ-

I’m doing today—or even what I did 15 years ago. It’s been such a great journey, and I still have a long way to go.” A Fulbright Scholar, Dr. ChisholmBurns won the Rufus A. Lyman Award for most outstanding publication in the American Journal of Pharmaceutical Education back in 1996, a feat she repeated in 2007. She has also won the Robert K. Chalmers Distinguished Pharmacy Educator Award from the American Association of Colleges of Pharmacy, the Clinical Pharmacy Education Award from the American College of Clinical Pharmacy, and the Daniel B. Smith Practice Excellence Award from the American Pharmacists Association. In addition, a textbook she co-edited, Pharmacotherapy Principles and Practice, received the Medical Book Award from the American Medical

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18 Up Front

Pharmacy Practice News • November 2011

Awards

HARD WORK continued from page 10

Writers Association in 2008. Christina A. Spivey, PhD, coordinator of research and administration in Dr. Chisholm-Burns’ department at the University of Arizona, was among the coauthors of the winning paper. “The project was a huge undertaking and would not have succeeded without her leadership and guidance,” Dr. Spivey said. “She keeps her team focused on task.” How Dr. Chisholm-Burns does it while

still enjoying cycling, playing chess and family time with her husband and 8-yearold son (both named John Fitzgerald) can perhaps be understood by the time management efficiency she espoused when she finally made it to the telephone for her delayed conversation. “Let’s punch it out before I have to put out another fire,” she said.

Michael L. Spinner Student Research Award At an age when most health-system pharmacists are settling into the prime

‘[Organ transplant patients] have a new lease on life and are so thankful. They’re a very rewarding patient population to get to work with one-on-one.’ —Michael Spinner, PharmD of their careers, Michael Spinner’s was just beginning. “I entered pharmacy school at 35 years of age,” said the winner of this year’s ASHP Student Research Award. “I had been doing medical research in a labora-

COMING SOON

Bridging the gap between the hospital and post-discharge care

In This Issue Technology Watch

Patient telemonitoring helps hospitals maintain seamless post-discharge care.

Cindy Kuzendorf, PharmD discusses the rewards of preceptoring the nation’s only ASHPaccredited home infusion residency program.

Business Case Study

TPN Regimens In Hospital Causing Problems at Home

For Aralast, Limiting Distribution Helps Boost Drug Safety

Overfeeding triggers risky electrolyte imbalances post-discharge

Registries, monitoring plan help ensure optimal outcomes

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Q&A

Volume 1 • Number 1 • November 2011

Fight or switch? One health-system’s strategy for becoming a specialty pharmacy contractor.

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Clinical Controversies

Continuous vs. intermittent IV antibiotic dosing: why the disconnect between hospital and home?

Educational Review

Compatibility of Commonly Used Intravenous Drugs

see ARALAST, page 1

Coding Consult POLICY WATCH

Joint Commission Eyes Stronger Oversight Of Specialty Pharmacy

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Top 10 Coding Mistakes—And How To Fix Them

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A new quarterly publication from the editors and publisher of Pharmacy Practice News. Each issue will provide essential clinical and business information for stakeholders in specialty pharmacies, home infusion providers, insurers and managed care organizations. Our goal: to help foster high-quality, cost-effective treatment across the entire patient-care continuum.

tory, but patient interaction was what was lacking for me. I was fortunate to be able to go back to pharmacy school full-time.” Now a Postgraduate Year 1 (PGY1) Pharmacy Practice Resident at the Johns Hopkins Hospital, in Baltimore, Dr. Spinner won for a study of prophylactic versus preemptive valganciclovir CMV management and the resultant long-term renal allograft outcomes published in Transplantation (2010;90:412-418). Having obtained a bachelor’s degree in chemistry and biochemistry from Bradley University in Peoria, Ill., and a master’s in biology from Washington University in St. Louis, Dr. Spinner entered St. Louis College of Pharmacy in 2007. When he rotated through the solid-organ transplant service at Barnes-Jewish Hospital in St. Louis, he knew he had found his specialty. “The patients are on very complex [drug regimens] from the day of transplant throughout the rest of their lives, and [face potentially] serious drug interactions,” he said. “At the same time, they have a new lease on life and are so thankful. They’re a very rewarding patient population to work with one-on-one.” Dr. Spinner’s co-author and preceptor at Barnes during that rotation said she was thrilled to learn he had won the award—but not surprised. “What is exceedingly different about Michael from other nontraditional pharmacy students is the degree to which he has proactively sought out additional opportunities to further his learning,” said Lyndsey Bowman, PharmD, BCPS, clinical pharmacist in the kidney, liver and pancreas transplant services at BarnesJewish Hospital. “He spent one summer in the Clinical Research Training Center Predoctoral Program through the Washington University School of Medicine, and another summer away from his friends and family to pursue a summer pharmacy internship at Johns Hopkins Hospital, in Baltimore.” When Dr. Bowman asked him why he had decided to pursue his PGY1 at Johns Hopkins, away from friends and family in St. Louis, “he told me it would simply be the best opportunity for him. That’s so like Michael—I have known him for almost four years now, and he has consistently demonstrated an exceptional work ethic, enthusiasm and undeniable dedication to the profession of pharmacy.” Speaking by telephone from his Baltimore apartment at 8 p.m. on a weeknight, Dr. Spinner confessed that he had awakened at 4:45 that morning and arrived at The Johns Hopkins Hospital before 6

Pharmacy Practice News • November 2011

Up Front 19

Events

Pundits, PPMI on Tap at ASHP Midyear F

or the first time since 2003, the American Society of Health-System Pharmacists (ASHP) returns to New Orleans to hold its 46th Midyear Clinical Meeting and Exhibition, Dec. 4-8. More than 20,000 hospital pharmacists, pharmacy leaders, technicians and others are expected to turn out for the conference, whose theme, Network, Opportunity, Learn, Advance (NOLA), gives a playful wink to the host city’s post-Katrina resurgence. The conference will feature a keynote presentation by James Carville and Mary Matalin, political operatives and commentators who have managed a measure of wedded bliss despite slinging political barbs from opposite sides of the ideological spectrum. They will discuss their experiences as perennial political insiders and provide insights from both sides of the aisle. Charles R. Denham, MD, chairman of the Texas Medical Institute of Technology, Austin, and an international leader in patient safety, will deliver the Spotlight on Safety talk on Wednesday morning. Dr. Denham also will receive ASHP’s Board of Directors’ Award of Honor for his contributions to the health field. Health-system pharmacy’s largest meeting will offer hundreds of hours of educational and networking sessions and hands-on workshops that stretch across a broad range of important clinical, technological and financial issues. Key among those topics are realizing the vision and meeting the challenges of the Pharmacy Practice Model Initiative (PPMI); trends and leadership challenges for multihospital pharmacy organizations; the evolving role of pharmacy technicians; preceptor development; starting and expanding residency programs; and improving medication safety during care transitions. “As we have done previously, we will strive to provide practical information throughout the conference,” said JoAnn Harris, RPh, MBA, ASHP’s director of educational services. “That’s our top

goal when we develop the program and that’s what our attendees want: workable solutions they can take home and implement.”

a.m. After working there for more than 12 hours, he still had another four hours of work to complete. “It’s a very demanding experience, both physically and emotionally,” he said with a laugh. “But I knew what to expect when I applied.” The senior author of the winning study, Daniel C. Brennan, MD, director of transplant nephrology at Washington University School of Medicine, St. Louis, suggested the study subject to Dr. Spinner when he served as his mentor during a predoctoral fellowship training program. The resulting study showed no sig-

nificant differences in the rate of acute rejection, graft loss or death between 115 renal transplant patients who received prophylactic versus preemptive valganciclovir but that four patients in the prophylactic group (8%) compared with none in the preemptive group died with a functioning graft (P=0.043).

PPMI Still a Hot Topic The hottest topic this year, added Ms. Harris, is the PPMI. “That theme will be woven through everything we possibly can: networking sessions, educational sessions, even the opening general session,” she said. “It’s a very big priority.” Various facets of PPMI will be highlighted in two separate sessions. On Monday afternoon, experts will discuss PPMI as it relates to pharmacy technicians and cover strategies to integrate pharmacy technicians into pharmacy practice to achieve PPMI recommendations and goals. “Each of the three speakers will look at the changing role of certified pharmacy technicians (CPhTs) from different viewpoints: CPhT, the Pharmacy Technician Certification Board [PTCB] and a University Health System Director of Pharmacy,” said program chair Angela Cassano, PharmD, BCPS, pharmacy consultant in Midlothian, Va. One of the clear messages that emerged from the November 2010 PPMI Summit, noted Dr. Cassano, was that technicians are critical to advancing the pharmacy profession. “Speakers will highlight evolving technician roles not only in the hospital setting, but in all areas of practices,” she said. The Tuesday afternoon session, “Implementing a New Health-System Pharmacy Practice Model,” will showcase three different institutions and how each has responded to the PPMI Summit recommendations, according to moderator Mary M. Hess, PharmD, FASHP, FCCM, FCCP, associate dean at Jefferson School of Pharmacy, in Philadelphia. “We want to keep the momentum of the Summit going. Throughout health-

‘Extraordinary Contributions’ Daniel J. Cobaugh, PharmD, FAACT, DABAT, vice-president, ASHP Research and Education Foundation, applauded the award winners for their “extraordi-

A Wednesday morning session, “Raising the Bar: Expand Your Residency Program and Improve Patient Care Services,” will provide attendees with some of the tools to begin a residency program or enlarge an existing one, said moderator Kelly M. Smith, PharmD, BCPS, FASHP, FCCP, associate dean for academic and student affairs, associate professor of pharmacy practice and science, University of Kentucky College of Pharmacy, in Lexington. The concept of the attending pharmacist and the advan-

tages and disadvantages of increasing the resident-topreceptor ratio will be among the issues addressed from the perspectives of commuScan for ASHP Midyear Clinical nity hospitals, academic medical Meeting Schedule at-a-glance. centers and resi- Instructions, page 3 dents themselves. “This topic is critical for the profession. Clearly, we don’t have nearly the residency capacity we need,” said Dr. Smith, who cited the forecast that 13,000 new pharmacists will graduate pharmacy school by 2015, while residency growth is not expected to keep up with the quickly growing demand. “Hearing about the frontline experiences of program directors who have engaged in the processes and deliberations to expand training programs will provide valuable lessons for those who attend.” Another Wednesday session, “Partner ship for Patients: Collaborations to Improve Safety and Care Transitions,” will highlight progress made to date in the Center for Medicare and Medicaid Innovation (CMI)—Partnership for Patients. Among the partnership’s goals are to improve quality of care by reducing preventable hospital-acquired conditions and decreasing hospital readmissions. This session will focus specifically on the program’s efforts to reduce adverse drug events and readmissions. “Safe and effective use of medications is so important to everything that underscores health reform,” said moderator Brian J. Isetts, PhD, BCPS, FAPhA, professor at the University of Minnesota College of Pharmacy, in Minneapolis, and a health policy fellow at the CMI, in Baltimore. “Our presenters will describe the impact of the partnership and explain how pharmacists can make a difference right now to heighten patient safety. We’re going to ask everyone in the room to be a part of this commitment to improving our health care delivery system; it will be a highly interactive session.” —Steve Frandzel

nary contributions to the biomedical literature. The journals to which these scientists have contributed—Health Affairs, JAMA, Medical Care, The New England Journal of Medicine, and Transplantation—speak to the impact of their work.” He said, “The papers by ChisholmBurns and Smith, with their focus on pharmacists’ value and roles in medical homes, are key to the ASHP/ASHP Foundation Pharmacy Practice Model Initiative. The JAMA article by Cooper-DeHoff provides critical evidence that pharmacists can use as they help patients attain

better blood pressure control.” Dr. Cobaugh added that the Literature Awards program “also recognizes pharmacists’ contributions across the career continuum by celebrating Dr. Christine Sorkness’ publications in leading journals and Dr. Michael Spinner’s article in Transplantation, which he completed as a pharmacy student. Each of the 2011 recipients is leading our profession as we work to ensure that medications are used safely and effectively in the care of our patients.” —Dan Hurley

system practice, pharmacy leaders are trying to take pieces of those recommendations and make practical changes. Our session will relate practical examples that fit many audiences and environments. Presenters will share their ideas and results—both good and unexpected—of the challenges they faced along the way. Many of those ideas should apply across the board to other pharmacy departments that are in similar practice environments.” A pair of sessions on Monday and Tuesday will zero in on the current trends and leadership challenges faced by multihospital pharmacy systems. With growing frequency, chief pharmacy officers and directors find themselves in charge of departments spanning more than one hospital. “It’s a challenging situation for pharmacy leaders,” said Kathleen S. Pawlicki, BS, MS, administrative director for professional services at Beaumont Hospital in Royal Oak, Mich., who will moderate both sessions. “We’ll present an overview of the landscape of multihospital pharmacy systems and discuss the factors that are critical to success when creating a synergistic multihospital organization. We’ll also cover topics such as goal setting, communication strategies for day-to-day operations and issues related to the Pharmacy and Therapeutics Committee.”

Raising the Residency Bar

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Utility and Stability of a Generic Sodium Ferric Gluconate in Complex With Sucrose The following report includes highlights from an interview with:

Rajiv Agarwal, MD Professor of Medicine Indiana University School of Medicine Indianapolis, Indiana

Introduction Anemia occurs in the majority of patients receiving chronic hemodialysis; it is associated with deteriorated cardiac function, decreased cognition and mental acuity, fatigue, and an increased risk for mortality.1-3 Although the use of erythropoiesis-stimulating agents (ESAs), such as recombinant human erythropoietin or darbepoetin alfa, can increase red blood cell production in patients receiving chronic hemodialysis, these drugs have drawbacks, including high acquisition costs and cardiovascular complications.4,5 As a result, a primary goal in the management of patients receiving chronic hemodialysis is to alleviate anemia using the lowest possible dose of ESAs.5 Patients on hemodialysis commonly experience iron loss from gastrointestinal bleeding, blood tests, and the dialysis itself.6,7 In fact, patients on hemodialysis may lose an estimated 2 to 4 g of iron per year.2 Because adequate iron stores are essential for achieving maximum benefit from ESAs, iron supplementation often is a critical strategy to improve outcomes in patients undergoing chronic hemodialysis.2 “Iron supplementation is used in people undergoing chronic hemodialysis to maintain a state of iron sufficiency such that [ESAs] can affect the hemoglobin response more appropriately,” said Rajiv Agarwal, MD, professor of medicine, Division of Nephrology, Indiana University School of Medicine in Indianapolis. “If [ESAs] were administered by themselves without iron supplementation, dialysis patients would ultimately not respond with an increase in hemoglobin very effectively.”

Iron Supplementation In Hemodialysis Patients Oral iron supplements commonly are used in patients with iron-deficiency

anemia. However, various studies have demonstrated that oral iron preparations are not effective for replenishing or sustaining iron stores in patients undergoing chronic hemodialysis. Parenteral iron supplements are much more effective for replenishing iron stores in these patients.8 In accordance with this data, a report from the Centers for Medicare & Medicaid Services found that approximately 70% of patients on hemodialysis were administered parenteral iron in 2005.9 Parenteral iron supplementation can be classified into 2 different approaches.10 For some patients, an iron loading or repletion phase may be necessary. “Initially, patients may have depletion of the iron stores and total iron deficiency, as reflected by a low ferritin and a low transferrin saturation,” said Dr. Agarwal. “In these patients, you would replete their iron stores by administering a gram of iron in divided doses.” The other approach to iron supplementation is a maintenance phase. “Most dialysis patients require ongoing iron therapy as long as they are receiving [ESAs] so they don’t become resistant to their effect. Periodic low-dose iron therapy using about 30 mg per week

should be sufficient, although this dose may vary depending on the degree of iron loss in the patient,” he explained. One of the first available parenteral iron formulations was a dextran-containing iron.11 These parenteral agents are effective in relieving anemia in chronic hemodialysis patients.11 “The major advantage to the dextran-containing irons is that they can be given as a large dose in a single setting,”12 said Dr. Agarwal. “However, the major concern with the use of these agents is the potential for [sometimes fatal] anaphylaxis.12 As a result, we do not use the dextran-containing irons at our institution.” In 1999, the first non–dextran-containing parenteral iron formulation, Ferrlecit®, was approved in the United States. Ferrlecit® is a branded preparation of sodium ferric gluconate in complex with sucrose (SFGC).11 Its efficacy is similar to that of iron dextran13; however, the absence of the immunogenic dextran moiety means that SFGC has a better safety profile than iron dextran.11 “With the newer non–dextran-containing agents, there is less of a concern about anaphylaxis, and they don’t have the black box warning of anaphylaxis,” said Dr. Agarwal. In fact,

Table 1. Stability of Nulecit® at Room Temperature Sample Control

Elemental Iron (mg/mL)

Apparent Molecular Weight (Da)

Lot A

Lot B

Lot A

Lot B

12.9

333,312

319,097

Syringe test (no dilution) 0h

14.0

13.9

341,418

319,243

24 h

14.0

13.8

340,264

314,602

48 h

12.4

12.5

323,653

316,254

Bag test (dilution to an approximate concentration of 0.625 mg/mL iron) 0h

0.620

332,035

331,673

0.620

0.609

348,846

335,087

Bag test (dilution to an approximate concentration of 1.25 mg/mL iron) 0h

1.17

1.15

323,106

306,114

1.18

1.19

338,604

316,356

Da, daltons; IV, intravenous; SFGC, sodium ferric gluconate in complex Based on reference 19.

PHARMACY PRACTICE NEWS • NOVEMBER 2011

studies have reported that SFGC may be safe for use in patients who are allergic to or intolerant of iron dextran.14 In its undiluted form, Ferrlecit® is administered as a slow IV injection (at a rate of up to 12.5 mg/min) because hypotension has been reported with rapid IV administration of iron.15 The most common side effects associated with Ferrlecit® include nausea, vomiting and/or diarrhea, injection site pain, hypotension, cramps, hypertension, dizziness, dyspnea, and chest pain.15 As a result of these properties, SFGC is widely used in the United States and a study has shown that it is associated with favorable pharmacoeconomics.16 However, SFGC cannot deliver the large absolute dose of iron in a single infusion like dextrancontaining iron formulations. Thus, SFGC requires multiple infusions over a specific period of time, especially during the loading phase of iron repletion.13

Nulecit®: A Generic Sodium Ferric Gluconate in Complex With Sucrose A generic version of SFGC, Nulecit®, recently was approved for the treatment of iron-deficiency anemia in adults and pediatric patients at least 6 years old on chronic hemodialysis receiving supplemental erythropoietin.17 Nulecit® is a sterile preparation of SFGC in 5-mL vials containing approximately 20% sucrose and 9 mg/mL of benzyl alcohol. Each dose has an elemental iron content of 62.5 mg (12.5 mg/mL).17 Nulecit® may be administered by slow IV injection with a syringe containing the undiluted product or by slow IV infusion from an infusion bag after dilution in 0.9% sodium chloride solution.17 The product is conveniently supplied in vial dose form.17 The iron content of 62.5 mg per vial17 allows continuous dosing in accordance with the National Kidney Foundation Clinical Practice Recommendations for IV iron (22 to 65 mg per week)10 and may optimize delivery and minimize waste. As with Ferrlecit®, the absence of the dextran moiety means that no test dose is required before Nulecit® infusion.14 A comprehensive pharmacokinetic analysis of Nulecit® and Ferrlecit® demonstrated bioequivalence between the products.18 The study included 240 healthy volunteers

Supported by

4. Wish JB, Coyne DW. Use of erythropoiesis-stimulating agents in patients with anemia of chronic kidney disease: overcoming the pharmacological and pharmacoeconomic limitations of existing therapies. Mayo Clin Proc. 2007;82(11):1371-1380.

Table 2. Stability of Nulecit® Under Refrigerated Conditions Sample Control

Elemental Iron (mg/mL)

Apparent Molecular Weight (Da)

Lot A

Lot B

Lot A

Lot B

12.9

333,312

319,097

Stability of Nulecit®

Syringe test (no dilution)

To ensure that patients receive an adequate dose of parenteral agents in solution—either in diluted or undiluted form—its short-term stability at room temperature (RT) and under refrigeration must be assessed. This data also influences the operations and workflow of the hospital, outpatient infusion center, dialysis center, and pharmacy. The stability of Nulecit® was investigated in a study by Baribeault. Samples of undiluted Nulecit® in 10-mL syringes or diluted in IV infusion bags containing 0.9% sodium chloride solution were stored at RT or under refrigerated conditions (2°C-8°C).19 Undiluted, RT samples were stored for up to 48 hours and diluted samples were stored for up to 24 hours. All refrigerated samples were stored for as many as 7 days.19 The parameters evaluated were iron concentration and the apparent molecular weight of SFGC.19 All tests were performed on 2 different lots of Nulecit®. A subsequent analysis showed that iron concentrations were identical in both lots and no substantial variations occurred over time under different conditions of storage or dilution.19 The apparent molecular weight of SFGC across all samples varied from 306,114 to 354,012 Da,19 well within the range of 289,000 to 440,000 Da specified in the FDA-approved prescribing information.17 Based on these data, the author concluded that the iron content and apparent molecular weight were stable under all experimental conditions. Undiluted Nulecit® was stable for no less than 2 days at RT and no less than 7 days under refrigerated conditions; diluted Nulecit® in IV infusion bags containing 0.9% sodium chloride solution was stable for at least 1 day at RT and at least 7 days under refrigerated conditions (Tables 1 and 2).19 “These stability data are of real value to pharmacists. They provide reassurance that the drug is relatively stable after adding the diluent, even at RT. This means waste

14.0

13.9

341,418

319,243

24 h

14.0

13.9

328,452

313,719

72 h

12.9

320,237

313,518

12.4

13.0

340,308

330,454

6. Eschbach JW, Cook JD, Scribner BH, Finch CA. Iron balance in hemodialysis patients. Ann Intern Med. 1977;87(6):710-713. 7. Pruett B, Johnson S, O’Keefe N. Improving IV iron and anemia management in the hemodialysis setting: a collaborative CQI approach. Nephrol Nurs J. 2007;34(2):206-213. 8. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg O, Gafter U. Intravenous 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.

Bag test (dilution to an approximate concentration of 0.625 mg/mL iron) 0h

0.620

332,035

331,673

0.614

0.607

339,258

323,178

0.633

0.612

354,012

338,468

9. Centers for Medicare & Medicaid Services. 2005 annual report, end stage renal disease clinical performance measure project. www.cms.gov/ CPMProject/Downloads/AnnualReport05final.pdf. Accessed August 30, 2011. 10. National Kidney Foundation. KDOQI Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. http:// www.kidney.org/professionals/kdoqi/guidelines_ anemia/index.htm. Accessed August 27, 2011.

Bag test (dilution to an approximate concentration of 1.25 mg/mL iron) 0h

1.17

1.15

323,106

306,114

1.17

1.16

323,882

308,096

1.18

344,201

324,874

11. Fishbane S, Wagner J. Sodium ferric gluconate complex in the treatment of iron deficiency for patients on dialysis. Am J Kidney Dis. 2001; 37(5):879-883.

Da, daltons; IV, intravenous; SFGC, sodium ferric gluconate in complex Based on reference 19.

is reduced because you don’t have to discard the product if it’s been sitting at RT for several hours,” said Dr. Agarwal. The stability of Nulecit® may also facilitate pharmacy workflow and efficiency. “In terms of pharmacy workflow, the stability data mean that pharmacists can potentially prepare the drug the evening before if, for example, they are anticipating the 5 AM arrival of 20 patients who need this drug,” he added.

Conclusion Parental iron supplementation is a critical aspect of the treatment of anemia in patients on chronic hemodialysis. Current SFGC formulations are safer for the treatment of anemia in patients receiving ESAs than dextran-containing parenteral iron formulations. Nulecit®, a generic, non–dextran-containing SFGC, has shown therapeutic

5. Szczech L. Chronic kidney disease: Association between ESA use and stroke in patients with CKD. Nat Rev Nephrol. 2011;7(7):365-366.

12. Faich G, Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans. Am J Kidney Dis. 1999;33(3):464-470.

equivalence to Ferrlecit® and in a study was associated with favorable pharmacoeconomics. The short-term stability of Nulecit® has the potential to enhance pharmacy workflow, minimize waste, and ensure the effective delivery of iron to patients with anemia.

Financial Disclosure Statement Dr. Rajiv Agarwal has been a paid consultant for Watson Pharmaceuticals, Inc.

References 1. Di Iorio B, Cirillo M, Bellizzi V, Stellato D, De Santo NG; Campania Dialysis Registry Research Group. Prevalence and correlates of anemia and uncontrolled anemia in chronic hemodialysis patients— the Campania Dialysis Registry. Int J Artif Organs. 2007;30(4):325-333. 2. O’Mara NB. Anemia in patients with chronic kidney disease. Diabetes Spectr. 2008;21(1):12-19. 3. Atti AR, Palmer K, Volpato S, Zuliani G, Winblad B, Fratiglioni L. Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging. 2011; 27(2):278-284.

13. Sunder-Plassmann G, Horl WH. Comparative look at intravenous iron agents: Pharmacology, efficacy, and safety of iron dextran, iron saccharate, and ferric gluconate. Semin Dialysis. 1999;12:243-248. 14. Michael B, Coyne DW, Fishbane S, et al; Ferrlecit Publication Committee. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61(5):1830-1839. 15. Ferrlecit®(sodium ferric gluconate complex in sucrose injection) [product information]. Bridgewater, NJ: Sanofi-Aventis U.S., LLC; 2010. 16. Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. 2008;74(12):1588-1595. 17. Nulecit® (sodium ferric gluconate complex in sucrose injection) [product information]. Corona, CA: Watson Pharma, Inc.; 2010. 18. Baribeault D. Sodium ferric gluconate (SFG) in complex with sucrose for IV infusion: bioequivalence of a new generic product with the branded product in healthy volunteers. Curr Med Res Opin. 2011;27(8):1653-1657. 19. Baribeault D. Short-term stability of a new generic sodium ferric gluconate in complex with sucrose. Curr Med Res Opin. 2011 Oct 12. [Epub ahead of print]

BB1127

who received a 125-mg dose of either Nulecit® or Ferrlecit® injection.18 Comparable concentrations of total serum iron and transferrin-bound iron were observed during the 36-hour assessment period, and the 90% confidence intervals for Cmax and area under the curve were within the required 80% to 125% range.18

PHARMACY PRACTICE NEWS • NOVEMBER 2011

Hem/Onc Pharmacy

Pharmacy Practice News • November 2011

In Focus

DRUG SHORTAGE continued from page 1

So Dr. Dinolfo and her treating oncologist placed the woman on a salvage regimen with liposomal doxorubicin (Doxil) every two weeks. But this year, Doxil became the first brand-name chemotherapy drug to join growing list of generic chemotherapies that are in chronically short supply in the United States. On Aug. 18, Dr. Dinolfo enrolled the patient in Doxil Cares, a rationing program established by manufacturer Johnson & Johnson (J&J). “They started putting people on a waiting list on August 9. I have no idea how many people are ahead of her. There’s no drug available right now and they have no idea when they will have any,” Dr. Dinolfo said. On Sept. 7, the patient received the last dose of Doxil that Premiere Oncology had in its pharmacy. As of press time, she had not been treated with the drug since then. “I’ve never interrupted anybody’s care before!” said Dr. Dinolfo. “Two things I have promised myself through all of this: Never have a patient miss or delay a treatment due to unavailability of drug, and never have to decide what regimen to choose based on a drug being in stock. I’ve worked my butt off to never have this happen, but now I’ve had to break that promise.” Dr. Dinolfo is not alone. The nationwide chemotherapy drug shortage crisis, which Pharmacy Practice News reported in detail in January 2011, has grown worse throughout the year. According to Erin Fox, PharmD, director of the Drug Information Service at the University of Utah, in Salt Lake City, as of Sept. 30, there were 213 drug shortages—surpassing 2010’s total of 211, with more than one-fourth of the year remaining. In 2010, 23 of those shortages were cancer drugs. As of September, 22 new cancer drug shortages have been reported, again with much of the year remaining.

First-Line Therapy Imperiled In addition to Doxil, two other drugs that are causing particular distress as

‘The problem is we don’t usually get informed of the drug shortage until we are down to a less than seven-day supply, which does not give us enough time to come up with a contingency plan at that point.’

—Sara Kim, PharmD

they run short are paclitaxel and 5-fluorouracil (5-FU), largely because of the prevalence of the diseases that they treat, including breast, testicular and small cell lung cancers. “It’s really getting to the point where standard of care or first-line therapies and even secondline cancer drugs are extremely scarce,” said Bona Benjamin, RPh, director of medication use quality improvement with the American Society of HealthSystem Pharmacists. “We’re hearing daily about the seriousness of cancer drug shortages from both patients and the providers who care for them.” Ali McBride, PharmD, clinical pharmacy specialist at Barnes-Jewish Hospital in St. Louis, is constantly checking in with his suppliers to determine the availability of common chemotherapy and supportive care drugs, which fluctuates on a daily basis. “What used to be really bad has now turned into mayhem,” he said. “As a large institu-

tion we’re doing better, but a lot of the smaller infusion centers and hospitals literally can’t get anything.” Skipping doses is becoming more and more frequent. “I’ve heard that other sites that have had ovarian cancer patients on Doxil with carboplatin are omitting the Doxil [component],” Dr. McBride said. “Or they’ve changed over to the generic doxorubicin, which is also on shortage, and it’s not liposomal. Busulfan and even carmustine, which we use for transplant patients, are on shortage. Ontak [denileukin diftitox], used to treat peripheral T-cell lymphoma, is on back order and we don’t know when we’ll get any.” Earlier this year, Dr. McBride and other oncology pharmacists discussed the tough decisions that had to be made in rationing chemotherapy drugs—putting patients with curable disease at the top of the waiting list. Now, it’s even worse. “In some cases, we have lost the

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ability to treat patients who have a curable disease state,” he said. For example, all-trans retinoic acid is a chemotherapy drug that’s used in combination with other therapies to treat acute promyelocytic leukemia in patients who have not responded to other treatments. “It has an 85% to 90% cure rate,” said Dr. McBride. “But last week we ran out of that.” In addition to chemotherapy drugs, supportive medications and supplies like antibiotics and electrolytes are almost completely out at many smaller centers. “It’s a new shortage every day,” said Michael Neuss, MD, past chair of the American Society of Clinical Oncology’s Clinical Practice Committee. “Yesterday, it was mesna, a chemoprotectant.”

Unsatisfactory Substitutions Substitutions are sometimes possible, of course, but they raise the risk for medical errors due to issues such as dosage conversion. Moreover, cost and new side effects are also problems. “If you’ve run out of 5-FU, the main drug used in combination therapy for colorectal cancer, you might go to capecitabine, but there are increased side-effect profiles and also payment issues with an oral drug,” said Dr. McBride. Some practices are switching from paclitaxel to docetaxel (because the first taxane is entirely unavailable) at a big increase in cost. “I know a practice in Orange County [California] that treats ovarian cancer almost exclusively, and has had to switch 100% of its patients,” Dr. Dinolfo said. “That makes the docetaxel people happy, but it’s much more expensive.” The University of Texas MD Anderson Cancer Center, in Houston, has managed to keep an adequate supply of 5-FU and paclitaxel, but like other centers, has its patients on a waiting list for Doxil. They maintain a pharmacy alert system: Green means reasonable supply of the drug, yellow means the drug is in limited supply and usage should

•

see DRUG SHORTAGE, page 24

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Hem/Onc Pharmacy

Pharmacy Practice News • November 2011

In Focus

DRUG SHORTAGE continued from page 22

be restricted and red means they can get no more of the drug. At press time, they were at level green on some drugs that other centers are short on, like paclitaxel, but had limited supplies of daunorubicin and were completely out of Doxil. “It’s very stressful for the patients, particularly the ones who’ve had a response to therapy,” said JoAnn Lim, PharmD, clinical pharmacy specialist in the Department of Investigational Cancer Therapeutics at MD Anderson. “To then take a drug away from them— they think, ‘is that going to change the outcome of my disease?’ The physicians have had to work very hard to reassure patients that they are doing everything they can and that they have found the best substitute.” But it’s often not the best substitute— just the only other option. On Sept. 27, the Kansas City Star told the story of Bryan Schearer, a 20-year-old man with Hodgkin’s lymphoma who had been responding well to a four-drug chemotherapy cocktail that included bleomycin—until that drug vanished from the pharmacy shelves. Instead of the chemotherapy, which offered a 90% cure rate, he has been forced to undergo a grueling and risky stem cell transplant. Sara S. Kim, PharmD, oncology pharmacy clinical coordinator, The Mount Sinai Medical Center, New York City, said that her institution is in the process of developing a contingency protocol in case of a shortage, regarding what needs to be done, who needs to be contacted and how the decision will be made to impose restrictions. “After much discussion, there was even a suggestion to have our Ethics Committee involved in the decision-making process,” she said. “The problem is we don’t usually get informed of the drug shortage until we are down to a less than seven-day supply, which does not give us enough time to come up with a contingency plan at that point.” It’s not just current patients who are threatened. The shortage has called a halt to literally hundreds of clinical trials, potentially slowing the pipeline for future therapies. In written testimony submitted to a Sept. 23 hearing on the crisis before the House Energy and Commerce Committee, Howard Koh, MD, MPH, assistant secretary of health for the Department of Health and Human Services, said that more than 300 studies funded by the National Cancer Institute involve a drug that is in short supply. “The inability to obtain adequate supplies of these cancer drugs for research has resulted in promising clinical trials being suspended indefinitely and patient enrollment

‘In some cases, we have lost the ability to treat patients who have a curable disease state.’ —Ali McBride, PharmD

being abruptly halted,” Dr. Koh wrote in his testimony.

A Web of Confusion “It’s easy to see how the vicious cycle happens: You hear there’s going to be a shortage, people start overbuying because they want to protect themselves, then there really is a shortage, and then a gray market pops up,” said Dr. Neuss. More than half of the 549 U.S. hospitals responding to a survey this summer by the Institute for Safe Medication Practices reported buying one or more drugs from gray market vendors; 7% of those doing so reported side effects or other problems. “It would be best for our practice if all manufacturers had a two-year supply on hand, but smart manufacturing practice has you decrease your total inventory.”

trying to craft a solution to the drug shortage problem lies in the complex web of drug company relationships. As a brand-name drug, Doxil would not have been expected to suffer from the short supply issues that impact many generic drugs. But J&J contracted with generic supplier Bedford to manufacture the drug. (J&J is now ramping up with someone new.) “Bedford is a company that has had a tremendous amount of problems, so this isn’t surprising,” said Dr. Fox. “It’s actually very difficult to figure out which products are contract-manufactured or not. I ask all suppliers what measures they have to prevent shortages, such as manufacturing redundancy and business continuity, and now I’ve started asking if they use contract manufacturers. Of course, they often decline to tell me and say it’s proprietary.”

‘It’s really getting to the point where standard of care or first-line therapies and even second-line cancer drugs are extremely scarce.’ —Bona Benjamin, RPh

With many centers starting to hoard product—perhaps understandably—it is taking longer and longer to resolve shortages. In the meantime, whether patients get their chemotherapy or not has a lot to do with where they live and where they are treated. “Each company can choose how they distribute a product that’s short,” said Dr. Fox. “They may have an allocation plan, something in place to prevent people from ordering large amounts—and that may be better overall for patients and clinicians [because] then everyone will be able to get at least some. But if a company has nothing like that in place, supply will be spotty. Some places will get huge amounts and hang on tightly, and others won’t get anything at all.” That’s because while the FDA has authority over drug safety, it has no control whatsoever over drug distribution. “There’s no standard method in this country for how drugs are distributed,” Dr. Fox explained. Another part of the problem with

At two recent forums on the issue— the Sept. 23 Congressional hearing and the Sept. 26 FDA meeting—fierce debate continued about these factors and other contributing causes behind the shortage. Some (mostly manufacturers) blamed over-regulation by the federal government, whereas others pointed to profit margins. “The profit margins on generic drugs are quite small compared with brand-name drugs, and over time, some companies may choose to discontinue production of generic drugs due to lack of profitability,” Dr. Koh said in his testimony.

A Prescription There’s no one single culprit, said Dr. Fox, and there will be no single solution. Instead, the experts Pharmacy Practice News spoke with offer several possible strategies to help ease the pain: Pass the Klobuchar-DeGette bill (Senate Bill 296/House Resolution 2245), which would require drug manufactur-

ers anticipating a shortage to immediately notify the FDA. “The FDA has told us directly that, when notified of an impending shortage in advance, Scan for more they’ve been able to information on drug shortages. prevent shortages because they knew Instructions, page 3 in time to get remaining manufacturers up to speed or look for alternative supplies,” said Ms. Benjamin. Establish a federal stockpile of “medically necessary” drugs. Dr. McBride suggested a list of perhaps 100 to 200 critical medications. “It will be expensive for the government to do, but if we continue on this route, what’s the alternative?” Establish practice guidelines. Currently, Dr. McBride said, oncologists and oncology pharmacists are flying blind and making up substitution practices as they go. “We could benefit from guidelines from the National Comprehensive Cancer Network or American Society for Clinical Oncology as to how to handle drug shortages,” he noted. “For example, there are no guidelines for how and what to substitute for Doxil in the face of a shortage. It would help out a lot of institutions, particularly smaller ones, who may not have the manpower or facilities to appropriately determine what to do instead. People are implementing practices based on journal articles, but there are no existing guidelines as to how to make substitutions or dose reductions in a drug shortage situation.” Allow emergency extended dating. “I have a drug that in the bottle, in the box, in the fridge, is good until 2013,” said Dr. Dinolfo. “It comes in a 40-mg vial. I am going to use 32 mg today, so there’s 8 mg hanging out there that we might not be able to use. If I were the manufacturer, I’d put out an emergency email granting extended dating—say, 30 days—providing that the sites are accessing and storing the bottle in a sterile fashion, refrigerating it and protecting it from light. It would at least make it easier for us to roll over supplies.” Provide tax incentives for the production of certain medically necessary drugs that are difficult to substitute— such as chemotherapy drugs. The Prescription Drug User Fee Act is up for review in 2012. At an FDA workshop held Sept. 26, there was some discussion of the possibility of pushing through such incentives as a part of that review. —Gina Shaw For more on the drug shortage, see page 86.

Hem/Onc Pharmacy

Pharmacy Practice News • November 2011

In Focus

Everolimus Touted as a Game Changer in Breast Cancer Stockholm—Researchers have identified a drug that is expected to change the treatment landscape for patients with estrogen receptor (ER)-positive breast cancer that is resistant to nonsteroidal aromatase inhibitors. Adding everolimus (Afinitor, Novartis) to exemestane therapy improved progression-free survival (PFS) by four months compared with therapy with exemestane alone, according to an interim analysis of the Phase III trial BOLERO-2 (Breast Cancer Trials of Oral Everolimus), presented at the recent European Multidisciplinary Cancer Congress (EMCC; abstract LBA9). “Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory ER-positive patients,” said José Baselga, MD, associate director of the Massachusetts General Hospital Cancer Center, in Boston. “Our results could represent a paradigm shift in the management of patients with hormone receptor–positive breast cancer.” Novartis plans to ask the FDA to approve everolimus for this indication. The standard of care for patients with HER2-negative/ER-positive metastatic breast cancer (MBC) is sequential use of several lines of endocrine therapy and chemotherapy. Patients who become resistant to endocrine therapy do not have a good prognosis, and there is a need for a targeted agent in this population. Researchers thought everolimus might fit the bill, because the drug inhibits the mammalian target of rapamycin (mTOR) pathway. Resistance to endocrine therapy has been associated with the activation of the mTOR pathway, which, in turn, activates the estrogen receptor. Two randomized Phase II trials have already shown positive results for everolimus in patients with breast cancer

(Table). Thus, investigators launched a Phase III trial to test whether they could use everolimus to reverse resistance to endocrine therapy and delay the start of chemotherapy. They recruited postmenopausal ER-positive/HER2-negative women with MBC who were refractory to letrozole or anastrozole. Patients were randomized to receive exemestane plus everolimus (n=485) or exemestane and placebo (n=239). In both arms of the

Table. Phase II Trials of Everolimus in Patients With HER2-Negative/ER-Positive Breast Cancer Drug Combination

Hazard Ratio

Number of Patients

Letrozole ± everolimus

0.61

270

J Clin Oncol 2009;27(16): 2630-2637

Tamoxifen ± everolimus

0.53

111

SABCS 2010, abstract S16

SABCS, San Antonio Breast Cancer Symposium

‘Everolimus is the most important advance in breast cancer since trastuzumab.’

—Fabrice Andre, MD

study, 84% of patients were sensitive to prior hormone therapy and roughly 75% had bone disease. Crossover was not allowed. In both arms, roughly 75% of patients were white and 20% were Asian. The median age was 62 years in the everolimus arm and 61 years in the placebo arm; other characteristics were well balanced in the two arms. A total of 528 events are required for the final analysis; an interim analysis was conducted after 60% of these events accrued. At the interim analysis, the PFS by investigator assessment was 6.9 months in patients who received everolimus compared with 2.8 months in patients who received placebo (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.35-0.54; P<00001). The PFS by independent central assessment was 10.6 months in the everolimus arm compared with 4.1 months in the placebo arm (HR, 0.36; 95% CI, 0.270.47; P<0.0001). The overall response rate (9.5% vs. 0.4%; P<0.0001) and clinical benefit rate (33.4% vs. 18.0%;

P<0.0001) by investigator assessment favored the everolimus arm. The benefit was observed in all patient subgroups. Adverse events have been consistent with previous experience with everolimus including stomatitis, fatigue, non-infectious pneumonitis and hyperglycemia (Figure). Overall survival (OS) data are not yet mature. Importantly, treatment with everolimus did not affect quality of life according to results from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, which was administered during the study (time to ≥5% deterioration was comparable; HR, 0.91; P=0.217). Fabrice Andre, MD, an oncologist from the Institut Gustave Roussy, Villejuif, France, served as the expert discussant for the abstract at the EMCC conference. He pointed out that clinical data from other studies supported the rationale for the study (Table), the trial

100 Everolimus + exemestane

Patients, %

80 60

Placebo + exemestane 56

33 26

20 0

Stomatitis

16 8

Fatigue

Dyspnea

13 6

Anemia

Figure. Most common grade 3/4 adverse events. AST, aspartate aminotransferase

Reference

12 0

AST

Pneumonitis

was well designed, and the results were “robust” and “clinically relevant.” Dr. Andre said, however, that information regarding outcomes in patients with more aggressive ER-positive disease is needed, and he wondered about the distribution of luminal A/B in the current trial. He also pointed out that inhibiting mTOR alone is not optimal because compensatory or parallel pathways can be activated. “The development of compensatory pathways will require sequential biopsies and use of kinome technologies to understand, reverse and personalize the mechanism of resistance,” said Dr. Andre. Other compounds are candidates in this setting including P13K/ mTOR dual inhibitors, P13K inhibitors, AKT inhibitors and mTOR Complex1/ Complex 2 inhibitors. A flurry of excitement has been building since the presentation at EMCC. Dr. Andre called everolimus “the most important advance in breast cancer since trastuzumab.” Other oncologists, however, are more cautious in interpreting the data. It was not very long ago that the FDA granted accelerated approval for bevacizumab (Avastin, Genentech) for patients with MBC based on a 5.5-month PFS benefit,

•

see EVEROLIMUS , page 28

Hem/Onc Pharmacy

Pharmacy Practice News • November 2011

In Focus

EVEROLIMUS continued from page 26

only to have subsequent trials show no improvement in OS, as well as smaller benefits in PFS for the drug. Are oncologists worried that everolimus might not show a benefit in OS? “It is a definite concern, as I suspect it will be more difficult to show a benefit in OS for a treatment that is added to endocrine therapy given the longer postprogression survival after endocrine therapy compared with patients treat-

ed with chemotherapy,” said Maura Dickler, MD, associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City. Responding to this comment, Dr. Baselga said comparing BOLERO with the Avastin trial is like comparing apples and oranges. “We are talking about very different disease entities,” he said, and most importantly, the study designs were very different. “The Avastin study was not a registration study and it was not placebo-con-

trolled. This allows for very significant biases. As a reflection of this and other design issues, follow-up registration studies were requested,” Dr. Baselga said. “In addition, the hazard ratio was lower than in our study (0.6). This is quite different from our study, which was a double-blind registration study with both local and central review and a much more impressive hazard ratio.” An expert on hormone therapy for breast cancer, Matthew J. Ellis, PhD, MB, director of the Breast Cancer Research Program at the Siteman

Cancer Center, in St. Louis, also said clinicians need to be cautious until survival data are available; however, he was optimistic. “I would be most Scan for data on comfortable with everolimus and neua new standard of roendocrine tumors. Instructions, page 3 care that involves improvement in overall survival, and I don’t think that is an unlikely scenario,” he commented. Dr. Ellis also said studies provide evidence that other candidates that inhibit the P13K kinase pathway (as mentioned by Dr. Andre) might prove to be even more effective. “In all the drugs that we have tested, everolimus is the weakest in inducing cell death in ER-positive cells that were deprived of estrogen,” said Dr. Ellis, referring to a study in Breast Cancer Research (2011;13:R21). “This BOLERO study is a very exciting result in terms of a multitude of agents targeting the PI3 kinase pathway in ER-positive breast cancer.” If the OS data pan out, researchers say the positive results of the BOLERO-2 trial could be just the tip of the iceberg in terms of using everolimus as a breast cancer therapy. The Phase III BOLERO-1 trial has just finalized accrual. This trial is testing the addition of everolimus to weekly paclitaxel and trastuzumab in patients with HER2-overexpressing MBC who are refractory to trastuzumab. And according to Dr. Baselga, future trials could test mTOR inhibitors in the early adjuvant setting in patients with ER-positive breast cancer. —Kate O’Rourke The BOLERO-2 trial was funded by Novartis. Dr. Baselga has consulted for companies, including Novartis, Roche, Merck SA and Bayer. Dr. Dickler consults for Novartis. Dr. Ellis has consulted for Novartis. Dr. Andre received grants from Novartis and served as consultant and speaker.

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Hem/Onc Pharmacy 29

Pharmacy Practice News • November 2011

In Focus

Radium-223 To Change Treatment Algorithm for mCRPC Stockholm—Clinicians are expected to soon have yet another agent in their armamentarium to treat metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC with symptomatic bone metastases who received the novel agent radium-223 (Alpharadin, Algeta ASA/Bayer Schering Pharma AG) lived 30% longer than those given a placebo in a multicenter, randomized study presented at the 2011 European Multidisciplinary Cancer Congress (EMCC; abstract 1). “This drug is likely to become a new standard of care for the treatment of patients with CRPC and bone metastases,” said lead investigator Chris Parker, MD, consultant clinical oncologist, Royal Marsden Hospital, London, United Kingdom. “If I was to speculate on the long-term role of the drug, I would say a combination of radium-223 and abiraterone acetate would be a very attractive option, given their efficacy, impressive safety profiles and different mechanisms of action.” The magnitude of the drug’s benefit, along with its favorable tolerability, compelled the study’s Independent Data Monitoring Committee to call for an early cessation of the trial, called ALSYMPCA. Radium-223 is a first-inclass alpha-pharmaceutical that targets bone metastases using high-energy alpha particles of extremely short range (<100 mcm). According to Dr. Parker, unlike the smaller beta particles, which have a longer range, the short range of action of alpha particles and their larger size means damage to bone marrow is limited and fewer molecules are needed to destroy tumor cells. The trial included 922 patients with progressive, symptomatic mCRPC and at least two bone metastases. Participants were recruited at 150 hospitals in 19 countries. Fifty-eight percent of the participants had previously failed or were intolerant to docetaxel treatment, whereas the rest were either ineligible for the drug or unwilling to take it. In addition to receiving standard care, 615 patients were randomly assigned to receive six injections of 50 kilobecquerel (kBq) per kg radium-223 every four weeks and 307 received a placebo in the same manner. The two groups had similar distributions of clinical and demographic characteristics at baseline. Interim findings from the study showed overall survival in the radium-223 group was a median of 14 months, compared with 11.2 months in the placebo group (hazard ratio [HR], 0.695; 95% confidence interval [CI], 0.552-0.875; P=0.00185). Furthermore, patients receiving the drug experienced a significantly longer period of

time with no skeletal-related events (SREs), averaging a median of 13.6 months before their first SRE, compared with 8.4 months among placebo recipients. Dr. Parker said quality-of-life data would be presented at a later date. Grade 3 and 4 hematologic events occurred in 2% and 4%, respectively, of radium-223

patients, compared with 1% and 2% of placebo patients, Dr. Parker reported, and no significant differences existed in the incidence of severe diarrhea or vomiting between the two groups. The FDA approval of radium-223 that is likely to follow the trial’s early cessation would make it the latest in

a string of drugs recently introduced for the treatment of mCRPC. In April, the FDA approved abiraterone acetate (Zytiga, Centocor Ortho Biotech) for mCRPC refractory to docetaxel therapy, and 2010 saw the approval of cabazitaxel (Jevtana, Sanofi-aventis) for the same indication and sipuleucel-T (Provenge, Dendreon) for asymptomatic or minimally symptomatic mCRPC.

• Vis

it u

see RADIUM-223, page 45

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30 Clinical

Pharmacy Practice News â&#x20AC;˘ November 2011

Educational Review

Changing Paradigms in the Management of

Metastatic Castration-Resistant Prostate Cancer Emmanuel S. Antonarakis, MD Assistant Professor of Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland

Andrew J. Armstrong, MD, ScM Assistant Professor of Medicine and Surgery Duke Cancer Institute and the Duke Prostate Center Duke University Durham, North Carolina

n the past year, great strides have been made in identifying effective, new therapies for men

with advanced castration-resistant prostate cancer (CRPC). Three novel agents (sipuleucel-T, cabazitaxel, and abiraterone acetate) have been shown to improve overall survival (OS) in

these patients, while another agent (denosumab) has been shown to result in a significant delay in skeletal-related events (SRE) in men with castration-resistant bone metastases.

Despite these advances, approximately 30,000 men still die of advanced prostate cancer in the United States each year,1 making it the second most common cause of cancer-related death among American men. Therefore, additional treatments are needed and available therapies need to be optimized. This review discusses the range of novel agents that are newly approved or expected to be approved soon for the management of metastatic CRPC (Figure 1) and highlights emerging agents that have shown promise and are in Phase III clinical development (Table 1).

Newly Approved Agents: Where Do They Fit In? Sipuleucel-T Cancer immunotherapy refers to approaches that attempt to treat cancer by activating an immune response against malignant cells while overcoming tumor-induced tolerance, a major resistance mechanism (Figure 2). Prostate cancer may be an ideal target for immunologic attack because it produces several tissue-specific proteins that may serve as tumor antigens, such as prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) (Figure 3). This notion has been applied to the development of sipuleucel-T (Provenge, Dendreon), an

autologous PAP-loaded dendritic cell immunotherapy.2 During treatment with sipuleucel-T, a patientâ&#x20AC;&#x2122;s own antigen-presenting cells are collected by leukapheresis and co-incubated with a fusion protein containing PAP linked to granulocyte macrophage colony-stimulating factor (GM-CSF). After this fusion protein is cultured with the antigen-presenting cells, the primed immunotherapy is reinfused into the patient, activating T cells via major histocompatibility complex class I and class II molecules and resulting in a PAP-specific antitumor attack.3 Several early-phase clinical trials using this immunotherapy have demonstrated the safety of this personalized cellular product and have hinted at the potential ability to improve outcomes. Two small, randomized Phase II trials powered to detect a progression-free survival (PFS) advantage failed in their primary end point but showed that sipuleucel-T resulted in a significant 4- to 5-month survival advantage over placebo.4,5 Adverse events (AEs) with sipuleucel-T are generally mild and include fever, chills/sweats, myalgia, and headache. These usually occur during or shortly after infusion of the immunotherapy. To definitively evaluate the effect of sipuleucel-T on survival, the pivotal multicenter Phase III IMPACT trial was conducted in men with asymptomatic or minimally symptomatic metastatic Text continues on page 32

32 Clinical

Pharmacy Practice News • November 2011

Educational Review Non-metastatic hormoneresponsive prostate cancer Text continued from page 30

Non-metastatic

CRPC,6 leading to the FDA approval CRPC of this agent in April 2010. In this douClinically Biochemically ble-blind, placebo-controlled trial, 512 localized relapsed Supportive prostate cancer prostate cancer patients were randomized (2:1) to sipCare uleucel-T or placebo, and the study (Prostatectomy (Salvage Radiation ± ADT radiation) was powered to detect an OS advanBrachytherapy tage. Notably, this study did not enroll Metastatic ChemotherapyPrimary ADT Metastatic men with visceral metastases or those hormone-responsive refractory Active CRPC taking narcotics for cancer pain, and prostate cancer CRPC surveillance) most patients (85%) were chemotherapy-naive. Impressively, median Observation ➞ ADT OS was 25.8 months in the sipuleucelT group versus 21.7 months in the placebo group (hazard ratio [HR], 0.78; Zoledronic acid or denosumab P=0.03), despite 64% of patients on placebo crossing over to receive salvage sipuleucel-T. In the subset of Abiraterone, Docetaxelcabazitaxel, patients with prior chemotherapy prednisone mitoxantrone exposure, OS trended in favor of sipuleucel-T, but this effect was not statistically significant. Therefore, although Sipuleucel-T this immunotherapy is approved for all patients with asymptomatic or minimally symptomatic CRPC, it likely will Secondary/tertiary hormonal therapies have its largest impact in the pre-che(anti-androgens, ketoconazole, steroids, = Standard of care estrogens) motherapy setting. = Speculative Similar to previous studies with sipuleucel-T, the IMPACT study found no MDV3100, orteronel, ipilimumab, abiraterone difference in PFS or PSA/radiographic response rates between the 2 treatment arms. Some investigators attribute the Figure 1. The treatment landscape for prostate cancer in 2011. discordance between PFS and OS to a ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer possible class effect of immunotherapy agents, relating to their mechanism of action, which is distinct from that of The most common serious AEs related to cabachemotherapy.12 Of these, 377 patients were rancytotoxic therapies. To this end, a similar phenomdomized to receive mitoxantrone 12 mg/m2 IV zitaxel were hematologic, including grade 3 or enon has been observed in a study using a PSAevery 3 weeks (with oral prednisone 10 mg daily) higher neutropenia in 82% of patients (febrile neudirected poxviral-based immunotherapy product and 378 patients were assigned to receive cabatropenia in 8%).12 This degree of myelosuppres(ProstVac-VF) in men with metastatic CRPC.7 Problematic end points such as PFS in CRPC (which sion begs the question of whether a lower dose of zitaxel 25 mg/m2 IV every 3 weeks (plus prednisone). This study was the basis for the FDA’s may be confounded by bone scan flare or delayedcabazitaxel (eg, 20 mg/m2) may have been more appropriate, and a randomized trial comparing approval of cabazitaxel with prednisone for the onset effects) may be better addressed by revised the safety and efficacy of these 2 doses (25 vs 20 second-line treatment of docetaxel-refractory guidelines using outcomes that are tailored to mg/m2) is being conducted. Use of growth facmetastatic CRPC in June 2010. immunologic agents.8 tor support should be strongly considered, as recAfter a median follow-up of 12.8 months, OS in Cabazitaxel With Prednisone ommended in several national guidelines.13 Nonmen receiving cabazitaxel was 15.1 months comCabazitaxel (Jevtana, Sanofi-aventis) is a novel hematologic toxicities included grade 3 or higher pared with 12.7 months in men receiving mitotubulin-binding taxane that differs from docetaxdiarrhea (6%) and grade 3 or higher fatigue (5%). xantrone (HR, 0.70; P<0.0001).12 Compared with mitoxantrone, cabazitaxel also significantly lengthel and paclitaxel because of its poor affiniAlthough peripheral neuropathy (all grades) was ened PFS (2.8 vs 1.4 months; P<0.0001), extendty for P-glycoprotein, the adenosine triphosobserved in 14% of patients receiving cabazitaxel, ed the time to PSA progression (6.4 vs 3.1 months; phate–dependent drug efflux pump.9 In preclinonly 1% developed grade 3 neuropathy. ical studies using cancer cell lines and mouse P=0.001), increased radiographic tumor response Abiraterone Acetate With Prednisone xenograft models, cabazitaxel was shown to be rates (14.4% vs 4.4%; P=0.0005), and increased active against both docetaxel-sensitive tumors as PSA response rates (39.2% vs 17.8%; P=0.0002). Ectopic (adrenal, intratumoral, paracrine) well as those with primary or acquired docetaxThere were no differences between the 2 treatandrogen production in the setting of gonadel resistance.10 ment arms with respect to pain responses or time al ablative therapies represents an important The first hint of cabazitaxel’s safety and efficato pain progression. resistance mechanism in CRPC (Figure 2). Abicy in men with prostate cancer came during Phase In subset analyses, the survival advantage raterone acetate (Zytiga, Centocor Ortho Biotech) I testing, during which cabazitaxel was adminisof cabazitaxel persisted regardless of whether is a potent, selective, and irreversible oral inhibtered by IV infusion every 3 weeks at escalating patients had measurable disease or pain or whethitor of the steroidogenic enzyme CYP17, blockdoses of 10 to 25 mg/m2.11 In that study, the princier progression had occurred during docetaxel ing 17a-hydroxylase and C17,20-lyase activity.14 pal dose-limiting toxicity was neutropenia. Given As a result, extragonadal androgen production is therapy or following a treatment holiday. In addithe lack of cross-resistance to this agent with impaired through the inability to convert pregtion, cabazitaxel’s survival benefit was most prodocetaxel and early reports of responses in men nenolone to dihydroepiandrostenedione and pronounced for men with Eastern Cooperative Oncolwith CRPC during this Phase I trial, a Phase III trial gesterone to androstenedione. In an initial Phase I ogy Group performance status 0 to 1 (vs 2) and was launched to evaluate efficacy. study in men with chemotherapy-naive CRPC, the for patients with disease progression less than 3 The pivotal Phase III TROPIC trial definitiveprimary toxicities of abiraterone (hypertension, months after docetaxel initiation (vs 3 or more ly evaluated the safety and efficacy of cabahypokalemia, and peripheral edema) were relatmonths after docetaxel initiation).12 The last observation implies that cabazitaxel may be effective zitaxel in 755 men with metastatic CRPC who ed to a syndrome of secondary mineralocorticoid Text continues on page 34 even in men with truly docetaxel-refractory disease. had progressed during or after docetaxel-based

34 Clinical

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Educational Review Text continued from page 32

excess due to feedback upregulation of mineralocorticoid synthesis and were largely reversible with administration of an aldosterone receptor antagonist or a corticosteroid.15 For this reason, in several subsequent trials, abiraterone was combined with low-dose prednisone, which also may enhance the efficacy of abiraterone. The initial efficacy of abiraterone in CRPC was investigated in several Phase II trials. In patients with chemotherapy-naive metastatic CRPC, PSA declines of at least 50% were seen in approximately 65% of men and radiographic tumor responses occurred in about 35% of men,16 with responses noted even among men who had prior ketoconazole exposure.17 Finally, in patients with docetaxel-refractory metastatic CRPC, PSA declines of at least 50% were observed in approximately 40% of men and objective tumor responses occurred in approximately 20% of cases.18,19 Notably, the use of a corticosteroid on PSA progression frequently led to subsequent secondary PSA declines, suggesting

a reduction in androgen receptor (AR) activation by upstream steroidal precursors that are increased by feedback mechanisms. To conclusively evaluate the efficacy and safety of abiraterone, a pivotal, multicenter, randomized, blinded, placebo-controlled Phase III trial (COUAA-301) was conducted in men with docetaxel-pretreated, ketoconazole-naive metastatic CRPC.20 This trial randomized men (2:1) to receive either abiraterone 1,000 mg daily plus prednisone 10 mg daily (n=797) or placebo plus prednisone (n=398). The trial met its primary end point, demonstrating a median OS of 14.8 months in the abiraterone arm and 10.9 months in the placebo arm (HR, 0.65; P<0.0001). In addition, when compared with placebo, abiraterone prolonged radiographic PFS (5.6 vs 3.6 months; P<0.0001), improved time to PSA progression (10.2 vs 6.6 months; P<0.0001), and produced more PSA responses (38% vs 10%; P<0.0001). Notably, the OS duration seen here (14.8 months) is similar to that seen with cabazitaxel/prednisone (15.1 months) in this second-line

population with similar baseline characteristics (Table 2); however, the survival of men treated with prednisone alone was slightly inferior to that associated with mitoxantrone/prednisone in the TROPIC trial (10.9 vs 12.7 months). Based on the results of the COU-AA-301 trial, on April 28, 2011 the FDA approved abiraterone with prednisone for patients with metastatic CRPC who have received prior docetaxel-based chemotherapy. Recently updated National Comprehensive Cancer Center guidelines specify that abiraterone acetate with prednisone should be considered for men who have failed docetaxel-based chemotherapy for metastatic CRPC or who are not candidates for chemotherapy.21 A second randomized Phase III trial (COU-AA-302) targeting men with docetaxel- and ketoconazole-naive CRPC has completed accrual of more than 1,000 patients. Given the comfort level and safety of using this and other hormonal agents in patients with prostate cancer prior to chemotherapy, it is very likely that abiraterone Text continues on page 36

Table 1. Selected Ongoing Phase III Clinical Trials in Men With Metastatic CRPC Target/Pathway

Phase

Treatment Arm(s)

Primary End Point

Identifier

Cabazitaxel

III

Cabazitaxel 25 mg/m2 IV every 3 wk vs docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

NCT01308567

Cabazitaxel

III

Cabazitaxel 25 mg/m2 IV every 3 wk vs cabazitaxel 20 mg/m2 IV every 3 wk (post-docetaxel)

OS (noninferiority)

NCT01308580

Abiraterone

III

Abiraterone 1,000 mg orally daily vs placebo orally daily (pre-docetaxel)

OS and PFS NCT00887198 (co-primary)

Orteronel

III

Orteronel 400 mg orally twice daily vs placebo orally twice daily (pre-docetaxel)

OS and PFS NCT01193244 (co-primary)

III

Orteronel 400 mg orally twice daily vs placebo orally twice daily (post-docetaxel)

III

MDV3100 160 mg orally daily vs placebo orally daily (pre-docetaxel)

OS and PFS NCT01212991 (co-primary)

III

MDV3100 160 mg orally daily vs placebo orally daily (post-docetaxel)

NCT00974311

III

Ipilimumab 10 mg/kg IV every 3 wk vs placebo IV every 3 wk (pre-docetaxel)

NCT01057810

III

Bone irradiation, then ipilimumab 10 mg/kg IV every 3 wk vs placebo IV every 3 wk (post-docetaxel)

NCT00861614

Agent

Chemotherapeutic agents Microtubules (taxane)

AR-directed approaches CYP17 (androgen synthesis)

Androgen receptor

MDV3100

NCT01193257

Immunotherapies CTLA-4 (immune checkpoint)

Ipilimumab

Other targeted therapies Src kinase (bone regulation)

Dasatinib

III

Dasatinib 100 mg orally daily plus docetaxel 75 mg/m2 IV every 3 wk vs placebo orally daily plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

NCT00744497

Clusterin (apoptosis)

Custirsen

III

Custirsen 640 mg IV every 1 wk plus docetaxel 75 mg/m2 IV every 3 wk vs docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

NCT01188187

III

Custirsen 640 mg IV every 1 wk plus docetaxel 75 mg/m2 IV every 3 wk vs placebo IV every wk plus docetaxel 75 mg/m2 IV every 3 wk (post-docetaxel)

Improvement in pain

NCT01083615

VEGF-Trap (angiogenesis)

Aflibercept

III

Aflibercept 6 mg/kg IV plus docetaxel 75 mg/m2 IV every 3 wk vs placebo IV plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

NCT00519285

Immunomodulatory drugs (angiogenesis)

Lenalidomide

III

Lenalidomide 25 mg orally (days 1-14) plus docetaxel 75 mg/m2 IV every 3 wk vs oral placebo (days 1-14) plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

NCT00988208

S100A9 (angiogenesis)

Tasquinimod

III

Tasquinimod 1 mg orally daily vs oral placebo daily (pre-docetaxel)

PFS

NCT01234311

Endothelin (bone targeting)

Atrasentan

III

Atrasentan 10 mg orally daily plus docetaxel 75 mg/m2 IV every 3 wk vs oral placebo plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS and PFS NCT00134056 (co-primary)

Zibotentan

III

Zibotentan 10 mg orally daily plus docetaxel 75 mg/m2 IV every 3 wk vs oral placebo plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

AR, androgen receptor; CRPC, castration-resistant prostate cancer; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CYP17, cytochrome P450 17; OS, overall survival; PFS, progressionâ&#x20AC;&#x201C;free survival; Src, signal-regulated kinase; VEGF, vascular endothelial growth factor

NCT00617669

36 Clinical

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Educational Review Text continued from page 34

will be used clinically in both the pre- and postdocetaxel settings.22 Denosumab: Osteoclast-Targeted Therapy Interactions between tumor cells and the bone marrow microenvironment have been postulated as an important mechanism in the pathogenesis of bone metastasis. Tumor-associated cytokines have been shown to induce the expression of RANKL (receptor activator of nuclear factorkB ligand), which binds and activates RANK found on osteoclasts.23 Inhibition of RANKL recently has been the focus of much clinical research and represents an effective osteoclast-targeting strategy for patients with bone metastases. Denosumab (Xgeva, Amgen) is a fully human monoclonal immunoglobulin G2 antibody with a very high affinity for human RANKL.24 Denosumab, which has been examined in a variety of clinical settings, including postmenopausal osteoporosis and several cancers, has demonstrated efficacy in bone-metastatic solid tumors predominantly. An early Phase II study demonstrated that denosumab (120 mg subcutaneously every 4 weeks) was associated with a reduction of bone resorption compared with zoledronic acid (Zometa, Novartis) (4 mg IV every 4 weeks), as indicated by a lowering of urinary N-telopeptide levels,

and also resulted in fewer SREs, that is, pathologic fracture, radiation therapy, surgery to bone, spinal cord compression, or malignant hypercalcemia.25 Following these encouraging results, a pivotal, multicenter, randomized double-blind, Phase III study was conducted comparing denosumab with zoledronic acid for the prevention of SREs in patients with bisphosphonate-naive metastatic CRPC. In that trial of 1,904 patients, compared with men receiving zoledronic acid (n=951), men receiving denosumab (n=950) had an improved time to first SRE (20.7 vs 17.1 months; P=0.008) and longer time to first and subsequent SRE (HR, 0.82; P=0.004).26 Notably, there were no differences in OS or PFS between study arms. Based partially on the results of this study (and partially on 2 other large randomized studies in metastatic breast cancer and other solid metastatic tumors), the FDA approved denosumab in November 2010 for the prevention of SREs in patients with bone metastases from solid tumors. Common toxicities of denosumab include fatigue, nausea, hypophosphatemia, hypocalcemia (5% â&#x2030;Ľ grade 3), and osteonecrosis of the jaw (2%). Prophylactic calcium and vitamin D supplementation is strongly encouraged when this agent is used. Denosumab is a reasonable alternative to zoledronic acid for the prevention of SREs in patients with metastatic CRPC, with the advantage that it

Immunologic escape/tolerance Proliferative signals (MAP kinases, Myc, tubulin signaling)

AR-independent mechanisms

Survival signals (PTEN loss, Akt activation, JNK, VEGF, MET) Bone microenvironment (Src kinase, endothelin, RANKL)

Metastatic prostate cancer

Stem cell factors (hedgehog), antiapoptotic signals (Bcl-2, clusterin), EMT programs, DNA repair Androgen ablation

CRPC Antiandrogens AR amplification/overexpression AR gene mutation (activating) or mRNA splice variants

AR-dependent mechanisms

Ectopic androgen synthesis (adrenal, intratumoral) AR-dependent fusion proteins (TMPRSS2-ERG) Non-canonical AR signaling (Src, G proteins, Akt, PKA/PKC)

Figure 2. Mechanisms of castration resistance in prostate cancer. AR, androgen receptor; CRPC, castration-resistant prostate cancer; EMT, epithelial to mesenchymal transition; JNK, Jun N-terminal kinase; MAP, mitogen-activated protein; MEK, MAP kinase kinase; PKA/PKC, protein kinase A/protein kinase C; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RANKL, receptor activator of nuclear factor-kB ligand; Src, signal-regulated kinase; VEGF, vascular endothelial growth factor

does not require dose adjustment or monitoring for renal impairment.

Emerging Agents in Phase III Testing: The Pipeline Novel Hormonal Approaches: Targeting the AR Orteronel. Orteronel (TAK-700) is a new oral, nonsteroidal, selective CYP17 inhibitor that is more potent than abiraterone at suppressing extragonadal androgen biosynthesis without impairing cortisol production,27 providing a theoretical advantage of preventing adrenocorticotropic hormone feedback upregulation and avoiding complications related to secondary mineralocorticoid excess. In a Phase I/II study using orteronel in patients with metastatic CRPC, 52% of men receiving daily doses 600 mg or greater demonstrated at least 50% PSA reductions (and 29% of men showed at least 90% PSA reductions).28 Importantly, the incidence of hypertension and hypokalemia in this trial was low, supporting the notion of preferential inhibition of C17,20-lyase over 17a-hydroxylase in humans. Based on the initial promising activity, 2 multicenter, randomized, Phase III trials have been launched comparing orteronel in combination with prednisone against prednisone alone both before and after docetaxel in patients with metastatic CRPC. MDV3100. A slightly different AR-directed approach has focused on the development of second-generation antiandrogens that have advantages over the established agents in this class (bicalutamide, nilutamide, flutamide). One such drug is MDV3100, a potent oral nonsteroidal AR antagonist.29 Importantly, MDV3100 remains a potent antagonist of the AR in the castration-resistant state, even in the setting of overexpressed or constitutively activated AR.30 In addition, unlike other antiandrogens that also may function as partial AR agonists, MDV3100 does not exhibit any measurable agonistic activity and is able to prevent AR nuclear translocation with resultant tumoricidal (not cytostatic) activity.31 Notably, recent studies have demonstrated the emergence of ligand-independent AR splice variants in CRPC, some of which may also be inhibited by MDV3100. A Phase I/II study of oral MDV3100 in men with chemotherapy-naive (n=65) or taxane-pretreated (n=75) metastatic CRPC recently was published.32 In that trial, PSA declines of at least 50% were seen in 62% and 51% of chemotherapy-naive and taxane-pretreated patients, respectively, and objective tumor responses were observed in 36% and 12%, respectively. Radiographic PFS was 6.7 months in the docetaxel-pretreated patients, and more than 17 months in chemotherapy-naive patients. Side effects of MDV3100 are generally mild, and include fatigue (27%) and nausea (9%). Rare seizures (3 of 140 patients), perhaps mediated by a direct effect of AR antagonism on central nervous system Îł-aminobutyric acid-A receptors, also were reported.33 A pivotal, double-blind, placebo-controlled Phase III study (AFFIRM), randomizing 1,170 patients with docetaxel-pretreated ketoconazolenaive CRPC to MDV3100 160 mg daily (n=780) or placebo (n=390), has completed accrual. A second randomized Phase III trial (PREVAIL) investigating Text continues on page 38

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Educational Review Text continued from page 36

the same treatment arms in men with chemotherapy-naive CRPC is under way. One advantage of MDV3100 over agents such as abiraterone or orteronel is the lack of requirement for concurrent corticosteroid administration. However, the optimal sequencing of this agent, if approved, with immunotherapies and other emerging hormonal therapies will need to be defined through future clinical trials. Novel Immune Approaches

Abiraterone, orteronel

Adrenal gland

Bevacizumab, aflibercept

Ipilimumab

APC

Dasatinib

IGF-1R

VEGF-R

CTLA-4

T cell

PAP peptide

T cell

Ras P13K

PAP

Cabozantinib

Src

Sipuleucel-T GM-CSF

Raf

PTEN

Src

Cell death Akt

Ipilimumab. Because of ongoing host MEK immunologic pressures on evolving Stress tumors, cancers have developed mechTOK-001 anisms to escape immune surveillance, A ERK mTOR effectively inducing a state of immune HSP HSP AR tolerance.34 One way to inhibit immunoClusterin logic evasion by tumor cells is through Growth, Survival, blockade of the immune checkpoint differentiation, proliferation, transformation angiogenesis MDV3100 molecule cytotoxic T lymphocyte-assoCustirsen ciated antigen-4 (CTLA-4), thus preventing the normal attenuation of antiApoptosis tumor T-cell responses.35 In murine prosA HDAC tate cancer models, CTLA-4 inhibition Transcription has been shown to potentiate T-cell PARP CoAct AR DNMT effects and induce tumor rejection. Several clinical trials using the monoclonal anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) have been conducted in men with metastatic CRPC. These include Phase I and II studFigure 3. Promising pathways and targets in metastatic CRPC. ies of ipilimumab as monotherapy or in A, androgen; APC, antigen-presenting cell; AR, androgen receptor; CoAct, transcriptional coactivators; DNMT, DNA methyltransferase; combination with radiation,36 as well as ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte macrophage colony-stimulating factor; HDAC, histone deacetylase; a Phase I study combining ipilimumab HSP, heat shock protein; IGF-1R, insulin-like growth factor receptor-1; MEK, MAP kinase kinase; mTOR, mammalian target of rapamycin; PAP, prostatic acid phosphatase; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin with GM-CSF.37 PSA reductions of at homolog deleted on chromosome 10; Src, signal-regulated kinase; VEGF-R, vascular endothelial growth factor receptor least 50% were observed in approximately 20% of patients, and radiologic tumor responses were seen in approxioncogenic kinases including Src. In experimental to this protein. Expression of clusterin in prosmately 5% of patients, which is particumodels, dasatinib reduced proliferation of prostate tumors increases after androgen ablation or larly noteworthy, given that PSA and tumor tate cancer cells, adhesion, migration, invasion, chemotherapy treatment,46 conferring a more responses were rarely reported in the immunotumor growth, and lymph node involvement in a resistant phenotype. Custirsen (Oncogenex) is a therapy trials with sipuleucel-T or other therapeuprostate cancer mouse xenograft model.41,42 novel intravenously administered antisense olitic vaccines. Common AEs of ipilimumab include Although single-agent dasatinib (Sprycel, Brisgonucleotide that inhibits clusterin at the mRNA fatigue (42%), nausea (35%), pruritus (24%), contol-Myers Squibb) has demonstrated little clinilevel, increasing sensitivity to androgen deprivastipation (21%), and rash (19%). In addition, because cal activity, more than half of CPRC subjects had tion as well as chemotherapy in prostate cancer CTLA-4 normally serves to attenuate autoimmuniat least 40% declines in urinary N-telopeptide cell lines and xenograft models.47 ty, immunologic toxicities resulting from an In a randomized Phase II study of docetaxel levels (a marker of bone resorption), and 60% unchecked immune response may occur. Such with or without custirsen in 82 patients with showed reductions in bone alkaline phosphaimmune-related AEs include colitis (8%), adrenal metastatic CRPC, PSA responses (58% vs 54%) tase, suggesting benefits on bone turnover indeinsufficiency (2%), hepatitis (1%), and even hypophand PFS (7.3 vs 6.1 months) were similar in both pendent of bisphosphonate use.43 In a separate ysitis (1%).38 Ipilimumab is in placebo-controlled Phase III testing in the post-docetaxel setting in Phase I/II study combining dasatinib with docetaxarms.48 However, OS trended in favor of the combination arm (23.8 vs 16.9 months; P=0.06), even men with CRPC following a palliative (and perhaps el in a similar patient population, PSA responses though survival was not the primary end point of immune-stimulatory) dose of radiation to a metawere observed in 57% of participants, objective this study and was potentially confounded by static site, with the intent to demonstrate a survivresponses were seen in 60% of patients, and 30% subsequent therapies. AEs associated with al advantage over radiation alone. A second of patients with bone metastases showed ameliocustirsen include fatigue (>80%), fever (30%pre-docetaxel placebo-controlled Phase III study ration in bone scans.44 A large randomized, placebo-controlled Phase III study evaluating this 50%), rigors (40%-60%), diarrhea (40%-60%), also is under way. combination in 1,500 men with metastatic chemoand rash (20%-40%). A placebo-controlled Novel Targeted Therapies therapy-naive CRPC has completed accrual and Phase III study of docetaxel retreatment with or is powered to detect an OS advantage. Adverse without custirsen for the second-line manageSrc kinase inhibitors. Src is a non-receptor effects of dasatinib include diarrhea (62%), naument of men with docetaxel-refractory disease tyrosine kinase signal transduction protein that sea (47%), fatigue (45%), and fluid retention (21%). was recently launched. However, the recent is involved in tumor cell proliferation, migration, Pro-apoptotic drugs. Clusterin, a stressapprovals of cabazitaxel and abiraterone and angiogenesis, survival, and transition to the casinduced anti-apoptotic chaperone protein changing standards of care call into question the tration-resistant state.39 Src also controls osteoclastic activity and has been implicated in the expressed in various cancers including prosvalue of docetaxel retreatment in all but a select development and progression of bone metastate cancer,45 has received renewed attention group of men in this setting. 40 Text continues on page 40 due to the development of antisense inhibitors tases. Dasatinib is an oral inhibitor of multiple

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Antiangiogenic strategies. Tumor angiogenesis may play an important role in prostate cancer maintenance and progression, and elevated plasma levels of vascular endothelial growth factor (VEGF) have been correlated with advanced clinical stage and decreased survival.49 Antibodies to VEGF slow tumor proliferation in prostate cancer xenograft models, especially when combined with chemotherapy.50 However, despite a strong preclinical rationale, a Phase III randomized study in men with chemotherapy-untreated CRPC (CALGB 90401) failed to show a survival advantage with the antiVEGF antibody bevacizumab (Avastin, Genentech) when combined with docetaxel compared with docetaxel alone (22.6 vs 21.5 months), although significant improvements were seen in PSA responses (70% vs 58%), radiographic responses (53% vs 42%), and PFS (9.9 vs 7.5 months).51 Additionally, a Phase III trial of sunitinib malate (Sutent, Pfizer) versus prednisone in men with docetaxelpretreated metastatic CRPC failed to demonstrate an OS advantage, despite modest improvements in response rates and PFS.52 These results call into question the role for VEGF-based therapies in unselected men with CRPC. Future development of this and other antiangiogenic agents may rely on combinations with other classes of angiogenesis inhibitors or other chemotherapeutic drugs whose toxicities do not overlap and will require careful patient selection for those men who are most likely to benefit from this class of agents. Another angiogenic/metastatic target that has

Table 2. Pivotal Second-line Trials For Men With Metastatic CRPC: COU-AA-301 Versus TROPIC Cabazitaxel/ Prednisone (TROPIC)

Abiraterone/ Prednisone (COU-AA-301)

Median baseline PSA, ng/mL

144

129

Pain at baseline, %

Presence of visceral disease, %

31 2 (or more) prior chemotherapies, %

Median OS, mo

15.1

14.8

Median time to tumor progression, mo

8.8

5.6

Median time to PSA progression, mo

6.4

10.2

PSA response rate (≥50% PSA decline), %

Objective response rate, %

Pain response, %

Investments in Prostate Cancer Research Are Starting To Pay Off William D. Figg Sr., PharmD, William D. Figg II, Cindy Chau, PharmD, PhD National Cancer Institute, Bethesda, Maryland

he past 12 months have been extremely exciting for those of us who focus on treating patients with prostate cancer. Four new agents have been approved for the treatment of this disease, 3 of which prolong survival and 1 of which delays skeletal-related events (SREs). Additional agents and combinations are being studied as well. The educational review by Antonarakis and Armstrong in this issue accurately describes how the newly approved agents fit into the treatment paradigm for prostate cancer. With that said, the real question will be how clinicians ultimately will use these new agents. Our sense is that there is some hesitation in the widespread use of sipuleucel-T (Provenge, Dendreon). Not only is the price excessive, but also the required leukapheresis has turned off most medical oncologists and urologists, and they have not adopted the therapy in their standard treatment regimens. We are excited about the ongoing Phase III of the vaccine PROSTVAC (Bavarian Nordic), which may provide an alternative immunologic approach to this disease. Likewise, the approval of cabazitaxel (Jevtana, Sanofi-aventis), the second chemotherapy agent to prolong survival in prostate cancer and the first in the post-docetaxel setting, was exciting. However, the use of cabazitaxel appears to be guarded because of concerns about adverse events (82% of patients developed grade 3 or higher neutropenia).1 The Phase III trial had reported 18 (5%) deaths in the cabazitaxel arm. We strongly recommend the use of growth-factor support concurrent with cabazitaxelbased regimens in patients at an increased risk for neutropenia complications. Denosumab (Xgeva, Amgen), an inhibitor of receptor activator of nuclear factor-κB ligand (RANKL) that results in osteoclast-targeting for patients with bone metastases, was approved for being more effective than zoledronic acid (a bisphosphonate) at decreasing the risk for bone fractures and other SREs (20.7 vs 17.1 months).2 Nonetheless, there was no effect on progression-free survival or overall survival (OS), and there is growing concern about osteonecrosis of the jaw in all of the bone-targeted agents (incidence of 4.6% in the denosumab-treated arm). Abiraterone (Zytiga, Centocor Ortho Biotech) has quickly gained clinical use. In fact, abiraterone may be used more in the pre-chemotherapy setting than the post-docetaxel setting (even before the Phase III trial results are reported). However, the cost of the agent has caused concern (approximately $5,000 per month). The role of angiogenesis inhibitors in prostate cancer has been called into question by the recent results of the Phase III trial of bevacizumab (Avastin, Genentech/Roche).3 Although we are confident that there is a place for these targeted agents in the treatment of metastatic castration-resistant prostate cancer, based on our clinical data, it is unclear whether we should simultaneously target more than one proangiogenic pathway.4 We are eagerly awaiting the results of the Phase III trial of aflibercept, also known as VEGF Trap (Sanofi-aventis). This trial is comparing docetaxel with aflibercept to docetaxel alone to assess whether there is an OS difference. Additionally, early bone scan data with cabozantinib (XL184, Exelixis) is encouraging and needs to be validated in a larger trial. Additionally, another Phase III trial has reported positive results in meeting the primary end point of OS with radium-223 chloride (Alpharadin, Algeta).5 Moreover, we are anxiously awaiting the results of several ongoing pivotal trials with other agents, such as orteronel (Millennium), MDV3100 (Medivation), dasatinib (Sprycel, Bristol-Myers Squibb), custirsen (OncoGenex), lenalidomide (Revlimid, Celgene), tasquinimod (Active Biotech), atrasentan (Xinlay, Abbott), and zibotentan (AstraZeneca). We are now beginning to see the fruits of labor after 20 years of investing in elucidating the molecular mechanisms underlying prostate cancer development and progression. Each of these agents can trace its origin to the knowledge gained through a better understanding of basic biology of prostate cancer. Furthermore, the clinical results are having an impact on the lives of patients with this disease. We are optimistic that several of the ongoing Phase III trials will meet their primary end points, resulting in an expanded armamentarium of agents to treat this disease.

References 1. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;2;376(9747):1147-1154. 2. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;5;377(9768):813-822. 3. Kelly WK, Halabi S, Carducci MA, et al. A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401. 2010 ASCO Annual Meeting. J Clin Oncol. 2010;28:18(suppl). Abstract LBA4511. 4. Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010; ;28(12):2070-2076.

OS, overall survival; PSA, prostate-specific antigen

5. Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit of radium-223 chloride (Alpharadin™) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a Phase III randomized trial (ALSYMPCA). Eur J Cancer. 2011;47(suppl 2). Abstract 1LBA.

received recent attention is MET, a transmembrane receptor whose only known ligand is hepatocyte growth factor. Aberrant activation or overexpression of MET is a common event in prostate cancer (especially in castration-resistant bone metastases) and is associated with proliferation, invasion, and angiogenesis.53 Moreover, androgen suppression can induce increased MET expression.54 Cabozantinib (XL184, Exelixis) is a potent oral inhibitor of MET and VEGF-receptor 2 that has demonstrated robust antiangiogenic, antiproliferative, and anti-invasive activity in preclinical systems.55

Preliminary results from a Phase II study in men with metastatic CRPC with up to one prior chemotherapy revealed objective responses in 10% of evaluable patients, and improvements in bone scans after 12 weeks in 95% of men with osseous metastases (often accompanied by pain improvements).56 Toxicities with this agent include fatigue (67%), diarrhea (55%), anorexia (51%), emesis (44%), and hypertension (22%). Although the 12-week success rates in bone lesions are striking (including complete resolution of skeletal Text continues on page 42

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abnormalities in some bone scans), the lack of robust PSA responses and the uncertainty over the durability of these results will require confirmatory controlled trials to assess the overall clinical benefit of this agent. Further investigation of this agent’s activity in the bone using novel imaging techniques (eg, 18Fluorodeoxyglucose-positron emission tomography) or pharmacodynamic studies should also be considered to further understand how cabozantinib influences

metastatic disease. differentiation as well as recruitment A final angiogenesis-inhibiting of tumor-infiltrating myeloid-derived agent that has received renewed suppressor cells.58 A randomized, douattention is the oral quinoline deriva- ble-blind placebo-controlled Phase II tive tasquinimod. Although the antian- study involving 200 patients with chegiogenic properties of this agent have motherapy-naive metastatic CRPC been amply demonstrated in sever- demonstrated that patients receiving al in vitro and in vivo prostate can- oral tasquinimod had a median PFS cer models,57 the exact mechanism of of 7.6 months versus 3.2 months in action remains elusive and appears to those receiving placebo (P=0.001).59 be unrelated to VEGF receptor inhi- AEs with this agent included gastrobition. It may include inhibition of intestinal disorders (40%), fatigue S100A9, a calcium-binding protein (23%), musculoskeletal pain (12%), involved in cell cycle progression and and asymptomatic pancreatic enzyme

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elevations. Rare but serious toxicities were venous thrombosis (4%), heart failure (1%), myocardial infarction (1%), and stroke (1%). A multicenter, randomized Phase III trial of tasquinimod versus placebo in patients with chemotherapy-untreated metastatic CRPC is under way.

Conclusion Despite more drugs for the treatment of metastatic CRPC at our fingertips than ever before and an increasing number of novel therapeutic targets being discovered every day, we are still left with several challenges and unanswered questions. First, we must determine how these approved and experimental therapies should ideally be sequenced in individual patients with CRPC. For example, should sipuleucel-T routinely be given prior to chemotherapy or abiraterone with prednisone? Should abiraterone be reserved for docetaxel-resistant patients? How should we treat cabazitaxel-refractory patients? Second, we need to develop strategies to optimally combine these drugs in a rational manner, taking advantage of our understanding of negative feedback loops and alternative pathway activation to overcome resistance to monotherapies. Ultimately, only prospective trials incorporating biomarker-driven hypotheses will be able to address these key clinical questions. Thus, the collection of tumor specimens or correlative samples may be essential in identifying novel targets or developing enrichment strategies for future study of these agents. Third, we must design smarter trials with the goal of quickly yet reliably identifying agents that do not hold promise while enabling those that do to move swiftly to registrational studies. For example, in the clinical development of MDV3100 and cabazitaxel, pivotal Phase III trials were designed directly following the initial Phase I/II studies that demonstrated significant drug activity in men with CRPC. Finally, we must select our patients more carefully based on clinical or molecular characteristics to identify the subset most likely to benefit from a particular therapy. For example, in men with significant pain, perhaps sipuleucel-T is not appropriate systemic therapy given the prolonged onset of action and lack of palliative benefits; additionally, immune-based biomarkers may shed light on which men may obtain a greater degree of benefit from immunotherapies. In summary, cabazitaxel was the first agent to be approved by the FDA for men with metastatic CRPC who have progressed after docetaxel chemotherapy, and abiraterone acetate

Pharmacy Practice News • November 2011

Clinical 43

Educational Review 12. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant prostate cancer progressing after docetaxel treatment: a randomised openlabel trial. Lancet. 2010;376:1147-1154, PMID: 20888992. 13. Mohler J, Bahnson RR, Boston B, Busby JE, D’Amico A, Eastham JA, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw. 2010;8:162-200, PMID: 20141676. 14. O’Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17a-hydroxylase/ C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer. 2004;90:2317-2325, PMID: 15150570.

15. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563-4571, PMID: 18645193.

18. Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castrationresistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489-1495, PMID: 20159823.

16. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-3748, PMID: 19470933.

19. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28:14961501, PMID: 20159814.

17. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castrationresistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481-1488, PMID: 20159824.

20. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005, PMID: 21612468. Text continues on page 44

Vi si tu s at AS HP Bo

also recently was approved in this same population. In addition, sipuleucel-T has been FDA approved for patients with asymptomatic or minimally symptomatic metastatic CRPC and may be best used in men without visceral metastases. In addition, denosumab gained FDA approval for the prophylaxis of SREs in men with castration-resistant bone metastases and may have some advantages over zoledronic acid. Palliative radiation or radiopharmaceuticals (eg, samarium, strontium, or investigational radium) also may play a significant role in the management of men with symptomatic disease, before or after systemic therapies. Several additional active agents are in Phase III development, and some of these therapies also are likely to further expand our therapeutic arsenal for men with metastatic CRPC in the near future.

ot h

References

Aztreonam for Injection, USP

2. Antonarakis ES, Drake CG. Current status of immunological therapies for prostate cancer. Curr Opin Urol. 2010;20:241-246, PMID: 20179598.

Available from APP

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300, PMID: 20610543.

3. Small EJ, Fratesi P, Reese DM, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000;18:38943903, PMID: 11099318.

No thawing required!

4. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089-3094, PMID: 16809734. 5. Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670-3679, PMID: 19536890. 6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castrationresistant prostate cancer. N Engl J Med. 2010;363:411-422, PMID: 20818862. 7. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a poxviralbased PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:1099-1105, PMID: 20100959. 8. Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102:1388-1397, PMID: 20826737. 9. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther. 2011;5:117-124, PMID: 21448449. 10. Attard G, Greystoke A, Kaye S, de Bono J. Update on tubulin-binding agents. Pathol Biol. 2006;54:72-84, PMID: 16545633. 11. Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15:723-730, PMID: 19147780.

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21. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Prostate Cancer. V3.2011. NCCN.org. Accessed June 3, 2011. 22. Antonarakis ES, Eisenberger MA. Expanding treatment options for metastatic prostate cancer. N Engl J Med. 2011;364:2055-2058, PMID: 21612475. 23. Brown JM, Corey E, Lee ZD, et al. Osteoprotegerin and RANK ligand expression in prostate cancer. Urology. 2001;57:611-616, PMID: 11306358. 24. Vallet S, Smith MR, Raje N. Novel bonetargeted strategies in oncology. Clin Cancer Res. 2010;16:4084-4093, PMID: 20643782.

25. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27:1564-1571, PMID: 19237632. 26. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized double-blind study. Lancet. 2011;377:813-822, PMID: 21353695. 27. Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J Steroid Biochem Mol Biol. 2011:125:23-31, PMID: 21092758.

28. Dreicer R, Agus DB, MacVicar GR, Wang J, MacLean D, Stadler WM. Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostate cancer: a phase I/II, open-label study. J Clin Oncol. 2010;28(suppl): Abstract 3084. 29. Chen Y, Clegg NJ, Scher HI. Antiandrogens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10:981-991, PMID: 19796750. 30. Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castrationresistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA. 2010;107:16759-16765, PMID: 20823238.

31. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-790, PMID: 19359544. 32. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:14371446, PMID: 20398925. 33. Foster WR, Car BD, Shi H, et al. Drug safety is a barrier to the discovery and development of new androgen receptor antagonists. Prostate. 2011;71:480-488, PMID: 20878947. 34. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51-81, PMID: 16730261. 35. Hodi FS. Cytotoxic T-lymphocyteassociated antigen-4. Clin Cancer Res. 2007;13:5238-5242, PMID: 17875750. 36. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810-1815, PMID: 17363537. 37. Fong L, Kwek SS, O’Brien S, et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 2009;69:609-615, PMID: 19147575.

Today I learned...

38. Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010;13:29-38, PMID: 196639414.

handling hazardous medications safely doesn’t have to slow me down.

39. Wheeler DL, Iida M, Dunn EF. The role of Src in solid tumors. Oncologist. 2009;14:667-678, PMID: 19581523. 40. Araujo J, Logothetis C. Targeting Src signaling in metastatic bone disease. Int J Cancer. 2009;124:1-6, PMID: 18942061. 41. Nam S, Kim D, Cheng JQ, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 2005;65:9185-9189, PMID: 16230377.

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42. Park SI, Zhang J, Phillips KA, et al. Targeting Src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res. 2008;68:3323-3333, PMID: 18451159. 43. Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15:7421-7428, PMID: 19920114. 44. Araujo J, Mathew P, Armstrong AJ, et al. Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1/2 study. Cancer 2011 Jul 25 [Epub ahead of print]. 45. Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res. 2010;16:1088-1093, PMID: 20145158. 46. July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate. 2002;50:179188, PMID: 11813210. 47. Gleave M, Miyake H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol. 2005;23:3846, PMID: 15770517.

48. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate

Pharmacy Practice News • November 2011

Clinical 45

Educational Review cancer. J Clin Oncol. 2010;28:4247-4254, PMID: 20733135. 49. George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res. 2001;7:1932-1936, PMID: 11448906. 50. Sweeney P, Karashima T, Kim SJ, et al. Antivascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin Cancer Res. 2002;8:27142724, PMID: 12171905. 51. Kelly WK, Halabi S, Carducci MA, et al. A randomized, double-blind, placebocontrolled phase III trial comparing

RADIUM-223 continued from page 29

The abundance of therapeutic options leaves clinicians with a fortunate dilemma: How do all these agents fit into the treatment algorithm? Emmanuel Antonarakis, MD, assistant professor of oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, said radium-223 is likely to be used as monotherapy primarily for patients with symptomatic mCRPC with bone metastases until further combination treatment studies in expanded patient populations are released. “There is currently a Phase I study being headed by Memorial Sloan-Kettering looking at the combination of docetaxel and radium-223, but in the absence of data from that study, it would be premature to use it in any way other than how it was administered in the ALSYMPCA trial,” commented Dr. Antonarakis, who was not involved in the study. “It is important to note that this agent could be used both in patients who had received prior docetaxel as well as in those who were ineligible or refused chemotherapy, consistent with the eligibility criteria of this trial.” According to Glenn Liu, MD, associate professor of medicine and director of Genitourinary Oncology Research and Phase I Programs at the University of Wisconsin’s Carbone Cancer Center, Madison, identifying newer therapies is important, but optimizing existing therapies is equally important. “Which agent is best for symptomatic versus asymptomatic men? Which is most effective in bone-only versus visceral metastases?” said Dr. Liu. “These questions will need to be addressed through clinical trials in order to understand how we can best serve our patients.” —David Wild Dr. Parker has served on the Bayer advisory board. Dr. Antonarakis is a consultant and advisor to Sanofi-aventis. Dr. Liu has nothing to declare.

docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer: survival results of CALGB 90401. J Clin Oncol. 2010; 28(suppl): Abstract LBA4511. 52. Ou Y, Michaelson MD, Sengelov L. Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU+P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2011; 29(suppl): Abstract 4515. 53. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett.

2005;225:1-26, PMID: 15922853. 54. Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z. The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res. 2007;67:967-975, PMID: 17283128. 55. Shojaei F, Lee JH, Simmons BH, et al. HGF/ c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70:10090-10100, PMID: 20952508. 56. Smith DC, Smith MR, Small EJ, et al. Phase II study of XL184 in a cohort of patients with castration-resistant prostate cancer and measurable soft tissue disease. J Clin Oncol. 2011;29(suppl): Abstract 127.

57. Isaacs JT, Pili R, Qian DZ, et al. Identification of ABR-215050 as lead second-generation quinoline-3carboxamide anti-angiogenic agent for the treatment of prostate cancer. Prostate. 2006;66:1768-1778, PMID: 16955399. 58. Björk P, Björk A, Vogl T, et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via their binding to quinoline carboxamides. PLoS Biol. 2009;7:e97, PMID: 19402754. 59. Pili R, Haggman M, Stadler WM, et al. A randomized, multicenter, international phase II study of tasquinimod in chemotherapy-naïve patients with metastatic castrate-resistant prostate cancer. J Clin Oncol. 2010;28(suppl): Abstract 4510.

46 Clinical

Pharmacy Practice News • November 2011

Face-off

Should Rivaroxaban Be Approved for Stroke Prevention in Patients With Atrial Fibrillation? R

ivaroxaban (Xarelto, Bayer/Johnson & Johnson) is undergoing FDA review for a new indication to help prevent strokes in patients with atrial fibrillation (AF). Based on the results of Rocket-AF (Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; N Engl J Med 2011;365:883-891), in which rivaroxaban was shown to be noninferior to warfarin for stroke prevention, an FDA advisory committee voted in favor of approval— a recommendation that ran counter to the FDA’s own

briefing documents. The availability of dabigatran (Pradaxa, Boehringer Ingelheim) for the same indication further clouds the issue, as do the results of the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, in which the investigational drug apixaban was shown to be superior to warfarin in preventing stroke. At press time, Public Citizen chimed in, urging that rivaroxaban not be approved due to safety and efficacy concerns. Given this controversy, Pharmacy Practice News asked two anticoagulation experts for their vote on the pending approval.

Henry I. Bussey, PharmD, FCCP, FAHA

C. Michael White, PharmD Professor of Pharmacy University of Connecticut, Storrs Director Evidence-Based Practice Center UCONN/Hartford Hospital, Hartford, Connecticut

arfarin cannot be used in everyone, and many patients hate it even though it is similarly effective and safe compared with rivaroxaban. The monitoring requirements for warfarin, such as blood draws to which the patient must travel, and the amount of dietary accountability, particularly with respect to vitamin K, can be burdensome to patients and caregivers. Warfarin also has the potential for more drug interactions. Dabigatran can cause gastrointestinal upset and may affect renal function. Apixaban stands a chance for approval as

‘Although some patients may not be good candidates for switching from warfarin [to rivaroxaban], others will be, and they should have that choice.’ an addition to aspirin therapy, but not among people with warfarin eligibility. Given these limitations, it is important to provide options that offer convenience for patients and caregivers as well as similar efficacy. Although well-trained anticoagulant pharmacists may help patients achieve better international normalized ratio (INR) values than what was shown in the ROCKET-AF trial, two-thirds of people with AF are treated outside a warfarin clinic. The average person who is not treated in a warfarin clinic will spend only about one-third of the year in the normal therapeutic range. A drug like rivaroxaban might give you some advantages in that regard, with more consistent levels of anticoagulation, particularly because it is not affected by dietary changes. In terms of study design, it is true that in most biomedical research, the approach is to show that one agent is superior to another, and that this is a new type of trial that shows only that one agent is not inferior to another. But the point here is to show that the new agent is as safe and effective as the other to get the new agent approved and provide the option for its use. Patients themselves may ask about alternatives, and although some patients may not be good candidates for switching from warfarin [to rivaroxaban], others will be, and they should have that choice.

Senior Editor and President Clotcare.org President Genesis Clinical Research San Antonio, Texas

one of the new agents, including rivaroxaban, have been compared with a well-managed warfarin regimen. With rivaroxaban, the study evaluated a group of patients in whom the INRs were in therapeutic range only 50% of the time. That is only as good as poorly managed warfarin. I would expect well-managed warfarin to be better. The incentive for developing these drugs is that it is a hassle to manage warfarin and keep patients’ INRs in range. But several groups, including my own, have shown how technology can enable self-management of warfarin and close communication between patient and

‘If the best a clinician can do with warfarin is have patients in range 60% of the time, then maybe it’s better to look at newer agents, but that is really a poor compromise over what can be done by improving warfarin management.’ clinician. Thorough monitoring can be achieved through methods that include finger sticks done at home, access to an online system, and several minutes of clinician review. With the newer drugs, there is no way to assess compliance and there is no close communication with clinicians. Considering that 50% of people taking a drug will stop taking it at some point, such use, or sporadic use, can cause problems with a short-acting drug like rivaroxaban. If a clinic is only aware of the INR when it moves extremely out of range, that’s like calling a rancher and saying the horse is out of the barn and the rancher needs to find it. The point is to try to head off the problem. The lack of monitoring with these newer drugs does not provide that opportunity. Cost is another factor. We now have a reimbursement model and the technology to transform warfarin. These newer drugs cost considerably more than warfarin, even accounting for warfarin monitoring. If the best a clinician can do with warfarin is have patients in range 60% of the time, then maybe it’s better to look at newer agents, but that is really a poor compromise over what can be done by improving warfarin management. Dr. Bussey disclosed that he is the 2008-2011 recipient of the GlaxoSmithKline Distinguished Scholar in Thrombosis Award for a proposal to develop a better method of oral anticoagulation management. He also disclosed that he serves as an advisor for Boehringer Ingelheim and Johnson & Johnson and is a minor shareholder of Alere, Inc., and part owner in a provisional patent for several vitamin K antagonist products. Dr. White reported no relevant conflicts of interest.

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Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemcitabine WHO Grades (% incidence)a

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Gemcitabine Injection 1 INDICATIONS AND USAGE 1.1 Ovarian Cancer Gemcitabine Injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinumbased therapy. 1.2 Breast Cancer Gemcitabine Injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. 1.3 Non-Small Cell Lung Cancer Gemcitabine Injection is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer. 1.4 Pancreatic Cancer Gemcitabine Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine Injection is indicated for patients previously treated with 5-FU. 4 CONTRAINDICATIONS Gemcitabine Injection is contraindicated in those patients with a known hypersensitivity to the drug. 5 WARNINGS AND PRECAUTIONS Patients receiving therapy with Gemcitabine Injection should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. 5.1 Infusion Time Caution - Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity [see Clinical Studies (14.5)]. 5.2 Hematology Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. 5.3 Pulmonary Pulmonary toxicity has been reported with the use of gemcitabine. In cases of severe lung toxicity, Gemcitabine Injection therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions (6.1 and 6.2)]. 5.4 Renal Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine Injection should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Use In Specific Populations (8.6)]. 5.5 Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine Injection should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemcitabine Injection in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Use In Specific Populations (8.7)]. 5.6 Pregnancy Gemcitabine can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of gemcitabine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations (8.1)]. 5.7 Laboratory Tests Patients receiving Gemcitabine Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see Dosage and Administration (2.4)]. 5.8 Radiation Therapy A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of gemcitabine. Non-concurrent (given >7 days apart) - Analysis of the data does not indicate enhanced toxicity when gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation. Concurrent (given together or ≤7 days apart) - Preclinical and clinical studies have shown that gemcitabine has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of gemcitabine, frequency of gemcitabine administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where gemcitabine at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that gemcitabine administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined in all tumor types. 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. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. Gemcitabine has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs. Single-Agent Use: Myelosuppression is the principal dose-limiting toxicity with gemcitabine therapy. Dosage adjustments for hematologic toxicity are frequently needed [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. The data in Table 4 are based on 979 patients receiving gemcitabine as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The gemcitabine starting doses ranged from 800 to 1250 mg/m2. Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of gemcitabine therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the gemcitabine arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed below were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories.

Pancreatic Cancer Patientsc

All Patientsb

Discontinuations (%)d

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratorye Hematologic Anemia Leukopenia Neutropenia Thrombocytopenia

68 62 63 24

7 9 19 4

1 <1 6 1

73 64 61 36

8 8 17 7

2 1 7 <1

Hepatic ALT AST Alkaline Phosphatase Bilirubin

68 67 55 13

8 6 7 2

2 2 2 <1

72 78 77 26

10 12 16 6

1 5 4 2

Renal Proteinuria Hematuria BUN Creatinine

45 35 16 8

<1 <1 0 <1

0 0 0 0

32 23 15 6

<1 0 0 0

0 0 0 0

Non-laboratoryf Nausea and Vomiting Fever Rash Dyspnea Diarrhea Hemorrhage Infection Alopecia Stomatitis Somnolence Paresthesias

69 41 30 23 19 17 16 15 11 11 10

13 2 <1 3 1 <1 1 <1 <1 <1 <1

1 0 0 <1 0 <1 <1 0 0 <1 0

71 38 28 10 30 4 10 16 10 11 10

10 2 <1 0 3 2 2 0 <1 2 <1

2 0 0 <1 0 <1 <1 0 0 <1 0

a b c d e f

All Patients

<1 <1 <1 <1

<1 <1 <1 <1 0 <1 <1 0 <1 <1 0

Grade based on criteria from the World Health Organization (WHO). N=699-974; all patients with laboratory or non-laboratory data. N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data. N=979. Regardless of causality. Table includes non-laboratory data with incidence for all patients ≥10%. For approximately 60% of the patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.

Hematologic - In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during gemcitabine therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. Gastrointestinal - Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients. Hepatic - In clinical trials, gemcitabine was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to gemcitabine or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.2)]. Renal - In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving gemcitabine in clinical trials. Four patients developed HUS on gemcitabine therapy, 2 immediately posttherapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemcitabine therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions (6.2)]. Fever - The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that gemcitabine may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable. Rash - Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients. Pulmonary - In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with gemcitabine therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of gemcitabine [see Adverse Reactions (6.2)]. The etiology of these effects is unknown. If such effects develop, gemcitabine should be discontinued. Early use of supportive care measures may help ameliorate these conditions. Edema - Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema. Flu-like Symptoms - “Flu syndrome” was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms. Infection - Infections were reported for 16% of patients. Sepsis was rarely reported (<1%). Alopecia - Hair loss, usually minimal, was reported by 15% of patients. Neurotoxicity - There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias. Extravasation - Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemcitabine is not a vesicant. Allergic - Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabine should not be administered to patients with a known hypersensitivity to this drug [see Contraindications (4)]. Cardiovascular - During clinical trials, 2% of patients discontinued therapy with gemcitabine due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions (6.2)]. Combination Use in Non-Small Cell Lung Cancer: In the gemcitabine plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of gemcitabine injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of gemcitabine plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions. In the gemcitabine plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of gemcitabine injections and 16% of cisplatin injections in the gemcitabine plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of gemcitabine plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the gemcitabine plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the gemcitabine plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with gemcitabine plus cisplatin treatment (~90%) compared to that with the gemcitabine monotherapy (~60%). With combination therapy gemcitabine dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required. Table 5 presents the safety data from the gemcitabine plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the gemcitabine plus cisplatin arm. Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatmentrelated deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the gemcitabine plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the gemcitabine plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued gemcitabine plus cisplatin use. Nausea and vomiting despite the use of antiemetics occurred more often with gemcitabine plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent gemcitabine, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities,

hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity occurred more often with gemcitabine plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms. Cardiac dysrrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with gemcitabine plus cisplatin compared to one (<1%) Grade 3 dysrrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the gemcitabine plus cisplatin combination arm. Table 6 presents data from the randomized study of gemcitabine plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the gemcitabine plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the gemcitabine plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the gemcitabine plus cisplatin arm. RBC transfusions were given to 29% of the patients who received gemcitabine plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received gemcitabine plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the gemcitabine plus cisplatin arm. On the gemcitabine plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of gemcitabine as compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the gemcitabine plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the gemcitabine plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm. Table 5: Selected CTC-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Single-Agent Cisplatin in NSCLC CTC Grades (% incidence)a Cisplatinc

Gemcitabine plus Cisplatinb All Grades Laboratoryd Hematologic Anemia RBC Transfusione Leukopenia Neutropenia Thrombocytopenia Platelet Transfusionse Lymphocytes

Grade 3

Grade 4

All Grades

89 39 82 79 85 21 75

35 22 25

11 35 25

2 3 3

1 1 1

22 19

10 13

1 0

0 0

0 0 <1

18 13 31

0 0 2

0 0 <1

4 4 2

0 3 0

23 17 7

3 2 0

0 0 <1

25 11 1 12 6 2 1 3 0 3 1 0 0 1 1 4 1 0

2 12 0 0 0 2 0 2 0 1 0 0 0 0 0 3 0 0

87 71 33 15 21 13 18 12 5 9 10 6 7 5 4 11 7 3

20 10 0 3 6 0 1 1 0 1 1 0 0 0 0 3 1 0

<1 9 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0

2 1

1 0

23 15 38

0 0 4

Other Laboratory Hyperglycemia Hypomagnesemia Hypocalcemia

30 30 18

Non-laboratoryf Nausea Vomiting Alopecia Neuro Motor Neuro Hearing Diarrhea Neuro Sensory Infection Fever Neuro Cortical Neuro Mood Local Neuro Headache Stomatitis Hemorrhage Dyspnea Hypotension Rash

93 78 53 35 25 24 23 18 16 16 16 15 14 14 14 12 12 11

d e f

Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse reactions with incidence ≥10% in either arm. N=217-253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days. Regardless of causality. Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. Non-laboratory events were graded only if assessed to be possibly drug-related.

Table 6: Selected WHO-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Etoposide Plus Cisplatin in NSCLC WHO Grades (% incidence)a Gemcitabine plus Cisplatinb All Grades

Grade 3

Grade 4

26 36 39

3 28 16

6 3 16 0

0 0 0 0

Renal Proteinuria Hematuria BUN Creatinine

12 22 6 2

0 0 0 0

Non-laboratoryf,g Nausea and Vomiting Fever Rash Dyspnea Diarrhea Hemorrhage Infection Alopecia Stomatitis Somnolence Paresthesias

96 6 10 1 14 9 28 77 20 3 38

35 0 0 0 1 0 3 13 4 0 0

Laboratoryd Hematologic Anemia RBC Transfusionse Leukopenia Neutropenia Thrombocytopenia Platelet Transfusionse

88 29 86 88 81 3

Hepatic ALT AST Alkaline Phosphatase Bilirubin

a b

d e f g

Etoposide plus Cisplatinc All Grades

Grade 3

Grade 4

36 20 8

7 56 5

12 11 11 0

0 0 0 0

5 10 4 2

0 0 0 0

4 0 0 1 1 3 1 0 0 0 0

86 3 3 3 13 3 21 92 18 3 16

19 0 0 0 0 0 8 51 2 2 2

7 0 0 0 2 3 0 0 0 0 0

77 21 87 87 45 8

Grade based on criteria from the World Health Organization (WHO). N=67-69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days. N=57-63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days. Regardless of causality. Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events. Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.

Combination Use in Breast Cancer: In the gemcitabine plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of gemcitabine injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of gemcitabine doses were omitted and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the gemcitabine plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm. Table 7 presents the safety data occurrences of ≥10% (all grades) from the gemcitabine plus paclitaxel versus paclitaxel study in breast cancer.

Paclitaxel (N=259)

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

69 69 26 21

6 31 5 10

1 17 <1 1

51 31 7 12

3 4 <1 2

<1 7 <1 0

18 16

5 2

<1 0

6 5

<1 <1

0 0

90 64 50 40 33 29 24 20 17 15 13 13 11

14 5 1 6 4 2 3 3 0 2 1 <1 <1

4 <1 0 <1 0 0 0 0 0 <1 <1 0 <1

92 58 31 28 33 15 22 13 12 10 8 3 5

19 3 2 1 3 2 2 2 <1 <1 <1 0 0

3 0 0 <1 <1 0 <1 0 0 0 0 0 0

Laboratoryb Hematologic Anemia Neutropenia Thrombocytopenia Leukopenia Hepatobiliary ALT AST c

Non-laboratory Alopecia Neuropathy-sensory Nausea Fatigue Myalgia Vomiting Arthralgia Diarrhea Anorexia Neuropathy-motor Stomatitis/pharyngitis Fever Rash/desquamation a

Grade 4

Gemcitabine plus Paclitaxel (N=262)

67 13 25 20 13 <1 51

Hepatic Transaminase Alkaline Phosphatase Renal Proteinuria Hematuria Creatinine

Grade 3

Table 7: Adverse Reactions From Comparative Trial of Gemcitabine Plus Paclitaxel Versus Single-Agent Paclitaxel in Breast Cancera CTC Grades (% incidence)

Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%). Regardless of causality. Non-laboratory events were graded only if assessed to be possibly drug-related.

The following are the clinically relevant adverse reactions that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus paclitaxel versus paclitaxel): febrile neutropenia (5.0% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus 0.8%). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Combination Use in Ovarian Cancer: In the gemcitabine plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of gemcitabine injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of gemcitabine doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse reactions between arms (10.9% versus 9.8%, respectively). Table 8 presents the adverse reactions (all grades) occurring in ≥10% of patients in the ovarian cancer study. Table 8: Adverse Reactions From Comparative Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemcitabine plus Carboplatin (N=175)

Carboplatin (N=174)

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Laboratoryb Hematologic Neutropenia Anemia Leukopenia Thrombocytopenia RBC Transfusionsc Platelet Transfusionsc

90 86 86 78 38 9

42 22 48 30

29 6 5 5

58 75 70 57 15 3

11 9 6 10

1 2 <1 1

Non-laboratoryb Nausea Alopecia Vomiting Constipation Fatigue Neuropathy-sensory Diarrhea Stomatitis/pharyngitis Anorexia

69 49 46 42 40 29 25 22 16

6 0 6 6 3 1 3 <1 1

0 0 0 1 <1 0 0 0 0

61 17 36 37 32 27 14 13 13

3 0 2 3 5 2 <1 0 0

0 0 <1 0 0 0 0 0 0

a b c

Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%). Regardless of causality. Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

In addition to blood product transfusions as listed in Table 8, myelosuppression was also managed with hematopoietic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoietic agents: 7.3% and 3.9%, respectively). The following are the clinically relevant adverse reactions, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of gemcitabine. 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. These adverse reactions have occurred after gemcitabine single-agent use and gemcitabine in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to gemcitabine. Cardiovascular - Congestive heart failure and myocardial infarction have been reported very rarely with the use of gemcitabine. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely. Vascular Disorders - Clinical signs of peripheral vasculitis and gangrene have been reported very rarely. Skin - Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely. Hepatic - Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. Hepatic veno-occlusive disease has been reported. Pulmonary - Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of gemcitabine administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last gemcitabine dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy. Renal - Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications - Radiation recall reactions have been reported [see Warnings and Precautions (5.8)]. 10 OVERDOSAGE There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

Pharmacy Practice News • November 2011

Clinical 49

Journal Scan

Pharmacist Care Improves Cardiovascular Risk Factors From Archives of Internal Medicine

harmacist care has a significant impact on cardiovascular disease (CVD) risk factors in outpatients, according to a review of the medical literature by researchers at McGill University, in Montreal and the University of Lausanne, in Switzerland (Arch Intern Med 2011;171:1441-1453). The researchers analyzed 30 randomized controlled trials and found that care provided exclusively by pharmacists or implemented in collaboration with physicians and nurses was associated with reductions in blood pressure, cholesterol and risk for smoking. The trials included 11,765 outpatients between the ages of 52 and 77 years who were followed over a mean of eight months. Patients had uncontrolled CVD risk factors and were taking antihypertensive or lipid-lowering drugs in 17 and 18 trials, respectively. The remaining studies included a mix of patients with controlled or uncontrolled risk factors, with or without pharmacol ogic treatment. Twenty of the studies were conducted

in North America, with the remaining done in South America (three), Asia (three), Europe (two) and Australia (two). Patients in 18 of the studies received pharmacist-directed care; those in the remaining studies received pharmacistcollaborative care. Interventions included education, such as counseling about medications, lifestyle or compliance; patient-reminder systems, including telephone contact, use of a

This month, Pharmacy Practice News introduces a new feature, Journal Scan, that covers pharmacist-focused studies in the literature. Journal Scan will summarize key findings from several studies and offer commentary from pharmacists with expertise in the relevant therapeutic areas.

Web site, home visits or drug adherence aids; medication management; feedback to health care professional; measurement of CVD risk factors; and review of laboratory data by a pharmacist during follow-up. Pharmacist care was associated with reductions in blood pressure (−8.1 mm Hg

systolic; 95% confidence interval [CI], −10.2 to −5.9; and −3.8 mm Hg diastolic; 95% CI, −5.3 to −2.3); total cholesterol (−17.4 mg/L; 95% CI, −25.5 to −9.2), low-density lipoprotein cholesterol (−13.4 mg/L; 95% CI, −23.0 to −3.8); and risk for smoking (relative risk, 0.77; 95% CI, 0.67-0.89).

COMMENTARY Gladys G. Dueñas, PharmD Assistant Professor of Clinical Pharmacy Philadelphia College of Pharmacy University of the Sciences Philadelphia, Pennsylvania

What stood out for me about this paper was that it was international in scope. A large number of these studies were done in the United States, and it is great to see that our

pharmacists are involved and doing collaborative practice with physicians and nurses, but it is also interesting to see such collaboration carried out in other countries. With respect to the heterogeneity of interventions used, this illustrates the differences and variability in our practice. As we evolve out of the traditional dispensing role, we can see that the way we provide care is different across the board. Some of our methods are disease state– driven; others involve comprehensive medical

management and review. In some scenarios, the pharmacists direct the care; in others, they consult. This paper is consistent with what was published in the past, including last year’s study by Marie Chisholm-Burns, PharmD, MPH, FASHP (Medicare Care 2010;48:923-933). I am excited to see this in a reputable medical journal. It will reach a broad audience and showcase the work of pharmacists. Physicians don’t often read pharmacy journals, but they will see this.

Pharmacists Promote More Consistent Testing in Amiodarone Patients From Journal of Managed Care Pharmacy

atients enrolled in a pharmacistmanaged amiodarone program were more likely to receive the recommended laboratory tests for liver, thyroid and pulmonary toxicity than patients at medical centers without such care, according to a retrospective study by researchers in the Kaiser Permanente Pharmacy Outcomes Research Group in Downey, Calif. (J Manag Care Pharm 2011;17:513-522). In the study, researchers analyzed the clinic and enrollment data of 2,292 patients in 10 Kaiser Permanente

Southern California medical centers to determine how often patients received alanine aminotransferase (ALT) testing for liver function, measurements of thyroid-stimulating hormone (TSH) and free thyroxine (T4), pulmonary function testing (PFT) and annual chest x-rays (CXR). Of the 10 centers, two had pharmacist-managed amiodarone programs. There were 191 patients in the pharmacist-managed group and 2,111 in the usual-care group. The researchers found that labora tory monitoring rates for ALT, TSH and T4 were significantly higher in the pharmacist-managed group at the

first and second six months and at baseline for ALT and TSH, although not T4. CXR rates were higher for the pharmacist-managed group than usual care at baseline (59.1% vs. 49.3%; P=0.011) and during the first six months (43.1% vs. 35.1%; P=0.030). Relatively few patients in either group received PFT tests at baseline (6.6% vs. 3.6%; P=0.042), but the percentage rose sharply in the pharmacist-managed care group over the first six months, (33.7% vs. 8.9%; P≤0.001). Although a higher percentage of patients in the pharmacist-managed group were taking a high-dose statin during the

follow-up period, a greater proportion of those patients were switched to another statin or a lower dose. There were 44 potentially avoidable hospitalizations and 22 emergency department (ED) visits in the usualcare group, for a cost of $382,267. The cost of the pharmacist-monitoring program for the length of the study was $10,425, or $58 per patient. The researchers extrapolated this cost to patients in the usual-care group to be $121,587, thus estimating that for every $1 spent on the program, $2.14 could be saved through reduced hospitalizations and ED visits.

COMMENTARY Cynthia A. Sanoski, PharmD, FCCP, BCPS Chair, Department of Pharmacy Practice Jefferson School of Pharmacy Thomas Jefferson University Philadelphia, Pennsylvania

There were several novel aspects to this study. Smaller studies have shown how well prescribers and patients adhere to monitoring, but these researchers take that one step further by including hospitalizations and emergency room (ER) visits. There has been a lack of studies that look at outcomes and cost avoidance, and the authors did a great job with estimating the return on investment (ROI). That the ROI was double

was very impressive. This is a fairly small operation, but if extrapolated out to all centers in the country, the potential is there to save a significant amount of money. The pharmacists in this study didn’t manage anticoagulation, so the analysis did not include warfarin. If that was included, the results might have been even more impressive. However, looking at statins was a novel approach.

The study has several implications for pharmacy practice. When you think of pharmacy-managed care, you think of hypertension and warfarin, but amiodarone is the most commonly used anti-arrhythmia drug. Many providers still are not doing a very good job managing this treatment; they underestimate the risk. Even if you avoid one or two hospitalizations or ER visits, this kind of program could have a great impact.

50 Clinical

Pharmacy Practice News • November 2011

Journal Scan

Pharmacists Demonstrate Value by Intercepting Med Errors in the ED From International Journal of Pharmacy Practice

esearchers at the University of Arizona College of Pharmacy report that most of the medication errors intercepted by the emergency department (ED) pharmacist are significant or serious (Int J Pharm Pract 2011;19:358-362). In a retrospective evaluation of a quality-improvement database at the university medical center’s level 1 trauma center, the researchers showed that the ED

pharmacist intercepted 237 medication errors over a seven-month period. A total of 36,747 medication orders were prescribed while the pharmacist was present, yielding a rate of medication error interception of 0.6 for every 100 orders. During the study, the ED was staffed with one full-time pharmacist with 10 years of experience, who was present for 10 hours per day, four days per week. The team categorized medication errors according to severity as follows: minor (patient harm is likely to be

minor), significant (error could result in a moderate level of patient harm), serious (severe harm could occur but not life-threatening) and potentially lethal (could result in life-threatening consequences). Over the course of the study, the ED pharmacist intercepted 42 minor errors (18%), 160 significant errors (67%), 35 serious errors (15%) and no potentially lethal errors. Medication errors also were categorized based on the probability of an adverse drug event (ADE). Of the 237 intercepted medication errors, 13 (6%)

had no probability of an ADE, 96 (41%) had a very low probability, 84 (35%) had a low probability, 41 (17%) had a medium probability and three (1%) had a high probability. Medication errors were most likely to be intercepted during the prescribing phase of the medication-use process, with 211 errors (89%) falling into that category. Of the remaining medication errors, 17 (7%) were intercepted during administration, eight (3%) at dispensing and one (<1%) at monitoring. No errors were intercepted during transcribing.

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

This study adds to the literature that demonstrates the value of pharmacist knowledge and training. It shows the impact one experienced person can make in the ED. Pharmacists at this center and others can use this data for justification when staffing EDs. The ED doesn’t necessarily use highcost medications, so the way to justify our presence is through our impact on safety. The rate of medical errors intercepted—0.6 per 100 orders—is lower

than what was previously published (Ann Emerg Med 2010;55:513-521). It is difficult to look at medication errors when the pharmacist has already been working there for some time. The lower amount of errors can be attributable to the pharmacist previously having changed or affected practice in the ED by educating providers. In other words, a pharmacist was on staff prior to the study, so this center will have a lower number of interceptions than you might see in an ED that had

not had a pharmacist present and then added one to the staff. From my experience, and from this study, many interceptions occur during the ordering process. However, you have to have a pharmacist there to catch the error. What happens when the pharmacist is not there? Are there errors that get through, errors that you don’t know about unless there is an ADE? If there is a pharmacist in the ED at all times, chances are you are going to catch more errors.

Pharmacy Students and Travel Medicine a Good Mix From Journal of Travel Medicine

ravel clinics often are run by pharmacists or by physician–nurse teams, but at Saint Vincent Hospital in Worcester, Mass., the travel clinic is run by a multidisciplinary team that includes pharmacy students, according to a report on the clinic in the Journal of Travel Medicine (2011;18:352-354). The weekly travel clinic at Saint Vincent Hospital has been in operation as part of an ambulatory care outpa-

tient clinic since 2009. The care team is comprised of an infectious disease physician, a nurse, a pharmacist affiliated with a college of pharmacy and pharmacy students who have taken a travel health class and are now enrolled in their advanced pharmacy practice rotations. All team members provide travelrelated education, with the pharmacist and pharmacy students focusing on vaccine-related adverse effects. Patients complete a screening form and the team performs an individualized

risk assessment that includes medical history, current medications, immunization records, travel destinations and length of stay. The pharmacist and nurse make recommendations that are reviewed by the physician. The pharmacist and pharmacy students conduct individualized counseling sessions in a private examination room, taking into account the patient’s itinerary, the immunizations to be administered, personal protective measures and, if appropriate, malaria

prophylaxis. Patients then receive educational handouts developed by the pharmacist and pharmacy staff that cover the medications and vaccines prescribed. However, local regulations limit the pharmacist to administering only influenza vaccines. The clinic operates on a fee-for-service basis and does not accept insurance. There is a nominal fee if the patient is prescribed only oral medications; the fee is waived if the patient receives injectable immunizations.

COMMENTARY Jodi Longueil, PharmD Kaiser Permanente International Travel Clinic Portland, Oregon

The inclusion of pharmacy students is an excellent way to enhance their knowledge base over the immunization modules in pharmacy school. Some of these modules do not include travel medicine specifically, and having this opportunity allows the practical application of the students’ knowledge. Pharmacists are in an excellent position to provide counseling to patients, who can be apprehensive about vaccines and malaria medications. It is a

natural extension of our skill set to be a resource not only for patients, however, but for providers, as collaboration is important in travel medicine. The counseling session allows the pharmacists to best use their knowledge by conducting a risk assessment that considers the whole patient, as opposed to assuming a dispensing role where the pharmacy staff fills a prescription for a medication like doxycycline and notices that the patient is on other

medications that could interact. The limited hours described in the paper can pose a challenge. Travel medicine is a specialty, and it is difficult to stay on top of the requirements and state of care if you aren’t providing that service every day. Most insurance carriers do not cover travel-related medicine, an obstacle that could possibly be overcome if the argument can be made that such care is provided routinely.

—Compiled by Terri D’Arrigo

Pharmacy Practice News • November 2011

Clinical 51

Pain Medicine

New Hydrocodone Formulation Eschews Acetaminophen

prescribing the drug will not have to adopt patient management approaches specific to the drug. “Our range of doses makes the conversion process from hydrocodone IR [immediate-release] to hydrocodone ER [extended-release] rather simple,” Mr. Farr added. Eliminating acetaminophen from the painkiller does not mitigate all of the problems associated with opioid analgesics—a class of drugs that comes with

important concerns regarding abuse, misuse and addiction. Charles Argoff, MD, professor of neurology and director of Albany Medical Center’s pain management program, in Albany, N.Y., noted that hydrocodone bitartrate may be coming to market “during a public health crisis” about extended-release opioid analgesics. “We currently are challenged by a significant epidemic of opioid prescription

drug abuse and misuse in the United States,” said Dr. Argoff, who is not involved in the studies of hydrocodone bitartrate. “Even if there prove to be attributes to Zohydro that distinguish it from other available agents, safety concerns regarding opioid analgesics in general cannot be and will not be overlooked by prescribers.” —Brian P. Dunleavy

Anti-Infective Therapy You Can Take To The Bank

Vi si tu s at AS HP Bo ot h 20 19

reliminary results of a Phase III trial show promise for a novel formulation of hydrocodone that does not include acetaminophen. Manufacturers of the new formulation—hydrocodone bitartrate—are billing the agent as “the first single-entity hydrocodone therapy,” pending FDA approval. Early data indicate that the drug, Zohydro (Zogenix), is effective in the treatment of moderate to severe chronic pain. The lack of acetaminophen in the formulation makes hydrocodone bitartrate particularly intriguing. Overuse of acetaminophen is the most common cause of acute liver damage in the United States (Clin Gastroenterol Hepatol 2008;6:918925). As a result, the FDA recommended limiting the dose of acetaminophen to 325 mg in combined prescription products earlier this year. In the 12-week, multicenter, Phase III study, investigators randomized 300 opioid-experienced patients with moderate to severe chronic low back pain and inadequate pain relief from their existing therapy to hydrocodone bitartrate (10-, 20-, 30-, 40- and 50-mg capsules) every 12 hours or placebo. Patients were aged between 18 and 75 years. Patients treated with hydrocodone bitartrate reported “significantly improved” chronic pain relief compared with placebo (P=0.008). The study met its primary efficacy end point, which was mean change in average 24-hour pain intensity ratings based on the Numerical Rating Scale. “There are many patients who benefit from long-acting opioids who do not want to be on a more potent compound,” noted lead clinical investigator Richard Rauck, MD, clinical associate professor of anesthesiology at Wake Forest University School of Medicine, Winston-Salem, N.C. “Zohydro will allow these patients to find an effective dose of hydrocodone without acetaminophen toxicity issues.” According to Zogenix, the formulation uses the patented Spheroidal Oral Drug Absorption System, a drug delivery technology manufactured by Elan that is designed to “provide consistent 12-hour pain relief.” Hydrocodone bitartrate was also safe and well tolerated. As with most opioid analgesics, the most common adverse events were constipation, nausea and urinary tract infection.

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REMS Program in Development Steve Farr, president and chief operating officer of Zogenix, said that the company is in the process of formulating a Risk Evaluation and Mitigation Strategies (REMS) program for hydrocodone bitartrate that will “be consistent with extended-release opioid standards,” so that pain specialists and primary care physicians

See full prescribing information at www.APPpharma.com

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Premixed Products Improve Safe Medication Practices Recent Innovations of Amiodarone IV John Fanikos, RPH, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Boston, Massachusetts

Introduction In the hospital setting, medication error is a common problem, with dosing1 and drug preparation being identified as underlying factors. Parenteral administration of therapeutic agents, in particular, is associated with a higher rate and severity of adverse drug reactions.2 This stems from a variety of factors, including the high peak drug levels that are inherent to intravenous (IV) delivery. Technical errors associated with the preparation or delivery of complex IV solutions are relatively common. These data, combined with the trend of increasing IV medication use in hospitalized patients, has prompted several medical quality assurance organizations to place special emphasis on improving drug delivery and ensuring safety in the hospital. The consensus, based on statements from the Institute of Medicine (IOM),3 the Institute for Safe Medication Practices (ISMP),4 and the American Society of Health-System Pharmacists’ IV Medication Summit5 is that IV therapy must be regarded as a high-risk activity and that providers must institute risk management procedures at every step of preparation, delivery, and administration to minimize risk to patients. Avenues to improve the safety associated with the use of IV medications include the development of manufacturer-derived premixed solutions.5 The use of premixed solutions obviates the need for admixture or other manipulations prior to clinical use, thereby reducing the possibility of admixing errors, improving efficiency and patient safety, facilitating adherence to policies and procedures, and minimizing waste and costs.5-7 This report provides a comparative analysis of the use of admixed and premixed IV formulations in the hospital setting, and describes amiodarone as an example available in both formulations.

Assessing the Use Of Admixed Formulations The preparation of admixed formulations consists of several steps— dosing calculations, dose regimens, reconstitution time allotments—all of which can

contribute to the risk for a medication error. 8 Because of the heightened risk associated with their dosing and preparation, IV medications require individualized treatment and careful calculation analysis.8 The steps for admixed preparation can be time-consuming, significantly impacting pharmacy and nursing workflow and potentially compromising timely delivery of critical drugs in emergent situations.6 In one hospital, it reportedly took 25 minutes or longer to order and receive stat medications from the pharmacy, which may delay medication administration.9 Studies show that IV preparation errors account for 7% to 14% (multiple-step preparations) of the admixed formulation error rate—omission of drug and errors in diluent were cited as common.10-13 These observations were consistent with those of Flynn and colleagues, who reported an error rate of 9% for admixed IV solutions among 5 US hospitals.7 An assessment of all errors identified dosing (69%) to be the most common (Table 1).7

Example of Admixed Medication Formulation: IV Amiodarone Amiodarone IV is a widely prescribed and well-established injectable antiarrhythmic agent. Various society guidelines and protocols (American Heart Association, American College of Cardiology, Advanced Cardiac Life Support) support the use of amiodarone IV as an antiarrhythmic agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia refractory to other therapy.14,15 Amiodarone is contraindicated for patients with known hypersensitivity to any of the components of amiodarone, including iodine, or in patients with cardiogenic shock, marked sinus bradycardia, and second- or

third-degree atrioventricular block unless a functioning pacemaker is available.16 The limited solubility of amiodarone necessitates the use of benzyl alcohol and polysorbate 80 (TWEEN) as cosolvents (final concentrations: amiodarone, 50 mg/mL; benzyl alcohol, 20.2 mg/mL; polysorbate 80 [TWEEN], 100 mg/mL).16 Several other limitations are associated with this formulation of amiodarone IV. The use of polyvinyl chloride (PVC) bags results in time-dependent adsorption of amiodarone; thus, infusions that are anticipated to last longer than 2 hours should be prepared in glass/ polyolefin containers to maintain amiodarone concentration.16 Second, polysorbate 80 (TWEEN) leaches the plasticizer, di(2ethylhexyl)phthalate (DEHP), from PVC bags and tubing and may result in exposure to elevated levels of DEHP, even with infusions shorter than 2 hours.17 Therefore, use of DEHP-free infusion materials is recommended. Third, amiodarone IV should be delivered by a volumetric infusion pump.16,18 Fourth, various ions can reduce the solubility of amiodarone, suggesting that amiodarone IV solutions should be prepared in dextrose solutions rather than in saline. Similarly, use of evacuated glass containers for admixing amiodarone IV may be problematic as incompatibility with a buffer in the container may cause precipitation.19 The use of amiodarone products that require admixing poses several other practical challenges. One inconvenience of this formulation is the required step of admixing 1 to 6 vials in dextrose prior to administration. The need for amiodarone often is emergent;15 thus, this dilution step consumes valuable time.6 In addition, because diluted formulations have a limited shelf life at room temperature, the resulting diluted

Table 1. Errors Cited With IV Admixed Formulations Error Category

Number of Errors (%)

Incorrect dose

100 (69)

Incorrect base solution

23 (16)

Wrong drug

10 (7)

Incorrect preparation technique

7 (5)

Omission

5 (3)

Adapted from Flynn EA, Pearson RE, Barker KN. Observational study of accuracy in compounding i.v. admixtures at five hospitals. Am J Health Syst Pharm. 1997;54(8):904-912.

PHARMACY PRACTICE NEWS • NOVEMBER 2011

formulations must be used within 24 hours of dilution or be discarded.16 The fact that these solutions cannot be prepared in advance combined with unpredictability and urgency of the patient need for amiodarone treatment means that preparation of amiodarone solutions often interrupts normal inpatient pharmacy workflows.6 Alternatively, admixing amiodarone solutions at the patient bedside, as often may occur during emergent situations, can be chaotic and carries a potential risk for dosage errors related to admixing.6

Evaluating Premixed IV Formulations Premixed formulations may obviate a variety of admixture-related problems, including admixture preparation errors, delays in administration, and interruptions in pharmacy workflow.6

Crash Cart Preparation The Joint Commission standards and American Society of Health-System Pharmacists guidelines for dispensing and storing medications suggest that: 1) medications should be available in readyto-administer form whenever possible; 2) drug concentrations should be standardized; 3) medications should be available to meet patient needs when the pharmacy is closed; and 4) preparation of admixtures by nursing staff should be minimized.20,21 Crash or code carts make it possible to meet these standards by streamlining medication access and preparation—2 factors that minimize the potential for error when using parental formulations.6 A survey of 811 respondents indicated that 75% of sites stored premixed formulations in their automated dispensing cabinets to accommodate the frequent use of the medication (60.9%) and/or to ensure efficiency (68.3%) (Table 2).6

High-Alert Medication Recommendation Premixed formulations extend the benefit of standardized dosing and improved inpatient pharmacy flow and efficiency.6 In fact, these advantages led the Joint Commission to specifically advocate the use of premixed IV formulations in a 1999 Sentinel Event Alert Regarding High-Alert Medications and Patient Safety. 22 Among the common risk factors for error, the Joint Commission cited dosing concentration to be a significant problem that could

Supported by

Factor

Number of Respondents (%)

Primary Efficiency

403 (68.3)

Frequent use

60 (10.2)

Pharmacy hours

43 (7.2)

Safety

30 (5.1)

Secondary Efficiency

173 (30.6)

Frequent use

344 (60.9)

Pharmacy hours

29 (5.1)

Safety

219 (38.8)

Adapted from Fanikos J, Erickson A, Munz KE, Sanborn MD, Ludwig BC, Van Hassel T. Observations on the use of ready-to-use and point-of-care activated products in automated dispensing cabinets in U.S. hospitals. Am J Health Syst Pharm. 2007;64(19):2037-2043.

be mitigated with the use of premixed solutions.22

Time Management and Efficiency Ready-to-use premixed formulations provide a way for hospital pharmacists to deliver medication when needed. The absence of an admixture step saves time and labor, reduces turnaround time, eliminates admixture errors, and reduces waste.23-25 In a study of 3 hospitals evaluating the amount of personnel time required for admixed versus premixed preparation, the results showed that premixed products required between 4.1 to 7.7 minutes to prepare compared with 5.6 to 9.1 minutes for admixed products.23-25 Premixed formulations provide a relatively efficient approach to administering IV therapy with less risk for admixture-related preparation errors. Although steps for preparation are eliminated, it is important to assess the products and their labeling to ensure proper dosing.26

Example of Premixed Medication Formulation: Amiodarone IV The recognition of the limitations associated with the traditional admixed formulation of amiodarone IV was a motivation to develop new formulations that are ready to use. Nexterone Premixed Injection is a novel amiodarone IV solution that is approved as a premixed bag in 2 ready-to-use concentrations with strengths of 1.5 mg/mL

(150 mg/100 mL) for rapid loading infusion (over 10 minutes) and 1.8 mg/mL (360 mg/200 mL) for subsequent infusion.27 Instead of benzyl alcohol and polysorbate 80 (TWEEN), the premixed formulation of Nexterone uses sulfobutyl ether-7-b-cyclodextrin (SBE7-b-CD) to enhance the solubility and stability of amiodarone.27 SBE7-b-CD is an excipient used to promote solubilization of drugs into aqueous solutions and is used in several other commercially available drug formulations. The premixed formulation of amiodarone HCl (Nexterone) does not include polysorbate 80 (TWEEN) and/or benzyl alcohol cosolvent. The premixed formulation lends several practical advantages. First, it is compatible with commonly used infusion materials (eg, PVC tubing).27 Second, the stability of the novel formulation has a reported shelf life of 24 months. The extended shelf life of Nexterone combined with the ready-to-use packaging means that the product can be stored at the point of care, including automated dispensing cabinets and crash carts.6,27 Third, the concentration of Nexterone Premixed Injection (amiodarone injection) reflects labeled and most commonly used concentrations. This standardization may help reduce confusion in terms of administration protocols and dosing errors.6,27 If hypotension occurs, treat initially by slowing the infusion; additional standard therapy may be needed, including

9. D’Arrigo T. Pharmacists speed drug delivery in postanesthesia care units. Pharmacy Practice News. 2010;37(6):4.

Conclusion

14. ECC Guidelines. Section 1: Introduction to ACLS 2000: Overview of recommended changes in ACLS from the guidelines 2000 conference. Circulation. 2000;102(suppl):I-86.

Admixing is a labor- and time-intensive process that is associated with an increased probability of admixture-related medication errors and a delay in administration. In the case of the traditional cosolvent-containing formulations of amiodarone, these problems are further complicated by limited stability (requiring just-in-time admixing) and incompatibility with commonly used infusion materials. With premixed, ready-to-use solutions and dosages, as seen with amiodarone IV, clinicians can reduce the probability of errors related to admixing while providing timely treatment.

10. Taxis K, Barber N. Ethnographic study of incidence and severity of intravenous drug errors. BMJ. 2003; 326(7391):1-4. 11. Taxis K, Barber N. Causes of intravenous medication errors: an ethnographic study. Qual Saf Health Care. 2003;12(5):343-348. 12. Hicks RW, Becker SC. An overview of intravenousrelated medication administration errors as reported to MEDMARX®, a national medication error-reporting program. J Infus Nurs. 2006;29(1):20-27. 13. Parashuram CS, To T, Seto W, Trope A, Koren G, Laupacis A. Systematic evaluation of errors occurring during the preparation of intravenous medication. CMAJ. 2008;178(1): 42-48.

15. Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician. 2003;68(11): 2189-2196. 16. Amiodarone hydrochloride for injection use (US prescribing information). Teva Pharmaceuticals; September 2008. http://www.tevausa.com/assets/base/ products/pi/Amiodarone_PI_9-2008.pdf. Accessed October 11, 2011. 17. Takehisa H, Naoko E, Masahiko S, et al. Release behavior of diethylhexyl phthalate from the polyvinyl-chloride tubing used for intravenous administration and the plasticized PVC membrane. Int J Pharm. 2005;297(1-2):30-37. 18. Attwood D, Mallona C, Ktistis G, Taylor CJ. A study on factors influencing the droplet size in nonionic oil-in-water microemulsions. Int J Pharm. 1992;88(1-2):417-422.

Baxter and Nexterone are trademarks of Baxter International Inc.

19. Strozyk WR, Williamson R, Thompson D. Incompatibility of amiodarone hydrochloride and evacuated containers. Am J Health Syst Pharm. 1996;53(2):184.

References

20. Rich DS. New JCAHO medication management standards for 2004. Am J Health Syst Pharm. 2004;61(13):1349-1358.

1. Leape L. Systems analysis of adverse drug events. JAMA. 1995;274(1):35-43. 2. Nuckols TK, Paddock SM, Bower AG, et al. Costs of intravenous adverse drug events in academic and nonacademic intensive care units. Med Care. 2008;46(1):17-24. 3. Institute of Medicine Report: Preventing Medication Errors. July 2006. http://books.nap.edu/openbook. php?record_id=11623. Accessed October 11, 2011. 4. Institute for Safe Medication Practices. http://www. ismp.org. Accessed October 11, 2011. 5. American Society of Health-System Pharmacists. IV Safety Summit. http://www.ashp.org/iv-summit. Accessed October 11, 2011. 6. Fanikos J, Erickson A, Munz KE, Sanborn MD, Ludwig BC, Van Hassel T. Observations on the use of readyto-use and point-of-care activated products in automated dispensing cabinets in U.S. hospitals. Am J Health Syst Pharm. 2007;64(19):2037-2043. 7. Flynn EA, Pearson RE, Barker KN. Observational study of accuracy in compounding i.v. admixtures at five hospitals. Am J Health Syst Pharm. 1997;54(8):904-912. 8. Kane-Gill SL, Jacobi J, Rothschild JM. Adverse drug events in intensive care units: risk factors, impact, and the role of team care. Crit Care Med. 2010;38 (6 suppl): S83-S89.

21. ASHP guidelines: minimum standard for pharmacies in hospitals. American Society of HealthSystem Pharmacists. Am J Health Syst Pharm. 1995;52(23):2711-2717. 22. Joint Commission. Sentinel event alert regarding high-alert medications and patient safety. http:// www.jointcommission.org/sentinel_event_alert_ issue_11_high-alert_medications_and_patient_ saftey. Accessed October 11, 2011. 23. Hoolihan RJ, Erickson BA. Strategies for reducing I.V. drug waste and coping with increased workload. Hosp Pharm. 1987;22(9):871-876. 24. Kirschenbaum BE, Cacace L, Anderson RJ, Ackerman LA. Personnel time and preparation costs for compounded versus premixed intravenous admixtures in three community hospitals. Am J Hosp Pharm. 1988;45(3):605-608. 25. Petroff BJ. Premixed i.v. admixtures for reducing costs and labor time in a home infusion company. Am J Health Syst Pharm. 2000;57(4):390. 26. Ruble J. Impact safety, efficiency, and the bottom line with premixed IV products. Pharmacy Purchasing & Products; 2008. http://www.pppmag.com/ article/353/February_2008/Premixed_IV_Products. Accessed October 11, 2011. 27. Nexterone (amiodarone hydrochloride). Deerfield, IL: Baxter Healthcare Corporation; 2010.

BB1044

Table 2. Reasons Cited for Storing Premixed Formulations In Automated Dispensing Cabinets

the following: vasopressor drugs, positive inotropic agents, and volume expansion. If bradycardia and atrioventricular block occur, treat by slowing the infusion rate or discontinuing Nexterone. The most common adverse reactions (1%-2%) leading to discontinuation of intravenous amiodarone therapy are hypotension, asystole/ cardiac arrest/pulseless electrical activity, ventricular tachycardia, and cardiogenic shock. Other important adverse reactions are torsade de pointes, congestive heart failure, pulmonary disorders, and liver function test abnormalities.

PHARMACY PRACTICE NEWS • NOVEMBER 2011

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: •

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

•

Cardiogenic shock

•

Marked sinus bradycardia

•

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

• 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.

• 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.

• 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.

• Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. • 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.

• Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. • 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 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. 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: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, 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 (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) 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 benefits 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 significant hypotension during infusions was seen most often in the first 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 difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant 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 confluent 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]. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In 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 fluoroquinolones, 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 There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates 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 fibrosis. 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 â&#x2030;Ľ2%) 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, Î˛-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

62 Clinical

Pharmacy Practice News • November 2011

Medication Safety

Interaction With Clopidogrel Differs Among PPIs New Orleans—The contention that proton pump inhibitors (PPIs) differ markedly in their relative risk for a significant interaction with the antiplatelet drug clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals) has gained support from a trial conducted by Harvard’s Center for Platelet Research Studies, in Boston. The trial included PPIs that depend on the hepatic cytochrome P450 system for metabolism, particularly the isoenzyme CYP2C19, but differ in their ability to inhibit CYP2C19. The PPIs that are considered to be strong CYP2C19 inhibitors not only adversely affected the pharmacokinetics (PK) of clopidogrel, including low-

joint guidelines from the ACC, the American Heart Association (AHA) and the American College of Gastroenterology (ACG) were revised late last year to conclude that clopidogrel and PPI cotherapy is generally appropriate in individuals who are indicated for each agent (Am J Gastroenterol 2010;105:2533-2549). The guidelines were revised because a multicenter, prospective and randomized trial called COGENT (Clopidogrel and Optimization of Gastrointestinal Events; N Engl J Med 2010;363:1909-1917) did not find any reduction in protection from cardiovascular events in patients randomized to receive clopidogrel in combination with the PPI omeprazole compared with clopidogrel alone.

dardized diet excluding foods known to affect CYP450 enzymes, such as grapefruit juice. Despite these controls, an evaluation of platelet function during exposure to clopidogrel alone without coadministration of PPIs found large variation in PK between subjects. Moreover, reductions in the AUC of the active metabolite of clopidogrel correlated with reductions in the degree of antiplatelet effect as measured by platelet function. Detailed studies designed to control for such confounders as patient weight or laboratory variability in PK analyses could not explain the majority of the interindividual differences in clopidogrel drug levels or platelet function, according to Dr. Frelinger.

of CYP2C19, which also metabolizes clopidogrel to its active form. Dexlansoprazole and lansoprazole are weak CYP2C19 inhibitors. The study was designed to compare on-PPI values to clopidogrel-alone values for each arm rather than to compare the therapies with each other, but the groups, which were similar during the clopidogrel-only period, did show greater variation in PK and platelet function measures when PPI and clopidogrel were administered together. Specifically, esomeprazole and omeprazole were associated with lower Cmax and AUC of clopidogrel; dexlansoprazole and lansoprazole were associated with less suppression of platelet function.

ering maximum (Cmax) and area-underthe-curve (AUC) drug concentrations, but also produced measurable reductions in antiplatelet effect. “Our results suggest that the potential effects of PPIs on clopidogrel could be minimized by selecting those agents with the least interaction on the cytochrome P450 system,” reported Andrew L. Frelinger III, PhD, associate director of the Center for Platelet Research Studies. Presenting these data at the 2011 annual meeting of the American College of Cardiology (ACC), Dr. Frelinger noted that the differences between the PPIs were observed on top of already major interindividual variation in clopidogrel response, even in the absence of PPIs.

However, there is abundant experimental as well as retrospective evidence from clinical trials that support a clinically meaningful interaction between PPIs and clopidogrel. Moreover, the newly revised guidelines acknowledged that questions remain about the potential for an interaction, particularly among poor metabolizers of clopidogrel.

To identify differences in clopidogrel metabolism with or without PPI use, two 10-day study periods were conducted in random order. In one study period, subjects received clopidogrel 75 mg alone; in the other, they received clopidogrel 75 mg in combination with a PPI. The PPIs were dexlansoprazole (Dexilant, Takeda Pharmaceuticals) 60 mg, lansoprazole (Prevacid, Takeda Pharmaceuticals) 30 mg, esomeprazole (Nexium, AstraZeneca) 40 mg and omeprazole (Prilosec OTC, Proctor & Gamble) 80 mg. All PPIs were administered in standard doses, with the exception of the higherthan-usual dose of omeprazole, which was designed to serve as a positive control. Although all PPIs are metabolized by the hepatic cytochrome P450 system, omeprazole and esomeprazole are considered to be potent inhibitors

In a challenge with adenosine diphosphate (ADP) 5 mcM, dexlansoprazole was associated with a 4% increase in platelet aggregability (P=not significant), and lansoprazole was associated with a 5.5% increase in platelet aggregability (P=0.035). Esomeprazole and omeprazole were associated with a highly statistically significant, more than 8%, increase in platelet aggregability (P<0.001). At a concentration of 20 mcM ADP, platelet aggregability increased further. Relative to baseline, the effect on platelet aggregability was statistically significant for all PPIs except dexlansoprazole. Differences between PPIs of similar magnitude were observed for platelet reactivity as measured with the VerifyNow assay. According to Dr. Frelinger, the reduction in the antiplatelet effect of clopidogrel in patients on the standard 40-mg

Controversy and Confusion The controversy about how to manage the potential interaction between PPIs and clopidogrel persists, even though

PPI Comparative Study In the current study, 160 healthy subjects were screened to rule out known causes of variation in clopidogrel PK. This included screening to ensure that all subjects were homozygous for the CYP2C19 extensive metabolizer genotype. Additionally, subjects were free of nicotine use for at least six weeks and free of alcohol or caffeine use for at least 72 hours, and none were receiving drugs of any kind, including over-the-counter (OTC) agents, at the time of evaluation. The subjects also were placed on a stan-

Pharmacist’s Perspective

sked to comment on the controversy surrounding PPIs and clopidogrel, Sarah A. Spinler, PharmD, BCPS (AQ Cardiology), professor of clinical pharmacy, Philadelphia College of Pharmacy, University of the Sciences, said, “I agree with all of the scientific facts regarding trial/study data and interpretation.” Dr. Spinler recommended that clinicians carefully review the most recent guidelines on clopidogrel and PPI interactions (Am J Gastroenterol 2010;105:2533-2549), “athough they also do not specifically state what to do.” On the other hand, “the Plavix warning label is very specific about what to do. It states that clopidogrel should be avoided with strong CYP2C19 inhibitors, such as omeprazole. So there are some regulatory/legal issues—not just guidelines—to consider.” Dr. Spinler added that esomeprazole has the same warning in its product labeling. Given those data, “my interpretation is that although controversy exists and data supporting negative clinical outcomes are not strong, FDA/manufacturer regulatory wording supports avoiding omeprazole, given the availability of other PPIs.”

Pharmacy Practice News • November 2011

Clinical 63

Medication Safety dose of esomeprazole was similar to the reduction observed with the relatively high 80-mg dose of omeprazole.

Interaction, Yes; Clinical Significance, Maybe

tion together, I think that it would be wise for the physician to be aware of the [pharmacodynamic] interaction and use PPIs selectively in those patients on clopidogrel who are at greatest risk of gastrointestinal bleeding,” Dr. Gurbel said. Although the blanket use of PPIs in everyone on dual antiplatelet therapy “was common before we had the [pharmacodynamic] data that we have now, this practice cannot be

advised at this time.” —Ted Bosworth This study was supported by Takeda Global Research & Development Center, Inc. (ClinicalTrials.gov Identifier NCT00942175). Dr. Frelinger has received research grants from Arena Pharmaceuticals, Bristol-Myers Squibb/Sanofi-aventis, Daiichi Sankyo, Eli Lilly, GLSynthesis and Takeda. He is a consultant to Daiichi Sankyo, Eli Lilly and PLx Pharma. Dr. Gurbel has received research grants, honoraria or other support from Accumetrics, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Helena, Medtronic, Merck, Multiplate, Nanosphere, Novartis, Portola, Pozen and Sanofi-aventis.

Vi si s at AS HP Bo ot h 20

Anti-Infective Therapy You Can Take To The Bank

tu 19

This study was conducted in healthy volunteers and did not assess cardiovascular end points. Many candidates for antiplatelet therapy also are candidates for PPIs to prevent gastric bleeding. Although the current ACC/AHA/ACG guidelines suggest that coadministration of a PPI and clopidogrel should be considered for those who can benefit from each, this study suggests that PPIs may not be interchangeable regarding their effects on clopidogrel PK. According to Paul Gurbel, MD, director of the Sinai Center for Thrombosis Research at Sinai Hospital, in Baltimore, a highly regarded expert in the area of antiplatelet therapy, “There is no debate about the significant attenuation of the pharmacodynamic effect of clopidogrel by omeprazole,” but there is debate about its clinical significance. Even though the current study “adds to the previous studies in the literature that overwhelmingly demonstrate that PPIs affect the pharmacokinetic and pharmacodynamic response of clopidogrel,” the clinical data derived from large trials, such as TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel; N Engl J Med 2007;357:2001-2015), “do not support a meaningful clinical interaction” regarding diminished protection from vascular events. The only randomized trial to address this issue, the COGENT trial, also was unable to demonstrate a clinically meaningful increased risk for cardiovascular events in patients taking omeprazole and clopidogrel concomitantly compared with patients on clopidogrel alone, even though a substantial pharmacologic interaction between these agents has repeatedly been shown. Although Dr. Gurbel cautioned that there were several limitations to the current study, it “is not the first study to demonstrate that the interaction varies with the specific PPI.” For example, several studies suggest that clopidogrel has a low propensity for interaction with pantoprazole (Protonix, Wyeth). One study cited by Dr. Gurbel included 336 patients who received clopidogrel after coronary stenting (J Cardiovasc Pharmacol 2010;56:91-97). In this nonrandomized study, no difference in antiScan for Sarah platelet effectiveSpinler, PharmD’s take on clopidogrel/ ness was detected between patients PPI interactions. Instructions, page 3 who received pan-

toprazole and those who did not. Based on these and other data, “pantoprazole would be a logical choice for a PPI in a patient on clopidogrel therapy,” Dr. Gurbel said. However, he cautioned that large definitive trials comparing the interaction of different PPIs with clopidogrel, particularly a trial analyzing cardiovascular events, has never been conducted. “Taking all of the above informa-

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64 Clinical

Pharmacy Practice News • November 2011

Medication Safety

Colchicine Algorithm Helps Avoid Drug-Drug Interactions Table. Recommended Colchicine Dose Reductions With Concomitant Drugs R

esearchers have developed an algorithm for reducing colchicine doses to prevent toxicity in patients who are also taking several agents known to interact with it (Arthritis Rheum 2011;63:2226-2237). The algorithm is based on the results of seven randomized open-label studies that looked at the interactions between colchicine, a treatment for gout and familial Mediterranean fever (FMF), and cyclosporine, ketoconazole, ritonavir, clarithromycin, azithromycin, verapamil extended release (ER) and diltiazem ER, all of which are known inhibitors of cytochrome P450 (CYP) 3A4 or P-glycoprotein (P-gp). The drugs often are coadministered with colchicine in patients with gout for concomitant disorders, such as high blood pressure and infections. Researchers believe that toxicity occurs because colchicine is metabolized by CYP3A4 and is a substrate for the P-gp transporter, noted lead study author Robert Terkeltaub, MD, chief of rheumatology at the Veterans Administration Medical Center in San Diego and professor of medicine and interim division chief at the University of California, San Diego. The 168 study participants were healthy, nonsmoking young adults who were not taking other medications. Twenty-four patients were enrolled in each of the seven studies. In each study, patients received two 0.6-mg doses of colchicine separated by a washout period of at least 14 days, and followed by a dose of one of the seven additional drugs. Blood samples were taken from patients before and after each dose of colchicine and the plasma concentration of the drug was determined. Clarithromycin, a potent CYP3A4 inhibitor, increased plasma concentrations of colchicine by 230%, while cyclosporine did so by 270%. Significant adverse events with the coadministered drugs ranged from nausea and headache to gastroenteritis to pain in extremities. Ketoconazole, known to be a strong CYP3A4/P-gp inhibitor, increased mean maximum colchicine concentrations by approximately 100%, whereas ritonavir increased the mean maximum concentration of colchicine by approximately 185%. In contrast, azithromycin (a weak CYP3A4 inhibitor) had minimal effects on colchicine concentration. The authors recommend azithromycin as a safer alternative to clarithromycin in patients taking colchicine. Both diltiazem ER and verapamil ER had more moderate drug interactions when coadministered with colchicine. Verapamil ER, a moderate inhibitor of

Colchicine Dose Concomitant Drug Acute Gout Flare

Prophylaxis of Gout Flare

Familial Mediterranean Fever

Cyclosporine

0.6 mg/d, to be repeated no earlier than 3 d

0.3 mg/d, or 0.3 mg every other day

0.6 mg maximum daily dose, may be given as 0.3 mg twice daily

Clarithromycin, ketoconazole, ritonavir

0.6 mg/d, or 0.3 mg twice a day, to be repeated no earlier than 3 d

0.3 mg/d, or 0.3 mg every other day

0.6 mg maximum daily dose, may be given as 0.3 mg twice daily

Diltiazem, verapamil

1.2 mg, dose to be repeated no earlier than 3 d

0.3 mg twice a day or 0.6 mg/d, or 0.3 mg/d

1.2 mg maximum daily dose, may be given as 0.6 mg twice daily

Azithromycin

No dose reduction required

‘Both the FDA and the manufacturer of colchicine have acknowledged the high potential for drug-drug interactions with this agent.’ —Geoffrey C. Wall, PharmD, FCCP, BCPS

CYP3A4 and P-gp, increased mean colchicine concentrations by about 40%, whereas diltiazem ER increased mean colchicine concentrations by 44%. Based on the results, the investigators devised an algorithm for administering colchicine. They recommended reducing dosages of colchicine by 33% to 66% when treating acute attacks of gout, and by 55% to 75% for prophylactic treatment, except when coadministered with azithromycin, for which no dose adjustment is necessary (Table). Patients taking cyclosporine, clarithromycin, ketoconazole or ritonavir should avoid colchicine use, if possible, the researchers noted. If these agents cannot be avoided, for cyclosporine, the authors recommended a 0.6-mg of colchicine for acute flares, 0.3-mg once a day or every other day for prophylaxis, and 0.6 mg per day maximum for FMF. For clarithromycin, ketoconazole and ritonavir, they recommended a 0.6-mg dose of colchicine followed by 0.3 mg one hour later for acute flares, 0.3 mg once a day or every other day for prophylaxis and 0.6 mg

per day maximum for FMF. For diltiazem and verapamil, the recommended colchicine dose was 1.2 mg for acute flares, 0.3 mg twice daily or 0.3 mg once daily for prophylaxis and 1.2 mg per day maximum for FMF. Dr. Terkeltaub noted that other medications available to treat gout, including nonsteroidal anti-inflammatory drugs and glucocorticoids, have their own toxicity profiles. On balance, he said, colchicine remains the favored agent for the disorder—a preference that “exists in part because when one balances the risks and benefits and looks at the comorbidities, colchicine becomes perhaps the easiest drug to use and probably has the best risk–benefit ratio.”

‘Very Important Information’ “This is very important information that needs to be included in what we teach primary care so they can safely manage this fairly common disease,” said Max Hamburger, MD, managing partner of Rheumatology Associates of Long Island, assistant professor of clinical medicine, Stony Brook Uni-

versity, N.Y., and president of the New York State Rheumatology Society, who was not affiliated with the study. “Gout is one of the most painful experiences that one can have and very disabling. … This article [provides] a basis for adjusting the dose and therefore being able to treat the patient safely.” Asked to comment on the study, Geoffrey C. Wall, PharmD, said that “both the FDA and the manufacturer of colchicine have acknowledged the high potential for drug-drug interactions with this agent.” The researchers “are to be commended for trying to bring clinical relevance to the pharmacokinetic studies done with colchicine,” added Dr. Wall, professor of clinical sciences, Drake University College of Pharmacy & Health Sciences, internal medicine clinical pharmacist, Iowa Methodist Medical Center, Des Moines. “This algorithm is definitely something that practicing pharmacists should be aware of and should discuss with prescribers when appropriate.” One concern “would be what the clinical outcomes from following this algorithm may show,” he said. “We do not know that the reduced doses listed in the algorithm will avoid the consequences of coadministering the drugs described with colchicine, and such follow-up should be considered for a prospective investigation.” —Laura Tendler The study was supported by URL Pharma. Dr. Terkeltaub has received consulting fees from Altus, Ardea Biosciences, BioCryst, EnzymeRx, Novartis, Pfizer, Procter & Gamble, Regeneron, Savient, Takeda, URL Pharma and UCB.

Pharmacy Practice News • November 2011

Clinical 65

Infectious Disease

XIGRIS continued from page 1

The new trial included 1,696 patients. A preliminary analysis found that 28-day all-cause mortality was 26.4% (223 of 846) in the drotrecogin alfa group, vs. 24.2% (202 of 834) in those on placebo, according to the EMA, which the agency said was not statistically significant. These results differed dramatically from the initial PROWESS trial, published in the New England Journal of Medicine (2001;344:699-709). “In that original study, we had 81 prospectively chosen subgroups. Of those, only two showed a point estimate on the side of harm, with the vast majority being on the side of benefit,” said E. Wesley Ely, MD, MPH, professor of medicine and critical care at Vanderbilt University School of Medicine, Nashville, Tenn., and one of the original coordinating center physicians for PROWESS. “That’s almost unheardof, and yet even then the [subgroups] with the clearest signal of ‘no benefit’ were those with the lowest death rates.” But 10 years later, Dr. Ely said, sepsis care has improved to such an extent that death rates in control patients are so low that demonstrating further improvement with drug therapy is difficult. “No matter how you slice it,” he said, “this study did not see benefit from this drug among those enrolled in the trial.”

Controversial Approval More than 200,000 people die of sepsis annually in the United States, and when drotrecogin alfa was first approved by the FDA, it became—and remained—the only drug with the stamp of approval to treat the condition. But the approval was controversial—the FDA advisory panel was split on its decision and restricted the drug’s use to adults with severe sepsis who have a high risk for death. In a sense, the finding is good news, said Michael Gropper, MD, PhD, who directs the ICU at the University of California, San Francisco Medical Center. “It says that we’ve made extraordinary progress without a magic bullet drug, with basic practices like handwashing, getting antibiotics to patients quickly, not using too many catheters, etc. There’s not a lot of industry interest in [those strategies], but they make an enormous difference.” Given the marginal benefits of drotrecogin alfa, the drug probably should never have been included in sepsis guidelines established by the Society of Critical Care Medicine (SCCM), according to Peter Papadakos, MD, professor of anesthesiology, surgery and neurosurgery at the University of Rochester, in New York. “It did nothing. Blocking one of several hundred cytokines does not make physiologic sense, but there was massive pressure to use it,” he said. The agendas of criticalcare meetings have been filled with talks

about activated drotrecogin alfa for several years, he noted, which gave the drug substantial momentum in the market. That market momentum has been part of the controversy surrounding the sepsis drug. In 2006, the New England Journal of Medicine (355;16:1640-1642) published an article that questioned some of the strategies used to promote more widespread use of drotrecogin alfa, including the funding of a task force to explore whether drug rationing in the ICU could negatively impact patient care. Drotrecogin alfa’s withdrawal raises a

more immediate question: what impact will its loss have on sepsis therapy? In Dr. Papadakos’ view, not much: “We still are down to supportive therapy only, including fluids, mechanical ventilation, antibiotics and vasoactive drugs.”

Critical Care Pharmacis’s Take Judith Jacobi, PharmD, a past president of the SCCM and a critical care pharmacist at Indiana University Health Methodist Hospital, Indianapolis, disagreed with the notion that drotrecogin alfa will not be missed. “Patients

with persistent shock due to community-acquired bacteremia, pneumonia and disseminated intravascular coagulation appeared to benefit significantly from drotrecogin alfa, and thus it will [create a gap] in our armamentarium.” In fact, “as a practitioner who has used drotrecogin alfa and a participant in the clinical trials, I’m disappointed in this decision [to withdraw the drug],” Dr. Jacobi said. “While PROWESS-SHOCK was not able to demonstrate a benefit in patients with persistent shock despite

•

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66 Clinical

Pharmacy Practice News • November 2011

Infectious Disease More oversight of antibiotic use in critically ill patients urged

In Liver Failure, Stewardship Lacking Chicago—Antibiotic stewardship in critically ill patients with liver failure needs improvement, according to a retrospective review presented during the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Dominic Chan, PharmD, BCPS, infectious disease pharmacist at the University of California, San Francisco Medical Center, presented data showing that most of the critically ill patients with liver failure in his center’s ICUs had received prolonged therapy for fungus, Pseudomonas and methicillin-resistant Staphylococcus aureus (MRSA) despite a surprisingly low occurrence of these organisms. Less than half of these patients had documented infections, and of these, only half presented with sepsis that required the continual use of antibiotics. “These patients look horribly sick when they get to the ICU. They are not transplanted yet, but are going through either an acute or an acute-on-chronic decompensation of the liver, and can look very septic when they come in,” Dr. Chan told Pharmacy Practice News. Because of this, he said, the first impulse is to bring on the big guns and give these patients broad-spectrum antibiotics. Although this practice of giving em piric, broad-spectrum antibiotics in a timely fashion has been drilled into the minds of the medical community, in the case of liver failure, not much data exist on the specific infections being treated, said Dr. Chan. Additionally, continued use of empiric antibiotics raises toxicity and drug interaction concerns and, in patients with liver dysfunction, clearance of these drugs can be altered; all of these factors make stewardship and de-escalation particularly important for this population. Dr. Chan emphasized that within the first 24 to 72 hours, it is acceptable to empirically and broadly cover with antibiotics, but once data start to return suggesting a lack of infection, health care providers must reconsider whether an infection that necessitates continual broad-spectrum therapy actually exists.

XIGRIS continued from page 65

volume resuscitation, vasopressors and source control, my experience has been different—both in the safety aspect and effectiveness.” Dr. Jacobi added that PROWESSSHOCK recruited investigators who were not regular prescribers of drotrecogin alfa—a necessity for ethical inclusion of a placebo arm, but a factor that could have negatively influenced the trial’s outcome.

have analyzed the data, we are having evidence-based conversations … between the transplant surgeons, the hepatologists, the infectious disease Scan for antibiotic doctors and the stewardship success pharmacists. While stories. Instructions, page 3 we will always defer to clinical judgment, using a protocol based on data … will hopefully be much better than flying blindly.”

A Call for Clinical Pharmacist

‘While we will always defer to clinical judgment, using a protocol based on data … will hopefully be much better than flying blindly.’

—Dominic Chan, PharmD, BCPS

Dr. Chan and his team reviewed all documented infections and antibiotic use among 108 liver failure patients who stayed in their liver transplant service ICU for at least three days between January 2009 and October 2010. The median length of stay in the ICU was eight days. None of the patients had received a previous transplant. They found that 50 (46%) of the patients had a documented infection; 24 (48%) had sepsis, which was microbiologically confirmed in 18 patients (75%). Additionally, intraabdominal infections were found in 11 patients (22%), pneumonia in nine (18%) and urinary tract infections in seven (14%).

Positive cultures were found in 65 (60%) of the study patients. Bloodstream isolates, including coagulase-negative Staphylococcus, Enterobacteriaceae, Candida and vancomycin-resistant enterococci (VRE), were found in 29 patients (27%). Urine isolates—primarily Candida species, Enterobacteriaceae and VRE— were found in 50 (46%) patients. On average, patients were on antibiotics for 19 days (range, 10-35 days). Antibiotics for MRSA were used in 83% of patients and antibiotics for Pseudomonas species were used in 88%. Antifungals were used in 44% of patients. “We were surprised to see that there wasn’t a significant amount of MRSA, which is always on everyone’s mind when you see a patient doing so badly,” Dr. Chan said. “The second surprise was that there wasn’t a lot of Pseudomonas. But we did see a lot of yeast coming out of the urine, which may … [suggest] a relatively overabundant use of antibiotics, which potentially clears out the normal flora.” The creation of an empiric antimicrobial therapy protocol that clearly states when to be aggressive and when to step back is an important way to help guide decisions in the ICU, Dr. Chan suggested. “It’s like a road map. Now that we

Dr. Jacobi also defended the inclusion of drotrecogin alfa in the 2008 update to the SCCM’s Surviving Sepsis guidelines. The decision to recommend the drug for selected patients in those guidelines was made “after a vigorous discussion and voting process,” she stressed. “The agent demonstrated efficacy in a broader population than was included in the FDA label, and further evidence of effectiveness was suggested by large clinical experience in other reports. Any guideline is limited by available data, and I believe this agent

was judged accurately at that time.” As for the potential for future sepsis drug research, some experts are skeptical. David Huang, MD, A critical care expert at the University of Pittsburgh, said that although he “gives credit to [Eli] Lilly for investing the money needed to do [the PROWESS-SHOCK] trial, I’m concerned that drugmakers will now give up on sepsis treatment and just churn out more drugs for allergies.” Without any new drugs looming, other approaches are needed. Dr. Jacobi’s

“Liver failure patients are relatively immunocompromised, so the thinking is to go as big as possible to ensure that we protect against the morbidity and mortality associated with infections in these patients,” he said. “But is this warranted? We wanted to characterize the epidemiology and the demographics of infections and antibiotic use in these patients, because we were surprised at the lack of infectious disease data specific to this vulnerable patient population.”

Study Detailed

Kwaku Marfo, PharmD, BCPS, clinical pharmacy manager for solid organ transplantation and adjunct clinical instructor for surgery at Montefiore Medical Center, The University Hospital for Albert Einstein College of Medicine, New York City, agreed with Dr. Chan that collaboration between surgeons, physicians and pharmacists is critical. “Proper antibiotic stewardship requires a multidisciplinary team approach,” Dr. Marfo told Pharmacy Practice News. “It is very important to not only have a hepatologist managing these patients; we definitely need a clinical pharmacist on board with expertise in organ transplant and we need an infectious disease expert to assess which agent or agents … will be the most appropriate for the patient.” Dr. Marfo reiterated Dr. Chan’s recommendation about the importance of reassessing the initial empiric regimen once the lab results are available. “While it is very important to initiate antibiotic therapy, you have to remember to de-escalate once you get any cultures back. The hepatic dysfunction could affect elimination of some of these antibiotics. So could complexities associated with an ICU stay. Being on multiple drugs could also pose a danger for drug–drug interactions, and there could be a lot of toxicities associated with all of these different drugs,” stressed Dr. Marfo. “So, de-escalation and good antibiotic stewardship are key.” —Fran Lowry Drs. Chan and Marfo reported no relevant financial relationships.

recommendation for practitioners, she noted, “is to focus on early sepsis identification and a systematic process of care using the sepsis bundles. That would be the most effective response to this lifethreatening syndrome.” —Gina Shaw Dr. Ely disclosed that Vanderbilt University received funding from Eli Lilly for the original PROWESS trial. Drs. Huang, Jacobi and Gropper reported no relevant financial relationships.

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Infectious Disease

Antibiotic De-escalation Reduces Mortality, Boosts Savings Chicago—The use of a de-escalation strategy to reduce the use of broadspectrum antibiotics has the potential to improve patient outcomes without compromising patient safety in a variety of important clinical settings, according to two studies presented at the 2011 Interscience Conference on Antimicrobial Agents and Chemotherapy. One study showed that a strategy of de-escalation after initial therapy with broad-spectrum antibiotics was associated with reduced mortality, shorter length of stay (LOS) and lower costs in intensive care unit (ICU) patients with pneumonia.

before the start of empiric antibiotics and were treated for at least 24 hours. De-escalation meant discontinuation of at least one antibiotic or a change to a narrower-spectrum drug. Dr. Destache and his colleagues found that 61% of the patients underwent deescalation. These patients were significantly more likely to be older than those who did not undergo de-escalation, with a mean age of 66 years compared with a

mean age of 55 years (P<0.01). They also were more likely to have diabetes (38% vs. 18%; P=0.04) and cardiovascular disease (38% vs. 15%; P=0.02). The most commonly isolated organisms were Staphylococcus aureus, found in 55% of patients, followed by Pseudomonas aeruginosa, found in 29%, and gram-negative rods, found in 27%. The investigators saw multiple benefits in the group that underwent de-

escalation. The mortality rate was 17% for patients who were de-escalated compared with 41% for those who were not (P=0.01) (Figure). Costs also were lower in the de-escalated group ($43,237±$45,640) than for patients not de-escalated ($60,640±$48,326). Although the difference was not statistically significant (P=0.08), because of the small number of patients and the

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see DE-ESCALATION, page 68

De-escalation No de-escalation 50 41

Mortality, %

40 30 20

10 0

Figure. Impact of antibiotic de-escalation on mortality.

‘Our results should help lead to a more judicious use of antibiotics.’ —Chris J. Destache, PharmD Noting that guidelines from the American Thoracic Society and the Infectious Diseases Society of America call for broad-spectrum antibiotic therapy early, with subsequent streamlining based on which organisms are isolated and their susceptibility patterns, presenter Chris J. Destache, PharmD, said the study was designed to evaluate whether antimicrobial de-escalation could reduce hospital LOS and expenditures. Dr. Destache, professor of pharmacy practice at Creighton University School of Pharmacy, in Omaha, Neb., Elizabeth Knaak, PharmD, instructor of medicine, and their colleagues retrospectively reviewed the charts of 95 adult patients admitted to the ICU at Creighton University Medical Center with presumed diagnoses of hospitalacquired pneumonia, ventilator-associated pneumonia or health care–associated pneumonia in 2009. All patients had blood and respiratory cultures collected

*Betamethasone 6 mg/mL as 3 mg/mL Betamethasone Sodium Phosphate and 3 mg/mL Betamethasone Acetate † Celestone® and Soluspan® are registered trademarks of Schering Corp. The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. Important Safety Information: As with any potent corticosteroid, adverse events have been associated with Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP, including fluid and electrolyte disturbances, as well as adverse reactions involving the following systems: allergic reactions, cardiovascular, dermatologic, endocrine, gastrointestinal, metabolic, musculoskeletal, neurological/psychiatric, and ophthalmic. Corticosteroids may also affect immune response. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP should not be administered intravenously or used in systemic fungal infections. Vaccination administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infections. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles and to seek medical advice without delay if exposed. Please see next page for brief summary of full prescribing information BB014, Iss. 3/2011

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68 Clinical

Pharmacy Practice News • November 2011

Infectious Disease

DE-ESCALATION continued from page 67

large standard deviations in the cost values, the $16,000 mean difference between the two groups “is a pretty big [variation],” said Dr. Destache, noting that it caught the eye of the medical center’s administrators. Additionally, ICU LOS was shorter for patients who were de-escalated vs. those who were not (9.4±12.2 vs. 12.8±10.2 days), but again the difference was not statistically significant (P=0.15).

‘The theory of streamlining antibiotics has been the approach for years, but now we are compiling data to support it.’ —Sandra Kane-Gill, PharmD, MSc “When patients get broad-spectrum antibiotics for empiric treatment, it is appropriate to monitor their clinical course and determine whether or not they can be de-escalated. This is safe to

do and also shows some cost benefit,” Dr. Destache told Pharmacy Practice News. “The biggest worry from an ICU standpoint is whether the patient will relapse if you stop antibiotics. What

we were able to show in this retrospective review was that patients who were de-escalated did not relapse. However, more patient data needs to be gathered to show conclusively that patients do not relapse. Our results should help lead to a more judicious use of antibiotics.”

Use of De-escalation Varies by Practice Site In another study presented at ICAAC, Harminder Sikand, PharmD, residency director at Scripps Mercy Hospital in San Diego, and her colleagues found that although de-escalation was more frequent in a teaching hospital than in a community hospital, resistance rates did not differ significantly between the two types of institutions. To evaluate the empiric use of fluoroquinolones, Dr. Sikand and her team retrospectively reviewed 204 patients treated at one of two San Diego area facilities— one a teaching hospital and the other a community hospital—between October 2010 and April 2011. De-escalation was defined as discontinuing levofloxacin or changing to a narrower-spectrum antibiotic within three days of the final culture. The researchers found that overall, 109 of 204 patients (58%) were de-escalated. Physicians at the teaching hospital were more likely to de-escalate therapy compared with physicians at the community hospital (78% vs. 41%; P<0.001). Resistance to levofloxacin did not differ significantly between the teaching and community hospitals (28% vs. 17%, respectively; P=0.063). “Our hope is that we will educate our clinicians that they are overusing fluoroquinolones and increasing collateral resistance,” Dr. Sikand told Pharmacy Practice News. “Further education … is needed to focus on narrow-spectrum antibiotic prescribing.”

Yet More Evidence Sandra Kane-Gill, PharmD, MSc, associate professor of pharmacy and clinical translational sciences at the University of Pittsburgh School of Pharmacy, said both studies confirm earlier data and thus “provide further support for the de-escalation strategy from an outcomes perspective.” The evidence suggests “that it’s OK to do this,” said Dr. Kane-Gill, “and it may actually be beneficial with regard to resistance patterns and costs.” She added, “The theory of streamlining antibiotics has been the approach for years, but now we are compiling data to support it.” —Fran Lowry Drs. Destache, Sikand, and Kane-Gill reported no relevant conflicts of interest.

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Clinical 69

Infectious Disease

When Seagulls Take Wing, So Do Resistant Bacteria S ‘These birds may fly up to 1,000 km with very little water and food, so they could spread these resistant bugs to many different environments.’ —Patrice Nordmann, MD two were CTX-M-32) and two Enterobacter cloacae isolates expressed SHV7. Additionally, 14 E. coli isolates carried CMY-2, an AmpC-type β-lactamase. Although the sample size in this study was small, Dr. Nordmann added that “two years ago, we found similar rates of ESBL-producing bacteria in the feces of seagulls in Porto, Portugal.” The specific types of ESBLs uncovered in the study were consistent with those commonly isolated from humans. This relationship underscores the

potential for seagulls to disperse these MDR bacteria elsewhere. “These birds may fly up to 1,000 km with very little water and food, so they could spread these resistant bugs to many different environments,” said Dr. Nordmann, although he noted that currently, there is no empiric evidence to link seagulls with the transmission of these bacteria to humans.

Scavengers by Nature Seagulls are scavengers by nature, eating and drinking whatever they come across. Urban seagulls often feed on discarded food or standing water that may be contaminated with pathogenic bacteria. They can shed these bacteria in their feces, which end up on the sandy beaches they share with humans. However, the ability to harbor ESBLproducing bacteria is not limited to seagulls. Dr. Nordmann mentioned that a study in Istanbul, Turkey, identified pigeons with similar resistance genes to those found in the Miami Beach study.

Source: CDC

eagulls may be a source for the spread of multidrug-resistant (MDR) enteric bacteria into the environment, according to new research presented at the 2011 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Researchers collected 52 fecal samples from seagulls in Miami Beach, Fla., and found that 8% of the Escherichia coli and Enterobacter cloacae isolates carried extended-spectrum β-lactamase (ESBL)–producing enzymes (ICAAC 2011; Abstract C2-1560). “They [seagulls] could be an important vector for the spread of drug-resistant bacteria,” said Patrice Nordmann, MD, PhD, chief, Department of Bacteriology-Virology, Bicetre Hospital in Paris, during a press briefing at ICAAC. The investigators cultured 83 enterobacterial isolates and 20 non-enterobacterial isolates overall. Among the enterobacteria, nine carried ESBL enzymes: seven E. coli isolates produced CTX-M (five were CTX-M-15,

But he pointed out that seagulls may pose a larger risk for more widespread dissemination of resistant organisms because of their ability to fly hundreds of miles at a clip. Because E. coli infections primarily occur within the community, an increased incidence of MDR strains could have serious public health consequences. “This is a real problem,” said Dr. Nordmann. “It is a worldwide phenomenon that may enhance the problem of MDR determinants for patients in the community.” —Seth Kandel

In Brief: Hepatology

Vitamin D Tests Urged In Patients With Chronic Viral Hepatitis Chicago—Nearly two-thirds of patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have low levels of vitamin D, according to retrospective findings presented at the 2011 Digestive Disease Week meeting (abstract Su1302). In light of the results, researchers are urging clinicians to monitor vitamin D levels in all patients with chronic viral hepatitis. “If we treat vitamin D deficiency, we can potentially decrease the high rate of osteopenia and osteoporosis in this population, including bone loss related to some of the antiviral therapies” said co-investigator Maya Gambarin-Gelwan, MD, assistant professor of clinical medicine, Weill Cornell Medical College, New York City. Up to 53% of patients with viral hepatitis–related cirrhosis develop osteoporosis. Given the risk for bone loss associated with low levels of serum 25-hydroxyvitamin D (25[OH]D), investigators set out to determine the prevalence of vitamin D deficiency and insufficiency among patients with HBV and HCV treated at Weill Cornell Medical Center. They defined vitamin D deficiency as serum 25[OH]D less than 20 ng/mL and vitamin D insufficiency as levels

between 20 and 30 ng/mL. Among 2,312 patients with chronic viral hepatitis seen at the center between 2007 and 2009, only 17% (395 of 2,312) had been tested for vitamin D levels. Of those who underwent vitamin D testing, 31% (122 of 395) were vitamin D insufficient and 33% (132 of 395) were vitamin D deficient. The prevalence of vitamin D insufficiency was similar among patients with chronic viral hepatitis who had cirrhosis and those who did not (26% and 33%, respectively; P=0.10). However, the difference in vitamin D deficiency between patients with cirrhosis and those without cirrhosis was significant (44% vs. 29%; P=0.01). Interestingly, vitamin D insufficiency was more prevalent among those infected with HBV than among those infected with HCV (73% vs. 60%, respectively; P=0.01). Although she suspects that ethnicity may play a role in this difference, Dr. Gambarin-Gelwan said that her data set did not include adequate information on ethnicity to draw a conclusion. Zobair Younossi, MD, MPH, a liver specialist who was not involved in the study, said that prior studies have shown low vitamin D levels tend to be more

common in patients with advancedstage fibrosis and cirrhosis. “However, this study shows insufficiency can also be seen in non-cirrhotic patients with hepatitis B and C, and particularly in those with chronic hepatitis B,” said Dr. Younossi, vice president for research, Inova Health System, and chairman, Department of Medicine, Inova Fairfax Hospital, Falls Church, Va. Dr. Gambarin-Gelwan said that she hopes her research will spur clinicians to routinely monitor vitamin D levels in patients with chronic HBV and HCV infection.” —David Wild Dr. Gambarin-Gelwan has nothing to disclose. Dr. Younossi reported relationships with Salix Pharmaceuticals, Tibotec Pharmaceuticals and Vertex Pharmaceuticals.

N-acetylcysteine Rx In Acute Liver Failure: No Impact on Survival Chicago—Intravenous N-acetylcysteine (NAC) does not improve oneyear survival in pediatric patients with non-acetaminophen acute liver failure (NAALF) and is associated with a significantly lower probability of one-year transplant-free survival (TFS) compared with placebo, according to data presented at the 2011 Digestive Disease Week meeting (abstract 622). Because IV NAC is effective in adults

with NAALF, lead investigator Robert Squires, MD, reasoned the same might hold true in a pediatric population. Dr. Squires, professor at Children’s

Hospital of Pittsburgh at the University of Pittsburgh Medical Center, and his colleagues at 21 sites in three countries randomly assigned 92 pediatric patients with NAALF to receive a continuous infusion of NAC (150 mg/kg per day) and another 92 patients to receive IV 5% dextrose in water for up to seven days in a double-masked fashion. Participants in the treatment and placebo groups were close in age and had similar distributions of hepatic encephalopathy grades, similar levels of alanine transaminase and aspartate transaminase and similar coagulation profiles at study entry. Approximately 55% of patients in both groups had indeterminate diagnoses. There were significantly more patients with a metabolic disease in the NAC group (n=17) than in the placebo group (n=6). The cumulative probability of survival

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70 Clinical

Pharmacy Practice News • November 2011

IVIG FAQ

IVIG and Hemolysis: Assessing the Risk Jerry Siegel, PharmD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

Table 1. Risk Factors For Hemolysis in Patients Taking IVIG

Routinely screen patients for possible hemolysis risk factors Limit the total dose per course of therapy administered per patient to 2 g/kg

Patient Risk Factors Non-O blood type3,5,7

Q: Can intravenous immunoglobulin (IVIG) cause hemolysis? A: One of the first publications to note this problem did so in 1986 after 2 patients receiving IVIG for prevention of Cytomegalovirus infection following bone marrow transplantation demonstrated profound hemolysis.1 Such reports of this relatively rare adverse event—the rupturing of erythrocytes and the release of hemoglobin into surrounding fluid—have been scattered throughout the IVIG literature over the past 25 years,1-4 but more questions about hemolysis have been reported recently. A recent study showed an incidence of hemolysis of 1.6% in a population of 1,000 patients.5 The 16 patients with hemolysis all had received large doses of IVIG, had a non-O blood group, were female, and had an underlying inflammatory state. The proposed mechanism was sensitization by ABO isohemagglutinins, followed by phagocytosis by activated macrophages.3,5 No one age group appears to be at higher risk than others, and both D-positive and D-negative patients have demonstrated hemolysis.3 In one case report, a child with Kawasaki disease received an infusion of IVIG and then 2 more doses a week later due to persistent fever and coronary artery inflammation.6 The patient experienced rapid hemolysis, followed by disseminated intravascular coagulation and serum sickness. Does this adverse event occur because of a change in IVIG manufacturing or the

HEPATOLOGY continued from page 69

at one year was lower, but not significantly so, in NAC patients than in placebo patients (73% vs. 82%, respectively). In contrast, the difference in TFS at one year was significantly different between groups, with a 35% cumulative probability of TFS associated with NAC and a 53% probability of TFS with placebo (P=0.04). Statistical analyses accounting for the differences in diagnoses did not change the significance of these outcomes. “There does not appear to be any use for NAC to treat non-acetaminophen acute liver failure [in the pediatric population],” said Raj Vuppalanchi, MD, assistant professor of medicine,

Underlying inflammatory condition5,6 Female gender5 IVIG Risk Factors Total dose >2 g5,6 Liquid IVIG product7 IVIG with high-titer IgG antibodies to isohemagglutinins A/B7 IgG, immunoglobulin G; IVIG, intravenous immunoglobulin

Table 2. Evidence Confirming IVIGassociated Hemolysis Positive direct antiglobin Signs of hemolysis within 10 days of IVIG infusion Decrease in hemoglobin >1 g/dL Any 2 of the following laboratory findings: ↑ reticulocyte count ↑ lactate dehydrogenase ↓ haptoglobin ↑ serum bilirubin Hemoglobinemia Hemoglobinuria Significant spherocytosis IVIG, intravenous immunoglobulin

use of an increased number of doses for immunotherapy? Although antibodies to isohemagglutinins A and B are found in Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, who was not involved in the study. “However, in cases where etiology is uncertain or there’s suspicion of unintentional or surreptitious acetaminophen-induced acute liver failure, clinicians should not hesitate to use NAC as the current study is not conclusive with regard to adverse outcomes from the drug.” Dr. Squires said his group will conduct further research to examine daily patterns of clinical and biological markers in children with acute liver failure. —David Wild Drs. Vuppalanchi and Squires reported no relevant conflicts of interest.

Table 3. Considerations To Reduce Risk for IVIGassociated Hemolysis

very low (trace) amounts in IVIG products, when higher doses are infused— especially in obese patients—even trace amounts may result in a problem. In a study of patients with end-stage renal disease receiving IVIG therapy, 18 cases of hemolytic anemia were noted in 16 patients.7 The investigators used 5 different IVIG products and measured isohemagglutinin titers. They ranged from 1:2 to 1:64. The higher titers were noted in liquid IVIG preparations. The big question is whether risk factors can be identified so that the risk for hemolysis can be reduced. For example, can changing the way IVIG is administered and monitoring the patient post-infusion be beneficial in patients with more risk factors? The Canadian Pharmacovigilance group has suggested specific criteria to confirm the diagnosis of IVIG-associated hemolysis.2 Although the evidence is limited, Tables 1-33,5-8 provide information to help reduce risk for IVIG-associated hemolysis and may be useful for screening purposes.

References 1. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion. 1986;26(5):410-412. 2. Canadian Blood Services. Important Information Regarding IVIG-Associated Hemolysis. Customer Letter #2009-02. Canadian Adverse Reaction Newsletter. 2009;19(4):1-4. http:// www.bloodservices.ca/CentreApps/Internet/UW_V502_MainEngine.nsf/resources/ CustomerLetters09/$file/CL_2009-02.pdf. 3. Morgan S, Sorensen G, Vercellotti G, Zantek ND. Haemolysis after treatment with intrave-

Telaprevir Slashes Duration of Standard Hepatitis C Therapy

he treatment duration of peginterferon and ribavirin can be cut in half—from 48 to 24 weeks—when it is given after 12 weeks of treatment with telaprevir in patients with chronic hepatitis C virus (HCV) genotype 1 infection who have exhibited extended rapid virologic response (eRVR), according to results from a Phase III clinical trial. Reporting their findings in the Sept. 15 issue of The New England Journal of Medicine (2011;365:1014-1024), Kenneth E. Sherman, MD, PhD, professor

Consider adjusted dose regimen for obese patients (>100 kg and BMI >30 kg/m2)8 Split dose over 4 to 5 days and avoid regimens of 1 g/kg per day, when possible Monitor hemoglobin 48 to 72 h after IVIG infusion7 Consider using a lyophilized IVIG product with low anti-A/B IgG antibodies3 BMI, body mass index; IgG, immunoglobulin G; IVIG, intravenous immunoglobulin

nous immunoglobulins due to anti-A. Transfus Med. 2011;21(4)267-270. 4. Wilson JR, Bhoopalam H, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve. 1997;20(9):1142-1145. 5. Zohra D, Padmore R, Neurath D, et al. Hemolysis transfusion reactions after administration of intravenous immune globulin: a case series analysis” Transfusion. 2008;48(8):1598-1601. 6. Comenzo RL, Malachowski ME, Meissner HC, Fulton DR, Berkman EM. Immune hemolysis, disseminated intravascular coagulation, and serum sickness after large doses of immune globulin given intravenously for Kawasaki disease. J Pediatrics. 1992;120(6):926-928. 7. Kahwaji J, Barker E, Pepkowitz S, et al. Acute hemolysis after high-dose intravenous immunoglobulin therapy in highly HLA sensitized patients. Clin J Am Soc Nephrol. 2009;4(12):1993-1997. 8. Siegel J. Immune globulins in obesity. Pharmacy Practice News. 2010;37(1):8-9.

Dr. Siegel reported that he has a consulting agreement with CSL Behring.

of medicine, University of Cincinnati, and his colleagues noted that 72% of the patients who entered the study (n=540) had a sustained virologic response (SVR) and 65% had an eRVR. At 20 weeks, the patients with an eRVR were randomly assigned to receive peginterferon and ribavirin for an additional four or 28 weeks. Among these patients, 92% in the 24-week treatment group and 88% in the 48-week group had an SVR. Overall, 18% of patients discontinued treatment due to adverse events (AEs)—1% in the 24-week group compared with 12% in the 48-week group (P<0.001). AEs included rashes (37%) and anemia (39%). “These results are likely to change treatment standards for patients with

Pharmacy Practice News • November 2011

Clinical 71

In Brief: Hepatology hepatitis C and reduce adverse effects of the treatment regimen,” Dr. Sherman wrote in a statement issued by the University of Cincinnati. “The high viral cure rates showed that there was no benefit to extending the therapy to 48 weeks for the majority of people in this trial.” He added, “Importantly, patients in this trial had a high likelihood of achieving a cure with 24 weeks of total therapy if they had a rapid response to these regimens by week 4. Knowing this may provide important motivation for people to continue therapy.” The study provides physicians with “an absolutely solid foundation of confidence that, provided the appropriate response criteria are met, telaprevirbased therapy can be stopped after 24 weeks without impairing the patient’s chance of sustained response,” said Ira M. Jacobson, MD, chief of gastroenterology and hepatology and the Vincent Astor Distinguished Professor of Clinical Medicine at Weill Cornell Medical College, New York City. The

Statement of Ownership

study confirms earlier nonrandomized trial results that suggested a 24-week therapy was sufficient for patients who took telaprevir and met the appropriate criteria for viral undetectability at four and 12 weeks, he said. There were too few patients with cirrhosis in the Phase III trials to draw definitive conclusions about duration of treatment. However, the FDA packaging states that these patients “may benefit” from extending therapy to 48 weeks. Dr. Jacobson said, “I do plan to give very strong consideration to heed

the package insert and strongly consider extending therapy in the cirrhotic patients who have an eRVR.” —Christina Frangou The trial was funded by Vertex Pharmaceuticals and Tibotec. Dr. Jacobson reported the following disclosures: Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, GlaxoSmithKline, GlobeIummune, Human Genome Sciences, Merck, Novartis, Pfizer, Pharmasset, Roche, Schering, Tibotec, Vertex Pharmaceuticals and ZymoGenetics.

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72 Clinical

Pharmacy Practice News • November 2011

Critical Care

Can Pharmacists Help Prevent SIDS? Pittsburgh—When you think of experts who provide education for new parents about how to prevent sudden infant death syndrome (SIDS), you probably envision a pediatrician or a family physician. But what about a pharmacist? An innovative new continuing education program sponsored by the National Institutes of Health targets pharmacists—both community- and hospitalbased—as potentially important sources of SIDS-prevention messages. The National Institute of Child Health and Human Development (NICHD) partnered with First Candle, a national nonprofit health organization focused on improving survival for infants in their first year of life, and leading pharmacy organizations—including the American Society of Health-System Pharmacists and the American Association of Colleges of Pharmacy—to create the training module, which is available online from NICHD and has also been presented at a number of state and national meetings. “I had conducted a SIDS education session at a meeting for nurses, and a pharmacist came up to me and asked, ‘Why aren’t you guys doing this with pharmacists?’’’ recalled Hanan Kallash, RN, MS, a health educator with First Candle, who presented the program as a poster at the annual meeting of the American College of Clinical Pharmacy (209E). “I said that we hadn’t considered pharmacists as a group we would target, as they’re not traditionally focused on education toward consumers. He kindly corrected me on that point.” The pharmacist explained to Ms. Kallash that pharmacists often are the most easily accessed health provider for many families, and are seen on a regular basis as people come in to pick up medications. “I learned that they do a lot of education and have a trusted role in the community,” she said. “There is also a cultural change occurring in the pharmacy world, where pharmacists are incorporating a broader clinical role and more counseling, beyond just medi-

‘I think it’s terrific that the federal government recognizes that pharmacists can make a difference in SIDS—that knowing our patients well, we can talk to them about important messages like this, even when it doesn’t involve medications.’ —Marcia Mueting, PharmD

cation management.” Ms. Kallash suggested to the pharmacist that he speak with NICHD about creating a program for pharmacists, which he did. NICHD was still skeptical, so it conducted four focus groups with pharmacists in different areas. “The participants did indicate that they thought it would be useful, so we created the learning module for them,” Ms. Kallash said.

Program Boosts SIDS Knowledge The course includes background on factors that increase SIDS risk—such as stomach sleeping; sleeping on soft, fluffy surfaces; room/baby overheating; exposure to secondhand smoke—and guidance on how to communicate SIDS risk-reduction messages to parents and caregivers. So far, 360 pharmacists and 118 students have completed the program; their average score in understanding the concepts of SIDS risk reduction and education increased by 26% to 34% as measured by pre- and post-tests, according to the poster study. Ms. Kallash has also presented the training at various state pharmacy meetings in Ohio, Nevada, Nebraska, Wyoming, Maryland and New York. “We’ve tried to target, with our limited funding, areas that have the highest rates of infant mortality,” she said. At a meeting of the Nebraska Phar macists Association, more than 80 people attended the SIDS presentation. “I think it’s terrific that the federal government recognizes that pharmacists

can make a difference in SIDS—that knowing our patients well, we can talk to them about important messages like this, even when it doesn’t involve medications,” said Marcia Mueting, PharmD, a pharmacist with the association. “It was really remarkable to recognize the role of pharmacists in the health care team as educators. This was a win–win session for our association.” Pharmacists attending the SIDS sessions often have been surprised by what they’ve learned, Ms. Kallash said. “Many of them knew the back to sleep position, but they weren’t necessarily aware of the huge body of science behind it that has shown us that back to sleep is best not only for SIDS but for overall health, reducing things like ear infections and GERD [gastroesophageal reflux disease]. Or the fact that babies only breathe through their nostrils. Unless you’re a pediatric specialty pharmacist, you might not be learning this.”

Opportunities for Counseling One way that pharmacists can engage parents in conversation about the SIDS issue is when they’re asked about treating a fever in a baby under the age of 2 years. “They can talk with the parents about how cold medication dampens a baby’s arousal threshold, increasing the danger of SIDS,” Ms. Kallash said. “Then they can teach them what to do instead of giving cold medication— providing them with an aspirator and asking if the physician has shown them how to use it to clear the baby’s nostrils.”

The University of Maryland School of Pharmacy included the learning module in its nonprescription medicine course this past year, right after a pediatrics lecture and right before sleep disorders. “The students really enjoyed it,” said Lauren Angelo, PharmD, assistant professor in the Department of Pharmacy Practice and Science, in Baltimore. “It was a topic we hadn’t done before. Some students who were younger hadn’t even been exposed to this issue at all, while the mothers in the audience were very engaged in the Q&A session about how things have changed over the years with regard to sleep positioning. As the pharmacist’s role expands, our graduates are going to see a variety of issues, and this fits nicely in that clinical arena.” Ms. Kallash said that she is still scheduling presentations of the continuing education course until funds for the program expire in July 2012. “After that, the online version will still be available, but if you want someone to come out to a conference, it has to be on the schedule by July.” For more information, contact Ms. Kallash at (800) 221-7437, extension 227, or hanan@ firstcandle.org. To access and complete the course online, scan the QR Scan to take the NIH code at right. SIDS continuing —Gina Shaw

Another Wake-up Protocol Improves ICU Outcomes Pittsburgh—A pharmacist-led sedation program designed to standardize wake-up assessments for mechanically ventilated patients in the intensive care unit (ICU) resulted in a statistically significant mortality reduction, as well as a trend for decreased duration of ventilation, according to a presentation at the American College of Clinical Pharmacy annual meeting. Although daily wake-up assessments were supposed to be standard proce-

dure for intubated patients who did not have contraindications, “I realized that the nurses here didn’t really understand how to do wake-up assessments,” said lead author Lisa Lederhouse, PharmD, clinical pharmacist at New Hanover Regional Medical Center, in Wilmington, N.C. In many cases, sedation (usually with propofol) was continued at high levels for patients who likely could have done well with a lower dose.

Earlier Research Established Protocol’s Efficacy Prior research has shown that daily wake-up assessments conferred several important benefits. The ABC (Awakening and Breathing Controlled) trial (Lancet 2008;371:126-134), a key multicenter study, found that a daily sedation and ventilator-weaning protocol reduced ventilator time and ICU length of stay, preserved cognitive function and reduced mortality rates. Yet,

education course. Instructions, p. 3

Pharmacy Practice News • November 2011

Clinical 73

Critical Care

‘Most ICU pharmacists have a role to play aside from just picking and dosing medications. In this case, it was driving a quality initiative and optimizing outcomes.’ —Ishaq Lat, PharmD, BCPS

vide further guidance and ensure that the protocol is practiced every day. “Something we thought was being done correctly really wasn’t done to

ABC Participant Comments Ishaq Lat, PharmD, BCPS, clinical coordinator, critical care/emergency medicine at the University of Chicago Medical Center, participated in the earlier ABC trial. “What’s novel is that in this study, a clinical pharmacist is driv-

ing the translation of research findings into clinical practice to improve patient care. That further reinforces the fact that most ICU pharmacists have a role to play aside from just picking and dosing medications. In this case, it was driving a quality initiative and optimizing outcomes.” He added that a larger sample size would add more weight to the findings and provide additional evidence that they could be applied to most hospital settings. —Steve Frandzel

Vi si tu s at AS HP Bo ot h 20 19

the authors noted, the protocol is used in less than half of U.S. hospitals. In Dr. Lederhouse’s retrospective/ prospective study, the retrospective control arm consisted of 50 patients admitted over a two-month period prior to initiation of the wake-up program. The prospective arm consisted of 50 patients admitted after the program was initiated. All patients were in the medical or general surgical ICU, were receiving mechanical ventilation and continuous sedatives and/or analgesics. Neurosurgery patients; patients on neuromuscular blockers; and patients with active seizures, withdrawal symptoms, evidence of increased intracranial hemorrhage or profound neurologic deficits were excluded from the study. Dr. Lederhouse trained the ICU nurses on detailing daily wake-up assessment procedures; the nurses also completed an online training module. The wake-up assessment was the same for all patients, and involved interruption of sedatives to determine if they were ready for liberation from the ventilator. Pharmacists would ensure that the assessments were performed daily and made recommendations related to sedation and analgesia. Prior to the study, the computerbased chart contained a single check box for nurses to record whether or not an assessment was done. The updated chart includes fields for details such as whether the sedative was turned off, what the result was, if it was turned back on and at what rate. Additionally, a poster describing the wake-up assessment protocol was placed in the ICU. After initiating the training program, Dr. Lederhouse observed an 18% decrease in the primary outcome of duration of ventilation, although the result was not statistically significant. The average duration of ventilation decreased from 138.45 hours among those treated before the protocol was initiated to 113 hours among those treated after (P=0.6675). Improvements in secondary outcomes also were reported: The mortality rate dropped from 36% to 14% (P=0.0111) and the number of wake-up assessments performed correctly increased from 12.5% to 67.8% (P<0.001). Although the change in the primary outcome measure was not statistically significant, the hospital updated its nursing documentation system to pro-

the best standard of care,” said Dr. Lederhouse. “It was a combination of both education and changing the computer system so that any new nurse who came in could see how the protocol was supposed to be done.”

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74 Clinical

Pharmacy Practice News • November 2011

Pain Management

Unlocking the Mysteries of Post-Op Oral Analgesics P

ractitioners know that oral analgesics offer patients pain relief, but they are less confident about which drugs and which doses confer optimal analgesia. To help quantify which combinations and doses of oral analgesics are most effective for relieving pain, researchers at Oxford University’s Pain Research Unit in the United Kingdom analyzed 35 previously published Cochrane Reviews of randomized clinical trials (RCTs) involving common oral medications used to treat severe to moderate postoperative pain. The researchers found a wide range of efficacy, with no single drug producing high levels of pain relief for all patients. “If the first painkiller a person tries doesn’t seem to work, then a doctor should look to find an alternative reliable drug and see if it is more effective in that patient,” said R. Andrew Moore, MD, lead author of the study published online Sept. 7 (Cochrane Database Syst Rev 2011;9:CD008659). “We do need lots of analgesic medicines. Pain is so complex in its pathways, in its genetics, in the modulation by the brain, and in the way in which our bodies handle and respond to drugs [that] it is inevitable that to do good for everyone, we need access to a range of therapies.” The meta-analysis examined 35 Cochrane Reviews involving 38 analyses of single-dose oral analgesics tested in acute postoperative pain settings. The analysis covered about 45,000 participants and 350 placebo-controlled RCTs. Results were obtained for 46 drug–dose combinations used in dental pain and other painful postsurgical conditions. The primary outcome was percentage of patients who experienced at least 50% pain relief over four to six hours. Efficacy rates ranged from about 30% to more than 70%, and the time to remedication varied from two hours to more than 20 hours for the same pain condition. The results varied significantly. For example, 600 mg of ibuprofen reduced postoperative pain by at least 50% for 77% of patients, whereas 600 mg of aspirin produced the same effect in only 39% of patients. Codeine 60 mg showed the worst results, producing effective pain relief in only 26% of those treated for all pain conditions. The researchers also determined the number needed to treat (NNT) for each drug–dose combination. Drug–dose combinations with good (low) NNTs included ibuprofen 400 mg (NNT, 2.5; 95% confidence interval [CI], 2.4-2.6), diclofenac 50 mg (NNT, 2.7; 95% CI, 2.4-3.0), etoricoxib 120 mg (NNT, 1.9; 95% CI, 1.7-2.1), codeine 60 mg plus

‘Pain is so complex in its pathways, in its genetics, in the modulation by the brain, and in the way in which our bodies handle and respond to drugs [that] it is inevitable that to do good for everyone, we need access to a range of therapies.’ —R. Andrew Moore, MD

paracetamol 1,000 mg (NNT, 2.2; 95% CI, 1.8-2.9), celecoxib 400 mg (NNT, 2.5; 95% CI, 2.2-2.9) and naproxen 500/550 mg (NNT, 2.7; 95% CI, 2.3-3.3). Most drug–dose combinations also had NNTs of less than 3, and higher doses of the same drug tended to produce lower NNTs. Long duration of action (at least eight hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg plus paracetamol 650 mg, naproxen 500/550 mg and celecoxib 400 mg. Reported adverse events were few and generally not different between active drug and placebo, except for aspirin and opioids. Reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam and tiaprofenic acid. Insufficient data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen and indomethacin, the authors reported. “Pain relief doesn’t have to be a mystery,” Dr. Moore said. “There is a body of reliable evidence about how well 46 different drug–dose combinations work against acute pain, but the review also shows there are many examples of drugs

for which there is insufficient evidence, and the drugs in question should probably not be used to treat acute pain.”

in anesthesiology and pain medicine and clinical director of the Oxford Regional Pain Relief Unit at Oxford Radcliffe Hospitals in the United Kingdom, said the study shows that there are simple agents that can significantly reduce acute pain for significant periods of time. “This is important because it shows we can do something with the tools we have available now,” Mr. Aldington said. “An NNT of less than 2 really is outstanding, and I will certainly reach for the etoricoxib as Plan A,” he said. Mr. Aldington is a colleague of Dr. Moore, but was not involved in the study. This study on acute pain is part of a larger effort in pain in general, Dr. Moore said. Next year, he and his colleagues plan to publish a study examining migraine and assessing overthe-counter medicines because most people with migraine do not visit a doctor for it. Also in the works are studies comparing chronic pain medications involving musculoskeletal, as well as nerve injury, pain. “Here, there are major methodological issues that mean that we have to look at chronic pain results with a cold and fishy eye,” Dr. Moore said. “To be honest, there are results coming here that really will surprise and will require substantial rethinking by all sorts of regulatory and clinical bodies.” —Ted Agres

in Your Inbox

Adapting Findings To Patient Care The findings can be useful for consumers and physicians, Dr. Moore added. “The consumer who wants to purchase analgesics for common painful events like a headache or period pain might find a message that relatively simple cheap analgesics are effective. They would be surprised, perhaps, that their expensive branded analgesic was not on the list. That’s because there are no trials published [for these drugs],” he explained. “A medical practitioner might want to prescribe an analgesic that is most likely to provide good pain relief to a large proportion of her or his patients, rather than a small proportion,” Dr. Moore added. “A hospital might be interested in duration of analgesia as a key element for designing an effective postoperative care pathway, because pain-free patients get better faster and are happier.” Dominic J. Aldington, BSc, a consultant

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Pharmacy Practice News • November 2011

Clinical 75

Infectious Disease

Rifaximin Prevents Spontaneous Bacterial Peritonitis Chicago—Patients with liver cirrhosis and ascites experienced a 76% reduced risk for spontaneous bacterial peritonitis (SBP) when taking rifaximin compared with those not receiving antibiotic prophylaxis, according to a study presented at the 2011 Digestive Disease Week meeting (abstract 729). The study’s authors also noted that prophylactic rifaximin was associated with a 30% higher rate of transplant-free survival at nine months of follow-up. Prior research has shown that about one in four cirrhotic patients with ascites develop SBP, with an associated mortality rate between 10% and 30% (Gastroenterology 1996;111:1011-1017). Practice guidelines for patients with ascites due to cirrhosis were issued in 2004 (Hepatology 2004;39:841-856). Although the guidelines recommend SBP prophylaxis in high-risk patients with cirrhosis and ascites, according to primary investigator Ibrahim A. Hanouneh, MD, there is no conclusive evidence that this practice increases survival. Part of the reason is that “selective intestinal decontamination with conventional antibiotics like norfloxacin or trimethoprim with sulfamethoxazole can lead to the emergence of resistant gut flora and subsequent SBP,” explained Dr. Hanouneh, from the Department of Gastroenterology and Hepatology, Cleveland Clinic, in Ohio. In this study, Dr. Hanouneh and his colleagues set out to document the efficacy of treating SBP with rifaximin, a drug with a wide spectrum of activity against gram-positive and gram-negative organisms as well as aerobes and anaerobes. The investigators examined data from 418 adult patients treated between 2003 and 2007, at the Cleveland Clinic, for liver cirrhosis and large ascites. None of the subjects had a history of SBP before the study. Fifty-three patients received 1,200 mg rifaximin daily for an average of 4.2 months and the remainder did not receive antibiotic prophylaxis. At study outset, the two groups had similar demographic and clinical characteristics, including Model for End-Stage Liver Disease (MELD) scores, serum sodium and ascitic fluid compositions. They were followed for a mean of nine months after their initial visit to the Cleveland Clinic. The investigators found that 13% of the 53 rifaximin-treated patients developed SBP during the study period, compared with 34% (124 of 365) of those who did not receive prophylactic treatment (P=0.001). Controlling for age, MELD scores, serum sodium and ascitic fluid compositions, rifaximintreated patients were 76% less likely than untreated patients to develop SBP (odds ratio [OR], 0.24; 95% confidence

interval [CI], 0.1-0.6; P=0.002).

Mortality, Transplant Benefits At the end of the follow-up period, Dr. Hanouneh’s team found that 31% (12 of 38) of rifaximin-treated patients had a liver transplant compared with 59% (121 of 205) of untreated subjects (P=0.001). Additionally, at this point, 28.6% (15 of High alert 7.625x9.375_F:Layout 53) of rifaximin recipients and 43.7%1 (160 of 365) of the control group had

died (P=0.045). Dr. Hanouneh’s group is planning a prospective study to compare rifaximin with conventional antibiotics used for this indication. “Rifaximin is approved and widely used for the prevention and treatment of hepatic encephalopathy in patients with liver cirrhosis, and according to our study, it also seems to be appropriate for long-term 5/22/09 9:47 AM of Page primary prophylaxis SBP1 in cirrhotic patients with ascites,” said Dr. Hanouneh.

Despite this, the cost of rifaximin may make it prohibitive to take, said Kymberly Watt, MD, associate professor, Division of Gastroenterology and Hepatology, and Liver Transplant Program, Mayo Clinic & Foundation, in Rochester, Minn. —David Wild Drs. Hanouneh and Watt reported no relevant conflicts of interest.

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76 Technology

Pharmacy Practice News • November 2011

Automation

One Telepharmacy Success Breeds Future Rollouts

Pittsburgh—As part of a process to improve medication safety, the University of Pittsburgh Medical Center (UPMC), which operates 21 hospitals in the Pittsburgh area, has successfully implemented a telepharmacy service at its Bedford facility—one of three rural critical access hospitals (CAH) in the UPMC network that were operating without the benefit of a 24-hour pharmacy department. Several indicators of safe medication use, such as the number of clinical interventions by pharmacists, Fileimproved sigSlug nificantly as a result of the initiative, ne qtrpg 1st Proof LaYout aPProvEd the UPMC team reported in a poster InItIaLs and datE (abstract 297) presented at the annuMaX sign-off al meeting of the American College of senior Editor Clinical Pharmacy. On the heels of that success, UPMCCopyisEditornow in the process of implementing telepharmacy for two other hospitalssales in its network that lack 24-hour onsite pharmacists: UPMC Horier 28, 2011 8:36 aM Production zon, scheduled to go live this November, Creative and UPMC Northwest, scheduled to go CoMMentS: ertical live after the first of the year. Madalyn Bates, RPh, lead pharmacist for automation and information systems at UPMC’s Presbyterian Shadyside campus, which provides telepharmacy

services to Bedford, helped oversee the telepharmacy rollout. She worked in conjunction with Matthew Jenkins, PharmD, MS, who at the time of the rollout in June 2011 was a pharmacy administrative resident at Shadyside. (Dr. Jenkins is now pharmacy coordinator at Shands at the University of Florida, in Gainesville.) Although operational efficiencies have not been fully quantified, there is no doubt that patient medication safety has been enhanced. “Verifying orders in real time is a defined safety feature for patient care,” Dr. Jenkins said, fInaL oK Proof 1 12/10 “plus, of improved InItIaLsyou and datEget the benefit rEv 1 12/17 turnaround time for pharmacy.” rEv 2 rEv 3

Meetings, Collaboration Crucial rEv 4

Initiating telepharmacy rEv 5 remote verification services at Bedford began with rEv 6 rEv 7 multiple meetings between leadership rEv 8 at the hospital and at Shadyside. Those rEv 9 helped estabmeetings, Dr. Bates said, lish what the expectations were for both staffs and determine which units the orders would be verified for. At Bedford, the units were medical/surgical, critical care and the emergency room. “We had to iron things out and then

educate our pharmacy staff about those various processes and in terms of how they were to set up their queues for order verification,” Dr. Bates said. Bedford’s pharmacy closes at 6 P.M. and opens again at 7 A.M. so the Shadyside telepharmacists cover Bedford’s order-verification process for those hours. Currently, Dr. Bates noted, the service averages 80 orders verified overnight, ranging from 30 to 40 some nights to around 150 other nights. Among the benefits to date, processing StatuS and HiStory time for routine orders averaged 15 minPICKEd uP froM: utes; aPPLIEd to: stat order processing averaged nine minutes. For routine orders, turnaround times greater than 60 minutes became almost nonexistent after telepharmacy services were implemented. The total number of clinical interventions documented increased by 20%. In a hospital that does not have a 24-hour pharmacy, “you definitely get a benefit of turnaround time for pharmacy,” Dr. Jenkins said. “Previously, the nurses were giving medications that were not being reviewed prospectively by pharmacy, so pharmacists would have to come in the next morning and retrospectively review what was given.”

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All the UPMC hospitals implement the same electronic health record (EHR) and electronic pharmacy information systems, and they are either on or transitioning onto a computerized prescriber order entry (CPOE) system and a bedside bar-code medication administration (BCMA) scanning system, the team reported. Working telepharmacy into that technology mix “was basically done from scratch,” Dr. Bates said. “It was just a matter of putting the units associated with the three facilities on a queue so the orders and other relevant health care information can be seen. It was very configurable.” The impetus for the initiative was fairly straightforward: not having pharmacist verification of the CPOE order for UPMC’s non-24–hour pharmacies in the off hours, Dr. Bates said, “would have created an issue for the nurse trying to comply with the BCMA process and for us trying to be in compliance with the Joint Commission’s Medication Management regulatory requirement that all orders, outside of emergencies, be reviewed by a pharmacist before administration. Telephone calls to the non-24–hour pharmacy departments when they are closed are automatically routed to a telepharmacist based at a sister hospital; in Bedford’s case that is UPMC Shadyside.” Telepharmacists in the UPMC system can review information through

the entire EHR for patients, including lab status, previous medications g i ve n , al l e rg i e s, documentations and clinician/physician notes.

Telepharmacy Veteran’s View

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Doug DeJong, RPh, MBA FASHP, senior director of pharmacy for Kansas City, Mo.-based Saint Luke’s Health System, has extensive experience with telepharmacy rollouts. Five years ago, St. Luke’s implemented a telepharmacy service for six of its 11 Missouri/Kansas hospitals, including two CAHs, without 24-hour hospital pharmacy departments. Dr. DeJong noted that telepharmacy is becoming more widely adopted, both for regulatory compliance and because nurses, using electronic medical record and bedside bar-coding systems, “cannot afford to let an order not get into the pharmacy system for eight hours a day and then wait for a pharmacist to catch up when they open in the morning. They need a current electronic copy of their MAR [medication administration record] at all times and having a pharmacist enter that quickly is critical.” Dr. DeJong says the only major difference between Saint Luke’s telepharmacy and UPMC’s, was that Saint Luke’s created a single, remote “e-pharmacy” facility where a telepharmacist reviews and verifies after-hour orders for six of their non-24–hour pharmacy department hospitals that include two CAHs. Saint Luke’s telepharmacy also covers a seventh hospital that is not part of its systems and is paid for its after-hours order-entry services. Not only does that “help leverage our costs,” Dr. DeJong said, “it also builds rapport with this facility, which we hope will facilitate other outreach activities that we have in their area for referrals.” Being able to have pharmacists prospectively review orders from non-24– hour pharmacies was also a major benefit for Saint Luke’s “because it’s safer,” Dr. DeJong stressed. “We have been able to leverage one pharmacist across multiple campuses that could never, ever, afford a 24-hour pharmacy. Another tangible benefit is that while pharmacists are still on call for our non-24–hour pharmacies, they don’t have to be called for every little thing. Our e-pharmacist can handle most things that come up and that has greatly improved satisfaction and we hope that long term, it will help improve retention.” —Liz Parks

Pharmacy Practice News • November 2011

Operations & Management 77

Finances

Prefilled Syringes Cut Drug Waste, Boost Savings S By using prefilled syringes, ‘you’re improving safety in how it’s

witching from vials to prefilled syringes may save hospitals thousands of dollars each year by reducing drug waste, according to new findings presented at the 2011 annual meeting of the International Anesthesia Research Society. Researchers at the Medical University of South Carolina, in Charleston, compared the amount of unused drugs before and after clinicians began using

doctors to draw up medications out of vials prior to surgery.

Study Details

labeled. There’s no question what you’re picking up.’ —Christopher Fortier, PharmD up front, Dr. Fortier said. However, the actual cost difference in materials alone is hard to estimate, because clinicians

who draw their own must purchase the syringes, labels and needles—and add overhead costs by asking technicians or

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To investigate whether prefilled syringes cut back specifically on drug costs by curbing waste, Dr. Fortier and his team measured the amount of discarded drugs—either unused or left over in used containers—from 154 surgeries

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prefilled syringes in a 10-room operating room (OR) suite. They found that the switch cut both the likelihood for and the volume of unused drug drawn into a syringe that would need to be discarded after the procedure. Comparing two time periods covering fewer than 200 surgeries each, the researchers found that this reduction in waste saved $126 per day (abstract S-124). Prefilled syringes likely reduce waste because they are sealed containers, ready to be used and able to be returned to the shelves if unused, explained study author Christopher Fortier, PharmD, manager of pharmacy support and OR services and clinical assistant professor at the institution. Often, anesthesiologists will draw up medications into vials in the OR “just in case they may need it,” Dr. Fortier noted. But if that medication is not used, it must be discarded. In contrast, if a prefilled syringe is not used, clinicians can return it, unopened, he said. “In that way, you’re only using the product you need, when you need it.” The system also cuts waste by reducing the amount of leftover medication in syringes, he added. For instance, an anesthesiologist may prepare 10 mL of a medication but use only 5 mL during surgery; the rest is discarded. But a 5-mL, prefilled syringe would obviate the waste, Dr. Fortier said. Prefilled syringes are more expensive

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78 Operations & Management

Pharmacy Practice News • November 2011

Finances

CUTTING WASTE continued from page 77

(Phase I). They then compared that amount with what was wasted from 171 surgeries (Phase II) in which doctors used prefilled syringes. The research was funded by an educational grant from PharMEDium, which sells prefilled syringes. Fewer cases in Phase II had drug waste (38%) than did Phase I cases, in which 71% had discarded medications. When there were drugs to discard, the total volume

decreased by 61%, going from 3,284 mL in Phase I to 1,266 mL in Phase II. As a result, the cost of drug waste fell from $3,106 in Phase I to $1,849 in Phase II, according to the researchers. The drugs that had the greatest decreases in waste included lidocaine (90%), followed by succinylcholine and glycopyrrolate. The current study did not look at safety with prefilled syringes, Dr. Fortier noted, but they have some important advantages over conventional syringes. Prefilled syringes are color-coded and have the name of the drug noted in different loca-

tions and angles on the syringe. They also contain bar codes that clinicians can scan to ensure they have the right drug. When clinicians draw up medications from vials, they also must label the syringe, and mistakes can happen, Dr. Fortier said. By using prefilled syringes, “you’re improving safety in how it’s labeled. There’s no question what you’re picking up.” Indeed, the Anesthesia Patient Safety Foundation has recommended that clinicians rely on prefilled or premixed solutions whenever possible, said Rob-

ert Stoelting, MD, president of the group, which has received support from PharMEDium. The increased up-front cost may cause some clinicians to hesitate before adopting prefilled syringes, Dr. Stoelting said. “This research addresses this issue and thus will be helpful to other institutions when they consider cost versus benefit— considering safety, less risk for contamination and the ability of an anesthesia professional to do other tasks.” —Alison McCook

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VOLUVEN® (6% HYDROXYETHYL STARCH 130/0.4 IN 0.9% SODIUM CHLORIDE INJECTION) 1 INDICATIONS AND USAGE Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia. It is not a substitute for red blood cells or coagulation factors in plasma. 4 CONTRAINDICATIONS The use of Voluven® is contraindicated in the following conditions: • known hypersensitivity to hydroxyethyl starch [see General Warnings and Precautions (5.1)] • fluid overload (hyperhydration) and especially in cases of pulmonary edema and congestive heart failure • renal failure with oliguria or anuria not related to hypovolemia • patients receiving dialysis treatment • severe hypernatremia or severe hyperchloremia • intracranial bleeding. 5 WARNINGS AND PRECAUTIONS 5.1 General Warnings and Precautions Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. [see Adverse Reactions (6)] Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction. In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration. Caution should be observed before administering Voluven® to patients with severe liver disease or severe bleeding disorders (e.g., severe cases of von Willebrand´s disease). 5.2 Monitoring: Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. 5.3 Interference with Laboratory Tests Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis. At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit. 6 ADVERSE REACTIONS 6.1 Overall Adverse Reaction Profile From the accumulated clinical development experience, expected adverse reactions after administration of Voluven® occurring in less than 10% of patients are as follows: Immune system disorders (Rare, >0.01% to <0.1%): Products containing hydroxyethyl starch may lead to anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema). In the event of an intolerance reaction, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated. [see General Warnings and Precautions (5.1)] Skin and subcutaneous tissue disorders (Common, >1 to <10%, dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is an undesirable effect observed with all hydroxyethyl starches. Investigations (Common, >1% to <10%, dose dependent): The concentration of serum amylase can rise during administration of hydroxyethyl starch and can confound the diagnosis of pancreatitis. At high doses the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit. [see Interference with Laboratory Tests (5.3)]

6.2 Adverse Reactions in Clinical Trials Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug may not reflect the rates observed in practice. During clinical development, 471 patients were exposed to Voluven®, and a total of 768 patients received the hydroxyethyl starch 130/0.4 drug substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative doses of several mL up to 66 L1). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.9 ± 3.3 days, mean cumulative doses were 3338 ± 3695 mL, and the longest follow-up period was 90 days. In the US trial, 100 patients undergoing elective orthopedic surgery were treated either with Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative volume replacement. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch. Adverse reactions observed in at least 1% of patients: In the US trial comparing Voluven® with hetastarch, a possible relationship to Voluven® was reported in five cases in a total of three patients (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to hetastarch was reported in five patients (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in patients receiving more than the labeled ceiling dose (20 mL/kg), whereas no serious coagulopathy occurred in the Voluven® group. 6.3 Postmarketing Experience The following adverse reactions have been identified during the post-approval use of Voluven® and other types of hydroxyethyl starch solutions. 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. The safety profile from postmarketing experience of Voluven® is not different from the profile obtained from clinical trials performed using the product. Based on spontaneous reporting of hypersensitivity reactions, urticaria, bronchospasm, or hypotension were the most frequently reported serious adverse drug reactions for patients treated with Voluven®. With the administration of hydroxyethyl starch solutions, disturbances of blood coagulation can occur depending on the dosage2). 10 OVERDOSAGE As with all plasma volume substitutes, overdosage can lead to overloading of the circulatory system (e.g. pulmonary edema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General Warnings and Precautions (5.1)] 16 HOW SUPPLIED/STORAGE AND HANDLING Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is supplied in the following primary container and carton sizes: Polyolefin bag (freeflex®) with overwrap: 500 mL Carton of 15 x 500 mL NDC 0409-1029-01 Store at 15° to 25°C (59° to 77°F). Do not freeze.

Manufactured by: Fresenius Kabi Norge AS, P.O. Box 430, NO-1753 Halden, Norway Distributed by: Hospira, Inc. 275 North Field Drive Lake Forest, Illinois 60045 USA Made in Norway

Baxa Unveils SureConnect®: Closed System for Hazardous Drug Handling

he American Society of Health-System Pharmacists, the National Institute of Occupational Health and Safety and the Oncology Nursing Society all confirm the importance of using a closed-system drug transfer device (CSDTD) for preparation and administration of hazardous drugs. To protect health-system personnel from dangerous exposure, Baxa extends its innovative technology for safe medication handling and delivery with SureConnect®– the simplest CSDTD available today. SureConnect features: • Intuitive connections that make SureConnect easy to learn • Fewer components for a less-complicated system • Secure connectors that eliminate the potential for dangerous leaks and spills

Visit Baxa booth #1147 at the Midyear Clinical Meeting for a SureConnect demonstration. www.baxa.com/sureconnect.

Enhanced TempTrak™ Software Version 4.5 Released

ooper-Atkins announced the release of the enhanced TempTrak version 4.5 software and four new Wi-Fi wireless transmitters. The enhanced TempTrak software, version 4.5, now supports a 32 and 64 bit Microsoft SQL Server. It allows a selectable default of Fahrenheit or Celsius and accepts the configuration of multiple contact transmitters. In addition, a new feature has been implemented that allows notes to be applied to the transmitter (sensor) readings. This allows the user to add comments and reference information to the temperature sensor graph that will be saved in the history data. The new Wi-Fi transmitters operate on a standard 802.11 b/g network and are capable of collecting, storing and transmitting temperature, relative humidity, contact (door open/close) and analog voltage data. Once configured, the transmitters connect to an existing Wi-Fi IP network and send data to the designated TempTrak server. Each Wi-Fi transmitter includes an on-board memory backup and optional AC Adaptor wall plug. Both the new Wi-Fi (802.11 b/g) transmitters as well as the traditional 900 MHz temperature transmitters can communicate within a single TempTrak installation.

For more information, visit www.cooper-atkins.com.

Pharmacy Practice News • November 2011

Operations & Management 79

Medication Safety

SECOND VICTIMS continued from page 1

lot more on this than I’m going to. You’re going to be a lot more careful, right?’ That was the extent of the counseling I got,” Dr. Tribble recalled. “To this day I look back on that incident in terror. I was functionally at less than half speed for about two weeks after that. I second-guessed every move I made. When this kind of thing happens, you don’t believe in yourself or in the quality of anything you do.” Dr. Tribble, like many health care professionals every year, had become what has been termed the “second victim” of a medical error—the pharmacist, nurse, doctor or technician who makes a mistake that leads to a bad outcome or even death. (The term was coined in 2000 by Johns Hopkins internist Albert Wu, MD, now director of the Center for Health Services and Outcomes Research at Hopkins’ Bloomberg School of Public Health, in Baltimore.) But in many ways, Dr. Tribble was actually lucky. His mistake, although disturbing and career-shaking, did not actually kill a patient. When a medical error results in a death, the personal and professional fallout can be catastrophic, ranging from loss of professional licensure to prison and even suicide. A few recent cases: • In April 2011, Washington registered nurse Kimberly Hiatt committed suicide seven months after accidentally overdosing a medically fragile infant with 1.4 g of calcium chloride, instead of the correct dose of 140 mg—a mistake she immediately realized, to her horror. The 8-month-old baby died and Ms. Hiatt, who had a 20-year unblemished record, was fired by her hospital. • In 2006, Wisconsin registered nurse Julie Thao, intending to give a 16-yearold patient in labor a dose of antibiotics, accidentally switched the bag for one containing an epidural that she had earlier used to explain to the nervous young woman how her anesthesia would work when the time came. She hung the epidural intravenously; the patient died, although her baby survived. Ms. Thao, who had been working a double shift, lost her license to practice and eventually pled guilty to two misdemeanor charges in exchange for prosecutors dropping a felony charge. • Ohio pharmacist Eric Cropp served a six-month prison sentence after he failed to detect a chemotherapy mixing error made by a technician. The overdose of saline killed 2-year-old Emily Jerry, who was receiving her last dose of chemotherapy that day. The tragedy involved “a confluence of human and systems errors,” according to the Institute for Safe Medication Practices (ISMP), which supported Mr. Cropp.

The ISMP, which specializes in understanding the root causes of medication errors and promoting error-reduction strategies, noted that the pharmacy’s computer system had been unavailable until mid-morning, Mr. Cropp was working alone on a Sunday with no support other than the tech, and the checking area was small and crowded.

Just Consequences? Nobody would argue that these cases weren’t horrifying and tragic. But were the outcomes—the loss of licensure, the firing, the criminal prosecutions—justified, given what the nurses and pharmacist had done? No, said Robert Wachter, MD, professor and associate chairman of the Department of Medicine at the University of California, San Francisco and a widely published expert on hospital safety and quality. “Calling something criminal is rarely the right answer unless it’s willful, involving something like coming to work drunk or doing something that you know is wrong in order to get out of work early,” he said. “What Cropp and Thao did both seem to be honest errors that don’t cross that line.” Loss of licensure implies that whatever caused an error is habitual and likely to harm another person. “There are cases like that, of course. Someone does

something once, and then you find out they’ve done it multiple times and have not responded to education and counseling,” Dr. Wachter said. “At that point, they have fallen below the standards of competence for their profession. But for me, it’s virtually always inappropriate to draw that line for a single instance of an error in someone who has an otherwise good record, unless that error meets some of the criteria of criminality I mentioned earlier.” Often, said Dr. Wachter, the ultimate consequence to the person who actually commits a medical error depends on nothing so much as luck. “A particular error may be one that many nurses, pharmacists or doctors might commit, but most of the time it luckily doesn’t reach a patient,” he said. “But this time, it does. And perhaps the patient is an infant, or critically ill, and the outcome is awful. The blame is placed on one person and it really has nothing to do with the nature of their transgression.” “The public wants an individual held accountable,” agreed ISMP President Mike Cohen, RPh, MS, ScD, FASHP. “They don’t look at the hospital, the space that wasn’t there, the extendedhours and other things that are controllable by the system but not the individual.” Dr. Cohen led the ISMP’s support of

Mr. Cropp during the Ohio pharmacist’s legal travails and wrote a letter to the presiding judge, urging leniency and avoidance of imprisonment. In the letter, Mr. Cohen advocated “for a fair and just path for individuals involved in adverse events,” and argued that “punishment simply because the patient was harmed does not serve the public interest. Its potential impact on patient safety is enormous, sending the wrong message to health care professionals about the importance of reporting and analyzing errors.” To further underscore the negative consequences of such a punitive approach, the ISMP scheduled a webinar entitled “When Caring Hurts: Understanding the Second Victim Experiences,” to be held Thursday, Nov. 17, 2011, 1:30 to 3 p.m. EST (www.ismp.org).

To Err Is Human Unrealistic expectations may partly explain why clinicians are sometimes punished for medication errors that occur on their watch, according to Dr. Tribble. “Research shows that the average human error rate in various cognitive tasks is about 3%. If I’m checking 100 orders, that means statistically I’m going to miss something in three of them,” he says. “It might be tiny and inconsequential most of the time, but

‘All of these [medication] errors occur as a result of the system that we’ve built that has too few people, too few resources, too many patients and too much acuity for our system.’ — Tom Van Hassel, RPh, MPA

Dennis Tribble, PharmD, chief pharmacy officer for Baxa Corporation (left), and Chris Jerry, whose daughter died as a result of a medication error, speaking to Baxa staff about the interplay between technology and medication safety.

•

see SECOND VICTIMS, page 80

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Medication Safety

SECOND VICTIMS continued from page 79

sooner or later the odds are going to catch up. The reality is that the culture of safety is something hospitals bring out and dust off when one of these incidents occurs. Safety takes a back seat to productivity. If safety hadn’t taken a back seat to productivity, Eric Cropp would have had extra staff to come in to help him on an out-of-control day.” Tom Van Hassel, RPh, MPA, director of pharmacy at Yuma Regional Medical Center, in Arizona, characterizes health care’s approach to medical errors like Mr. Cropp’s, Ms. Hiatt’s and Ms. Thao’s as a massive game of whack-a-mole. “We wait for an error to pop up, and then we try to whack at it,” he says. “We don’t do anything to stop the mole—the error—from popping up. We just whack at it when we see it. The question needs to be, what is the nature of the system that led to the error, so we don’t do it a second time?” To some extent, automation can add a failsafe step that remedies some of the faults caused by unavoidable human error. “If I’m reading 100 orders, and I’m checking them, and they’re all correct, as a human I’m designed to learn,” Dr. Tribble said. “So on the 101st order, my confirmation bias is that I believe it’s correct. But a pharmacy bar-code scanner is not only faster and more accurate in its reading, it is incredibly literal. It’s Monk. It’s obsessive-compulsive. It doesn’t know a thing about the last bar code it read.” Pharmacy automation tools have helped enormously in reducing the kind of medical errors that leave both first and second victims in their wake. Chris Jerry, the father of Emily Jerry, has created the Emily Jerry Foundation, which aims to raise awareness about safe medication practices and errorreduction technology. Remarkably, Mr. Jerry and pharmacist Eric Cropp now speak together in webinars and other events about patient safety technology. But Dr. Wachter stressed that technology provides only a partial solution. “Over the past several years, the hope that technology would solve everything has been replaced by more realistic expectations. We overhype technology. It seems magical, but then you put it in and it doesn’t work as well as it did with the early adopters,” he said. “We’ve seen all sorts of errors due to glitchy technology. There’s no one solution. This is a really, really complex issue.” “Nobody gets up saying, ‘Gee, I’ll go to work and make some errors today,’ added Mr. Van Hassel. “All of these [medication] errors occur as a result of the system that we’ve built that has too few people, too few resources, too many patients and too much acuity for our system. So many of the broken parts

‘In most health care settings, caregivers have no one they can turn to for support and/or guidance in the face of a terrible, unanticipated clinical outcome or medical mistake, often resulting in them suffering in silence.’ — Susan Scott, RN, MSN

‘The reality is that the culture of safety is something hospitals bring out and dust off when one of these incidents occurs. Safety takes a back seat to productivity.’ —Dennis Tribble, PharmD

of health care just kind of fulminate in the background and create this environment where errors can happen.” In August 2011, an article in Chest called for something labeled “collective accountability” when it comes to medical errors. “The concept of collective accountability requires doctors to adopt transparent behaviors, learn new skills for improving team performance and participate in institutional safety initiatives to evaluate errors and implement plans for preventing recurrences,” wrote the authors, a team from Beth Israel Deaconess Hospital. “It also means that institutions need to prioritize team training; develop robust, nonpunitive reporting systems; support clinicians after adverse events and medical error; and develop ways to compensate patients who are harmed by errors.”

Caring for the Second Victim(s) True support for clinicians after adverse events and medical errors remains rare at many institutions, as Dennis Tribble found out. If a pharmacist, nurse or doctor who commits an error isn’t fired, disciplined or prosecuted, he or she may still feel very isolated within the hospital. There may be a fear that seeking support and talking about what happened could lead to criminal prosecution. “In health care, we don’t always handle people sensitively or kindly whom we perceive as transgressors,” Albert

Wu, the father of the term “second victim,” told Johns Hopkins Dome publication recently. “Caregivers internalize those reactions and beat themselves up” if they are involved in errors.” Interestingly, although Dr. Wu coined the phrase more than 10 years ago, it was only in late 2010 that Hopkins itself launched a “Second Victim Committee,” a program that aims to assist caregivers who are traumatized as the result of unexpected patient death or injury. In a survey taken at the Johns Hopkins Medicine Patient Safety Summit held in summer 2010, 60% of the respondents recalled an event in which they were second victims; 65% of the second victims reported experiencing anxiety, depression or concern about their ability to perform their jobs. That’s not uncommon, says Susan Scott, RN, MSN, patient safety officer at University of Missouri Health Care and doctoral student at the MU Sinclair School of Nursing, in Columbia, who has extensively researched the secondvictim phenomenon. “Once the phenomenon was identified, it became clear that in most health care settings, caregivers have no one they can turn to for support and/or guidance in the face of a terrible, unanticipated clinical outcome or medical mistake, often resulting in them suffering in silence,” she wrote in Perspectives on Safety in May 2011. “The term ‘second victim’ has evolved

to include many of [those involved in] the traumatic situations health care providers sometimes face in delivering care,” Ms. Scott said. “We define a second victim as a member of the health care community who is involved in an unanticipated or stressful event and is traumatized by the event.” Seeing that need, Ms. Scott and her colleagues created the forYOU Team at their health system, which they characterize as something of an emotional first-aid squad for staff in the aftermath of an unanticipated clinical event or outcome. The team focuses not just on medical errors, although that’s a part of its charge, but any traumatic situation that health care providers sometimes face in delivering care. “Our slogan is ‘You care for our patients, let us care for you,’” she said. “We provide one-onone peer support for the clinician, but also team debriefing. Sometimes, after an incident, an entire group of caregivers is impacted.” First launched in 2009, the team now comprises 84 members—54% nurses but also physicians, pharmacists, social workers and a licensed professional counselor. They all go through training to help them provide specialized support for a colleague who’s become a second victim. “We also have monthly meetings where we do case reviews to learn from each other,” Ms. Scott said. “We do a lot of role playing. The meetings also include in-service programming on topics such as initiating conversations with someone in crisis, and knowing what all the hospital’s resources are for a staff member in need of help. Participants keep their forYOU roles distinct from their other professional positions. “I’m the patient safety officer, so one day I may find out more details about a particular case, and the next day I might be a supporter to someone involved,” said Ms. Scott, who worked closely with the hospital’s general counsel to ensure that the team could provide support while maintaining the integrity of the hospital’s medicolegal position. “We keep our roles very separate. We don’t take notes or talk about a case, but rather talk about what a person is feeling and how they’re coping.” This approach is still rare, but like Hopkins, many institutions are beginning to pursue it, and forYOU has been recognized as a national and international model for other hospitals seeking to develop similar programs. “I would imagine that in the next five years, we’re going to see a huge wave of facilities taking the next step beyond just an employee assistance program, figuring out different kinds of support projects they can have in place for clinicians who become second victims.” —Karen Blum

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Wicked Change

Designing a Framework for Organizational Change Kyle E. Hultgren, PharmD Managing Director Center for Medication Safety Advancement Adjunct Assistant Professor of Pharmacy Practice Purdue University College of Pharmacy West Lafayette, Indiana

ake just a moment and look out a window. Some of you, like me, may see a rather rural landscape, marked by farmland, intermittent glades of trees, birds darting back and forth between these two locations and the occasional car heading down the road. Those in a more urban setting observe quite the opposite, but they still see an active and ever-changing environment unfolding before them. The complex ecosystems that we observe in the world around us are analogous to those we experience in our health systems. Much as the birds and other animals in the rural ecosystem compete for food, water, shelter and other scarce resources, we must make very similar decisions and analyses in our health care environment. These challenges are incredibly dynamic, especially in today’s health care system. To better understand the complexity of the environment within which we operate, we require a framework that is equally as dynamic as the system within which it operates. This framework must be rationally designed and allow for adequate assessment of the current system, diagnosing its weaknesses and treating its ills so that it may be redesigned to function at a higher level. Using a clinical microsystems framework within the health system will allow for a systematic assessment, diagnosis and treatment of problems that arise within the institution’s microenvironments. Godfrey et al define a microsystem as “a small group of people who work together on a regular basis—or as needed—to provide care and the individuals who receive that care. … It has clinical and business aims, linked processes, a shared information environment and produces services and care [that] can be measured as performance outcomes.” A microsystem is significantly more than just a team of individuals—it includes the environment that surrounds them, the patients for whom they provide care, the processes through which that care is provided and the outcomes data that provides valuable feedback regarding the status of the microsystem. Another incredibly important distinction when looking at microsystems is that the simple analysis of a clinical

“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.

microsystem is not a process improvement methodology in the traditional sense that we may have come to know Plan Do Study Act (PDSA), Lean, Six Sigma or any number of others. Rather, the study of our clinical microsystems provides a systematic approach for managing microsystem environments, giving critical markers to the most immediate improvement opportunities and creating an interdisciplinary team-based learning laboratory. The Assessment Being able to apply a robust, reliable, systematic process to analyzing microsystems is a fundamental key to understanding and designing a framework for improvement. The first step is to assess the microsystem. This assessment is similar to an environmental analysis. We need to be able to understand how each element of the microsystem is incorporated and how each mechanism functions with another and to what end. There are five key areas that we need to understand further as part of our analysis. This is identified as a 5P analysis. Each of these areas is reviewed and each is associated with a recently completed case study at a large academic medical center inpatient pharmacy. 1. Purpose: First and foremost we must ascertain the purpose of the microsystem. We must ask our peers and truly dig down to find out why each

part of this microsystem works with the other and what our desired outcome is when the microsystem functions as expected. The purpose of the dispensing microsystem in the example medical center inpatient pharmacy was the accurate, safe and timely delivery of medications to all patients. 2. Professionals: Who are we? Who is involved in this microsystem? Pharmacists, technicians, nurses, housekeeping, informatics, students, physicians, administration, dietary and the list could go on, depending on which microsystem is being assessed. What services does each professional provide and during what hours of the day? This is the time to understand not only which professionals are on the team, but more specifically what, where, why, how and when do they do what they do. The professionals in the study microsystem include pharmacists, technicians, nurses, prescribers and information technology support staff. 3. Processes: What processes do our professionals engage in on a daily basis? Pharmacy operations processes could be anything from sterile compound preparation to clinical services and beyond. This is where we begin to draw up a process flow map and assign individuals to specific steps in a process. We want to start to assess and understand not only who is in the microsystem but also the regular processes in which they

are involved. The study medical center took the opportunity to create process flow maps to illustrate each step in the dispensing process from receipt of a medication order to the time the receiving nurse takes possession. Process flow maps are very powerful tools for analyzing the processes in a microsystem. 4. Patients: Who do we serve? What does the patient population look like? How old are they, why are they in the health system, how long do they stay, do they like the services we provide? At the sample medical center there are more than 800 beds served by the central inpatient pharmacy, spanning units from general adult medicine to oncology to pediatrics. 5. Patterns: Here is the data. Take a look at the professionals in the microsystem and the steps they complete in various processes and start to ask questions such as “How long does it take to…” or “How many phone call interruptions do I receive during…” Patterns can be just about anything: staffing patterns, financial information, doses dispensed, pager and phone call volume and patient satisfaction scores. This represents anything that can be gathered to help create a picture of what patterns exist in the microsystem. The academic medical center in this study assembled a litany of run charts and other data to illustrate the underlying trends occurring as a result of the processes described in the center’s process flow maps. General trends included a high proportion of medications being delivered late, a large volume of phone calls for missing medications and a significant performance gap in turnaround time from order to delivery.

The Diagnosis Microsystems analysis is a powerful tool for creating order out of chaos. As the first article in this series accurately identified, health care today is facing a set of truly “wicked problems” that require complex solutions, requiring a great number of people to change their mindsets to move forward (Pharmacy Practice News, October 2011, page 40). To begin framing some of these complex solutions, we must first look back at the analysis that was just completed. A completed 5P analysis provides a complete picture of the microsystem. We can now begin to look at the interplay between the professionals in the system, the processes that they are performing on behalf of a given patient population and the patterns that arise out of these actions. We then have the opportunity to start asking critical questions about the results we are receiving. Are they what we are expecting? Much like a complete medical chart for a patient, we can

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Operations & Management 83

Wicked Change diagnosis and treatment of the key issues. PDSA helped this team to restructure and standardize dispensing practices, which greatly streamlined the flow and dramatically decreased the overall turnaround time for delivery and subsequently the number of missing doses. The application of microsystems thinking is the framework for improvement. Fostering a sense of ownership in that microsystem can help the team develop the will to change. This robust and reliable process will promote the exchange of new ideas for change by assessing

and diagnosing individual issues within a microsystem and facilitating the design and execution of sustainable change to treat and improve a microsystem.

References 1. Godfrey MM, Nelson EC, Batalden PB, eds. Clinical Microsystem Action Guide. Version 2: Rev 4/13/2004. © 2004, Trustees of Dartmouth College. http://clinicalmicrosystem.org/materials/workbooks/action_guide/CMAG040104. pdf. Accessed October 20, 2011. 2. Nelson EC, Batalden PB, Godfrey MM, eds. Quality by Design: A Clinical Microsystems Approach. San Francisco, CA: Jossey-Bass.

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The Treatment It is finally at the treatment stage in the process where we come to the realization that it’s not clinical microsystems or process improvement, it’s clinical microsystems and process improvement. Studying your microsystem is not meant to be a replacement or a substitute for any process improvement methodology your organization may already have been striving to develop. Process improvement is used now when we need to treat our microsystems. Once we have been able to successfully assess and diagnose the microsystem, we need to have a systematic approach to improving it. Many organizations use process improveScan for “Wicked ment methodoloChange” debut column. Instructions, gies such as PDSA, Lean, Six Sigma page 3

or some combination thereof, but the important piece is that some methodology is used at this point. This will continue to be focus of this series, so I strongly encourage you to keep coming back to learn more about treating your microsystem. The medical center studied here treated its microsystem by deploying a rapidcycle PDSA methodology. As a direct result of using the microsystems framework, the medical center had already assessed and understood its overall baseline conditions. This enabled a quick

now begin to piece together the puzzle and diagnose what may be ailing the microsystem. If a desired outcome is not achieved, there is a framework, or a roadmap to trace back and isolate why that may be occurring. Specific patterns can be aligned with their associated processes and professionals to question whether they are furthering the overall purpose. The medical center studied here assembled its 5P analysis and used this assessment in this very manner. The center was able to diagnose and address some weaknesses in its microsystem. Aligning the processes that were being conducted by the center’s professionals and analyzing the patterns that resulted, it was ascertained that there was a lack of standardization in many of the steps in the dispensing process and additional work was needed to prioritize medications for delivery. Thus far, the process of conducting an assessment and diagnosing the microsystem may seem less than a revolutionary concept. You may already collect mountains of data and know your staffers quite well. You can also look up your patient information and create a process flow map for any of your given processes. Why is it so important to put it all in one place? The reason is ownership. Although you may already have access to much of that data, it is likely that it never has been shared in this fashion before and never woven into smaller microsystem units by those who are in the microsystem. A microsystem assessment and diagnosis is not done by management and handed to staffers to follow up on. When you hand the people in a microsystem the opportunity to assess and diagnose their own environment, you begin to foster more accountability and ownership of the microsystem.

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Finances

Two Illinois Hospitals Find Lost Drug Dollars Using Patient Assistance Programs T director of pharmacy services at SwedishAmerican Hospital, also in Rockford. Each manufacturer sets its own criteria to qualify for drug replacement; the criteria differ for each medication; they change frequently; and there’s no standardized way to access this support. “Manufacturers want to help … but they make it very hard because they don’t want people gaming the system,” added Mr. Lesher. So, for a long time, SwedishAmerican and Rockford Memorial dedicated mini-

‘This is the second-most significant cost savings I’ve been able to produce in my 11 years as director, after implementation of the 340B program.’

—E. Thomas Carey, RPh, PharmD

“Our need to serve the uninsured is greater now due to the economy. Some people just don’t have the means to pay for their drugs,” said Curt Lesher, RPh, director of pharmacy at Rockford Memorial Hospital in Rockford, Ill., an area 90 minutes west of Chicago beleaguered by a 9.9% unemployment rate. “It’s not unusual for us to have 5% to 6% of our patients as self-payers, plus 17% or more paid by Medicaid. … We treat everybody. We don’t have a threshold. If a patient will cost us $1 million a year in drugs, we’ll plan the care with our medical leaders and the primary physician.” Until recently, PAP drug replacement was “an untapped commodity” because the programs are so difficult to track, noted E. Thomas Carey, RPh, PharmD,

mal pharmacist time to pursue PAP benefits and earned scant rewards. At SwedishAmerican, for example, one-tenth of a full-time equivalent pharmacist’s time generated the replacement of four or five drugs valued at $2,000 per month. Similarly, Rockford Memorial turned up about $10,000 a year in drug-replacement benefits from PAPs. But, as budgetary pressures escalated, both hospitals sought outside help to tap into PAPs. SwedishAmerican began using the McKesson MedSource Medication Assistance Program in January 2010 to replace the medications it provided to uninsured and indigent patients. Within the first six months, SwedishAmerican had collected $166,000 in gross cost sav-

‘We’d be tickled to death to have a clinical program that generated this much for us. These are real dollars saved on the expense side.’ —Curt Lesher, RPh

ings; between June 2010 and May 2011, the gross annual savings was $450,000 (Figure). Current savings exceed $40,000 per month and represent 30 different medications from all lines of care, Dr. Carey noted. These annual savings represent a 2.25% savings on the hospital’s total annual drug budget of approximately $22 million, of which oncology drugs account for about 45%, he added. “This is the second-most significant cost savings I’ve been able to produce in my 11 years as director, after implementation of the 340B program,” said Dr. Carey, calling PAP support an inpatient complement to 340B.

Leveraging Savings Into Improved Patient Care

Rockford Memorial Hospital (inset) and SwedishAmerican Hospital benefited from patient assistance programs.

imposes no up-front costs or implementation fees, works with any pricing contracts including 340B and typically replaces medications within 90 to 120 days. As part of the program, McKesson hospitals pay a percentage of their cost savings to McKesson. “I never believe when I’m told something will be easy to do. But I would never have guessed it would be this seamless,” said Dr. Carey, who estimated he spent less than eight hours of transitional time identifying patients for the MedSource administrator, finding a physical workspace for her and introducing her to essential pharmacy colleagues.

Meanwhile, Mr. Lesher sees the PAP support improving the hospital’s ability to care for both inpatients and outpatients. Rockford Memorial began using MedSource 18 months ago when the hospital was forced to reduce staff and seek ways to save money. Over the first 12 months, the hospital gained between $150,000 and $200,000 in the net value of reimbursed drugs and replaced implantable devices (such as stents and wires). Medical devices, which are unique to McKesson’s MedSource program, accounted for about one-third of the total savings—which overall trans- PAP Partnerships ‘a Great Idea’ Mary Mihalyo, BS, PharmD, clinilated into a 1% to 1.5% savings on the $14 million total annual drug budget. cal pharmacy coordinator at Trin“We’d be tickled to death to have a clinical ity Health System, Steubenville, Ohio, program that generated this much for us. assistant professor of pharmacy pracThese are real dollars saved tice at Dusquesne University Mylan on the expense side,” Mr. School of Pharmacy, in Pittsburgh, said Lesher said. Both hospitals considered sev500,000 450K eral vendors to get the most out of PAPs after finding it impossible to optimize efforts with the time they could spend on it internally. What swung the deal for McKesson was its role as the primary drug whole250,000 saler for SwedishAmerican and 166K Rockford Memorial. To Dr. Carey, it meant “we’d speak the same language.” To Mr. Lesher, it was easier to bundle and “a hierarchy of con0 tacts was already in place.” Jan-June June 2010Both hospitals share the services 2010 May 2011 of one MedSource representative who administers the program at Figure. Impact of patient their locations, although as benassistance programs on efits and workload grow, they gross cost savings. may each get their own. McKesson

Savings, $

he number of uninsured Americans rose to an estimated 50 million, according to the latest U.S. Census Bureau data. Many of these people lack primary care providers and use hospital emergency departments for that role, putting increased pressure on health systems to provide care that goes unreimbursed. Drug manufacturer patient assistance programs (PAPs) can help hospitals offset the squeeze they feel from lower average reimbursement rates and more self-pay and uninsured patients.

Pharmacy Practice News • November 2011

Operations & Management 85

Finances that having a software-enabled strategy for administering PAPs makes sense on multiple levels. First, “PAPs are quite time-consuming to [manage],” she said. Thus, “having an electronic software program that pre-populates patients’ demographic information on PAP forms and tracks applications and refill dates greatly improves application-process efficiency.” Those gains in efficiency can yield significant downstream benefits, Dr. Mihalyo said. By making drugs more affordable, she pointed out, PAPs can help uninsured patients who lack a pharmacy benefit and who thus often struggle to comply with costly medications stick to their drug regimens postdischarge. “Hospitals are at significant risk today when patients require readmission subsequent to medication noncompliance,” she stressed. “So if a PAP program can help with that, the patient and the hospital benefit.” But there is one remaining question for hospitals: whether to work with PAP facilitators, and if so, how to choose the best partner. Dr. Mihalyo said that wholesalers can be less complex to work with on PAPs than specialty vendors that charge fees, and they can generate more benefits than pharmacies that lack time to prioritize this effort. “Vendors that manage the PAP process require a fee,” she pointed out. “When a patient is in the hospital, it isn’t convenient to use a feefor-service PAP program because requiring the patient to pay the fee is logistically cumbersome.” Therefore, hospitals have two viable alternatives to specialty vendors—they can purchase the software to facilitate the PAP application process or they can gain access to the software

How MedSource Works

hrough McKesson’s MedSource program, hospitals can use pharmaceutical manufacturer patient assistance programs to help health system or hospital pharmacies replace drugs dispensed or administered to low-income, uninsured and under-insured patients. Working directly with manufacturers, MedSource can assist hospitals in replacing the medications provided to uninsured and indigent patients—even if those medications are purchased with 340B pricing. McKesson provides a MedSource manager who is dedicated to that facility’s inpatient and outpatient recovery process. The manager leverages proprietary software and tools for tracking, reporting and troubleshooting, ensuring successful patient enrollment in each patient assistance program and the subsequent manufacturer approval and replacement of those eligible medications provided.

through a wholesaler outsource program, she noted. Other considerations may need to be addressed, depending on the specific hospital involved. One complication at SwedishAmerican, for example, related to the fact that the hospital has computerized prescriber order entry (CPOE)

and uses bar codes for bedside scanning, requiring exact medication replacements with the same bar code, dose and strength. “For us, 100 mg doesn’t necessarily equal two 50-mg vials,” said Dr. Carey. “Our MedSource rep knows that’s our strong preference” and works to get replacements that match the hospital’s formulary. Hospital pharmacy directors could face pressure in the future to deliver the same PAP benefits using in-house resources only, stressed Mr. Lesher. Given that, Dr. Mihalyo noted that it

is important to “prepare an executive summary for administrators that communicates the successful use of the wholesaler PAP program, and points out that it doesn’t make sense to change what is working efficiently.” She added that to develop an in-house program, “all stakeholders in the PAP process, which extend beyond pharmacists, would have to be taught how to use the internal program,” and that would not necessarily be the most efficient approach. —Al Heller

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86 Policy

Pharmacy Practice News • November 2011

Supply Chain

Policymakers, Practitioners Target Drug Shortages A s the crisis over the nation’s drug shortage deepens, responses are coming from two major fronts: legislators and regulators, such as the FDA, and clinicians who have developed several innovative strategies for mitigating the impact of the shortages on patient care. Although some might debate which approach is best, there’s general agreement that the scope of the drug-shortage problem is widespread. “By the end of [2011], the number of drug shortages for the year will probably be close to 280,” Erin Fox, PharmD, manager of the Drug Information Ser-

vice at the University of Utah Hospitals & Clinics, in Salt Lake City, told Pharmacy Practice News. Dr. Fox added that the number of shortages up to September of this year was triple what it was in all of 2005. “There are many causes to this problem, and because we don’t know what all of these are, it is very difficult to target responses,” she stressed. Indeed, as Edward Cox, coordinator of the drug shortage program at the FDA, told attendees of a public workshop held on Sept. 26 by the agency, there are several reasons for the increasing shortages: 54% of the

‘Adequate warning on the scope and duration of an upcoming drug shortage is critical for implementing management approaches like Duke’s.’ —Arnold Berry, MD, MPH

Table. Summary of Conservation Measures Implemented by Duke MDSRT Phase I: Initial notification of supply disruption 1. Cease prophylactic preparation of succinylcholine 2. One vial used for multiple doses 3. Use rocuronium as alternative for RSI when clinically appropriate 4. Use vecuronium or rocuronium if RSI is not needed Phase II: Second notification of shortage and critically low supply at Duke University 1. Succinylcholine no longer permitted for elective cases 2. Limit succinylcholine use to emergent airway rescue where other techniques not appropriate 3. R educe drug stock to 1 ampule per anesthesia cart (1 full vial or 2 partial vials) 4. D istribution of succinylcholine not permitted without approval from attending anesthesiologist 5. Use of succinylcholine no longer permitted for routine ECT Phase III: Additional supply received but no national notification of full market resupply 1. S uccinylcholine permitted as primary agent for life flight, in the emergency department and in critical ICU situations 2. Routine use of succinylcholine in ECT permitted Phase IV: Full supply resumption and national notification of market resupply 1. Use in elective surgery permitted 2. Use as single-dose vial permitted 3. P rophylactic preparation of succinylcholine discouraged in adult population 4. Encourage use of nondepolarizing alternatives when clinically appropriate 5. Continue to supply only 1 vial per cart 6. No longer need attending anesthesiologist approval for distribution ECT, electroconvulsive therapy; ICU, intensive care unit; MDSRT, multidisciplinary drug shortage response team; RSI, rapid sequence intubation

shortages in 2010 were due to quality or manufacturing issues, 21% were a result of delays and capacity issues, 11% were due to manufacturer discontinuation of unprofitable drugs and 5% were a result of problems obtaining reliable raw material. Many drugs in short supply are low-profit generic injectables, which are susceptible to contamination and also are costly to produce because the manufacturing process needs to ensure against this. “A variety of solutions will be needed, including regulatory changes, manufacturing changes and ways to make sure people aren’t hoarding drugs and diverting them to the gray market to sell at much higher prices,” Dr. Fox said. The number of drug shortages would be even higher if not for FDA action. At the public workshop, the agency said that it helped avert 99 drug shortages in 2010 by acting on manufacturers’ advance notice of imminent shortages. Specifically, they sought out alternative manufacturers who were able to ramp up production and also helped manufacturers source raw materials in cases where these materials were in short supply or contaminated. Dr. Fox holds out hope that FDA efforts, along with Senate Bill 296, which will require that manufacturers notify providers six months in advance of an anticipated drug shortage, will help stakeholders manage these shortages, if not limit them in number.

Duke University’s Collaborative Approach to Drug Shortages For their part, pharmacists and clinicians are doing what they can to mitigate the impact of drug shortages on the quality of care. For example, Duke University formed a multidisciplinary drug shortage response team (MDSRT) to address drug shortages at the institution. The team convenes at the first

sign of an impending shortage, devising ways of scrimping, saving—and practically scraping—whatever existing stocks of essential drugs are available. The MDSRT includes senior pharmacy managers, procurement and distribution staff, medication policymakers, pharmacy informaticians, clinical pharmacists, anesthesiologists, intensivists and emergency physicians. During more severe shortages, the team further involves the chair of the ethics committee, director of risk management, chief medical officer or the chief nursing officer. “This team has put together a coherent policy on drug shortages, how staff are notified, what action items need to be carried out, what measures need to be taken and also how to address ethical concerns,” said Christopher Murray, PharmD, pharmacy manager, perioperative services, Duke University Medical Center, Durham, N.C. Dr. Murray and his anesthesiologist colleagues Thomas Hopkins, MD, and Holly Muir, MD, shared the Duke approach to managing shortages at the 2011 annual meeting of the American Society of Anesthesiologists (abstract 368). By way of illustration, the team managed a recent succinylcholine shortage using a four-phased approach, initially implemented at the first notification of the shortage and continuing through to full resumption of supply (Table). Before the team’s intervention, Dr. Murray said, perioperative use of succinylcholine stood at 50 vials daily. After the most conservative measures were implemented, daily use of the drug fell to seven vials. Although a regular supply of the drug had resumed at press time, Dr. Murray said the team was maintaining some conservative measures and use of succinylcholine remained low, at approximately 18 vials daily. Not surprisingly, the overall cost of succinylcholine use at Duke dropped

Pharmacy Practice News • November 2011

Policy 87

Supply Chain from $83 to $26 per day over the same period, amounting to an estimated $42,000 in annual cost savings, Dr. Murray reported. The conservative measures also have kept the number of canceled or postponed procedures low and helped Dr. Murray’s team avoid looking to the gray market for “expensive and potentially unsafe drugs.” “We’ve managed to do OK by just reducing our use of drugs in short supply,” he said. “Occasionally, we’ve had to purchase directly from manufacturers, and this has resulted in significant costs increases.”

Labor-Intesive Undertaking Scott Knoer, MS, PharmD, chief pharmacy officer, Department of Pharmacy, Cleveland Clinic, in Ohio, said in an interview that the effort at Duke is typical of what is being done at institutions all across the country. “In addition to a similar team of providers, we now have a full-time pharmacist closely monitoring shortages, redistributing supplies and seeking out alternative sources of medications when possible,” said Dr. Knoer, who also spoke at the FDA public workshop. These increases in manpower come at a cost. Although the Duke financial analysis did not account for the added costs of labor associated with managing drug shortages, Dr. Knoer cited an article in the Oct. 1 issue of the American Journal of Health-System Pharmacists (2011;68:1811-1819) that estimated that the additional labor costs associated with drug shortages nationally in 2010 were $216 million. Dr. Fox echoed his point. “If you consider how much time the Duke team took to manage their succinylcholine shortage, and how much time they spent being pulled away from their regular duties to do so, and you multiply that by 30 or 40, you can begin to understand the impact this is having on labor availability and labor cost,” she said. A recent impact report by the Associated Press also estimated the costs of purchasing pharmaceuticals during a drug shortage (“AP Impact: Hospital Drug Shortages Deadly, Costly,” AP Sept. 24, 2011). The report cited a survey of 549 hospitals, which found that more than half had procured scarce drugs from alternative distributors, paying an average of 650% more than usual. Drug shortages also have human costs, the AP report found. It said improper preparation and errors in administering unfamiliar gray-market medications contributed to 15 reported deaths over the past 15 months.

Anesthesiologist Survey Also Shows Compromised Care Arnold Berry, MD, MPH, vice presi-

dent for scientific affairs at the American Society of Anesthesiologists (ASA), also delivered a presentation at the Sept. 26 FDA workshop, sharing results from an ASA survey conducted in April. The survey found that 48% of the 1,373 anesthesiologist respondents said the shortage of anesthesia-related drugs—most commonly propofol, succinylcholine, neostigmine and epinephrine—had compromised “optimal patient outcome.” “In most cases, these have included

prolonged awakening, longer stays in the recovery room and increased nausea and vomiting, but there have been reports of significant adverse events, including deaths in some critically ill patients,” added Dr. Berry, professor of anesthesiology at Emory University School of Medicine, in Atlanta. Like Dr. Fox, Dr. Berry believes that Senate Bill 296, the legislation requiring a six-month advance notice of impending shortages, will ensure that institutions are given the lead time they need to ready themselves and

conserve existing stock. “Adequate warning on the scope and duration of an upcoming drug shortage is critical for implementing management approaches like Duke’s,” Dr. Berry said. “Using these measures will help prolong the availability of existing stocks of the drug in short supply and will lower the chances that a provider will need to purchase from alternate sources at high prices and minimize the impact on patient care.” —David Wild

88 Operations & Management

Pharmacy Practice News • November 2011

Leadership in Action

The Science of Influence I continue this month’s column with the ongoing exploration of some of my favorite leadership “nuggets” taken from the book Leadership Gold, by author John Maxwell (Nashville, TN: Thomas Nelson Publishers; 2008).

The Best Leaders Are the Best Influencers If you are a true leader, you have influence. Perhaps you have worked long and hard in your career and throughout your life, and others now seek your feedback and advice. I remember one management job I held earlier in my career. Another pharmacist joked with me that I always had a line of people at my office door waiting to talk with me. As I think back about that now, I owe it to the fact that my goal was to help people in whatever way I could. I would try to give them the wisest advice I could about whatever topic was of concern to them. At the time, I wasn’t really thinking about influence, just doing my job to encourage people. Maxwell states the following characteristics as important to increase your influence and become someone who

people admire and will want to follow: • Insight: what you know • Ability: what you do • Character: who you are • Passion: what you feel • Success: what you achieve • Intuition: what you sense • Confidence: how secure you make others feel • Charisma: how you connect As you look at this list, consider whether people seek you out because you exhibit these characteristics. Have you advanced in your career to where you have the ability to help someone develop his or her influence over others?

Putting Influence Into Action It is a great gift if you are in a position to help others develop their own influence as leaders. Sometimes this involves introducing them to others of influence who will advance them. I was recently at a small meeting of pharmacy leaders where I encountered a pharmacy director who expressed a desire to serve on a council for the American Society of HealthSystem Pharmacists (ASHP). I consider

this individual a great leader who had established himself in his local hospital system and in other regional pharmacy organizations. I quickly offered to write a letter of recommendation and also to contact the incoming ASHP president directly. It was clearly worth my time and effort to use my influence on his behalf. He deserved the endorsement, and was deeply appreciative. I have a small group of pharmacists who I mentor. A few years ago, I introduced one of them to the leaders of a regional program where he wanted to work. I assured them that the pharmacist would do a fabulous job as program chair of the regional society. Since taking the post, he has clearly met everyone’s expectations. More recently, I strategized with some national leaders at an annual meeting on how we could elevate this same pharmacist to the next level. I find it a thrill when I see people grow in their positions of influence.

Challenging Yourself To Expand Your Sphere of Influence As we grow in our careers, it can sometimes be tempting to become complacent and comfortable in the positions that we hold. Maxwell quotes his friend

“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

Fred Smith, who gave him wise advice and encouraged him to make a hard choice to quit what was comfortable and move toward new opportunities. The quote is as follows: “Something in human nature tempts us to stay where we’re comfortable. We try to find a plateau, a resting place, where we have comfortable stress and adequate finances. Where we have comfortable associations with people, without the intimidation of meeting new people and entertaining strange situations. Of course, all of us need to plateau for a time. We climb and then plateau for assimilation. But once we’ve assimilated what we’ve learned, we climb again. It’s unfortunate when we’ve done our last climb. When we have made our last climb, we are old, whether forty or eighty.” I often encourage people to take the leap, stretch, and make that climb. I

•

see INFLUENCE, page 90

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AHFS Drug Information 2011 American Society of Health-System Pharmacists

ASHP, January 31, 2011 Written and published by pharmacists and reviewed by more than 500 experts, AHFS DI is the most comprehensive evidence-based source of drug information complete with therapeutic guidelines and off-label uses. This is the most authoritative and best-selling reference trusted by pharmacists for more than 50 years.

American Drug Index 2012 Norman F. Billups

Lippincott Williams & Wilkins, October 21, 2011

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This exhaustive drug listing includes composition, strength, dose form, packaging, schedule and usage for approximately 22,000 brand and official USP generic drugs. Organized in an easy-to-follow dictionary format with extensive cross-referencing, American Drug Index includes Tall Man lettering and hard-to-find generic drug pronunciations.

Best Practices for Hospital and Health-System Pharmacy 2011-2012

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Drug Interaction Facts 2012

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Drug Interactions Analysis and Management 2011

Philip D. Hansten Lippincott Williams & Wilkins, March 15, 2011 Designed for health care providers who prescribe, dispense or administer medications, this book emphasizes management options for improved patient outcomes and includes recommendations for alternative medications, as appropriate. Based on clinical as well as case-study findings, each monograph includes a clinical evaluation section with references.

Immunology for Pharmacy

Dennis Flaherty Elsevier/Mosby, September 2, 2011 With a new pharmacy-specific approach to immunology, Immunology for Pharmacy prepares pharmacists for practice by providing a complete understanding of the basis of immunology and the consequences of either suppressing or enhancing immune function. It covers key subjects such as prophylaxis and vaccination, antibodies as therapeutic and diagnostic agents, biological modifiers and the rationale for use and mechanisms of therapeutic agents. PPN1111

90 Technology

Pharmacy Practice News • November 2011

Documentation

Pharmacy Intervention Tracking Reveals Cost Savings

said he was also impressed with the Baystate initiative. “Monitoring the effect of pharmacists’ interventions on patients’ therapeutic, safety and economic outcomes is important to our efforts to provide safe, effective and efficient health care,” Dr. Cobaugh noted.

The intervention categories associated with the highest cost avoidance (Figure) were dose evaluation ($12,393), warfarin dosing ($5,355) and insulin dose titration ($4,437). A total of 198 unique medications were cited in the interventions. The four most commonly documented medications accounted for 29.9% of total interventions and were associated with the most significant cost avoidance: warfarin ($8,274), vancomycin ($5,894), insulin ($5,126) and heparin ($1,866). “When training students at our institution, I try to convey the importance of documenting interventions to help justify resources, clinical services and even more full time–equivalent pharmacists in clinical roles,” said co-author Adam B. Woolley, PharmD, BCPS, assistant clinical professor at Northeastern University. Many institutions, he added, don’t have many decentralized pharmacists who can make rounds as part of a clinical team, which was one impetus for enlisting students. At community hospitals, pharmacy residents rather than pharmacy students may be able to participate in similar initiatives. Dr. Woolley noted that estimating cost savings or avoidance resulting from interventions is difficult. He plans to evaluate how well the cost-avoidance model built into the database matches up with actual costs at his institution.

An Education in Savings

Data ‘Critical’

In a second study presented at the ACCP meeting, researchers found that clinical interventions made and documented by fourth-year Doctor of Pharmacy students contributed to significant cost savings. The students, from Northeastern University, in Boston, were asked to document all interventions performed while completing their six-week general medicine Advanced Pharmacy Practice Experience, using a clinical intervention database tool used throughout the pharmacy department. The students were also provided with a list of expectations and job responsibilities during work rounds and told that they would be held to the same standards as pharmacy staff. The investigators reviewed the interventions recorded by 17 students over a 36-week period beginning in August 2010. Interventions were evaluated by associated cost avoidance estimated by the intervention system, intervention category and drug class. A total of 727 interventions were recorded, with an estimated total cost avoidance of $55,879. The most common interventions by category were drug dose evaluations (11.4%), recommendation for medication change or addition (10.3%) and medication reconciliation (8.7%).

“These data are critical, as pharmacy executives make the business case to hospital/health-systems for expansion of pharmacist services to advance the organization’s pharmacy practice model,” Dr. Cobaugh said. Dr. Woolley’s study, he added, demonstrates that appropriately supervised student interventions can affect patient outcomes. —Steve Frandzel

‘The novelty of our study is that we worked with our information services department to integrate the [intervention] documentation tool into the existing CPOE.’ —Adam B. Pesaturo, PharmD, BCPS

14,000

Cost Avoidance, $

Pittsburgh—More than $2 million in annualized cost avoidance and an approximate 2.5-fold increase in clinical interventions were just two of the impressive outcomes documented in studies of pharmacist outreach presented at the 2011 annual meeting of the American College of Clinical Pharmacy (ACCP). In one investigation, the hospital pharmacy department partnered with the information systems and finance departments to create an institution-specific intervention documentation tool within the hospital’s computerized prescriber order entry (CPOE) system, according to lead study author Adam B. Pesaturo, PharmD, BCPS, critical care pharmacist at Baystate Health–Department of Pharmacy Services, in Springfield, Mass. Prior to the integration of the documentation system into the CPOE, pharmacy staff had documented interventions in a separate database that was not part of the medical record. The new system is accessible from multiple locations within the electronic medical record. Predefined interventions were assigned a value based on available pharmacoeconomic studies, institution-specific acquisition costs and average treatment duration. The pharmacy department reported cost avoidance of $271,162 over two months and an associated return on investment of 54 cents for every dollar spent. The monthly interventions per 1,000 patient-days increased from an average of 37 to 90 (P=0.50). (The relatively low number of interventions made at the 650-bed hospital stems from the fact that the pharmacy department staffs only five clinical pharmacy specialists who provide patient-centered care four to five days per week during business hours, according to Dr. Pesaturo. Thus, the department’s ability to perform direct patient care is limited compared with other institutions of similar size.) “Our department is primarily centralized, so a lot of our cost savings comes from either dose adjustments based on organ function or indication and adverse drug events that we caught during order verification or review,” said Dr. Pesaturo. “The novelty of our study is that we worked with our information services department to integrate the documentation tool into the existing CPOE. That led to a dramatic increase in the number of interventions we collected.” Documentation systems that are outside the electronic medical record and require clinicians to spend time opening another program create a significant barrier to use, Dr. Pesaturo added.

12,393

12,000 10,000

8,274

8,000 5,894

6,000

5,126

4,000 1,866

2,000 0 Dose evaluation

Warfarin

Vancomycin

Insulin

Heparin

Figure. Costs avoided by pharmacy interventions. “With our system, it’s all on the same screen. You just have to click one button and the data are captured.” Future actions will involve additional staff training to ensure accurate documentation and designing services that match those identified within the economic tracking tool. “In designing future services, we would obviously keep the interventions that have a high cost associated with them and therefore probably a higher benefit to the patient as well,” Dr. Pesaturo said. Should the financial benefits from the program continue to accrue as expected, he hopes to use the results as evidence that shows the value of an expanded clinical pharmacy program. “Documentation of the impact of pharmacists’ clinical actions is vital in the promotion and/or solidification of pharmacists as vital members of the health care team within an institution,” commented Karen E. Trenkler, PharmD, MS, BCPS, pharmacy clinical coordinator at Sinai Health Systems, in Chicago, who was not involved in the study. “Communicating such statistics is not only important for upper levels of hospital administration but also is valuable information for health care provider peers. The fact that this hospital pharmacy did not have a mechanism to document interventions in the system, yet they created a tool for use within the medical record, is very positive and is key in greatly enhancing system utility.” Daniel J. Cobaugh, PharmD, FAACT, DABAT, vice president of the American Society of Health-System Pharmacists Research and Education Foundation,

OPerationS & Management

Leadership

INFLUENCE continued from page 88

believe that these new adventures in our professional lives are essential to stimulate personal and professional growth. Should you always seek to continue climbing the corporate ladder? To answer that question, you’ll need to trust your gut. Sometimes, it is not until you’ve taken that step or have moved to that new position that you can look back and see how that action helped you grow. Moreover, this personal experience of growth through challenges becomes a foundation for us to “pay it forward” by helping someone else rise to new levels.

UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1

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

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). Reference: 1. Market Rx 2010.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

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

February 2011

0711A-2015C