November 2013

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The Pharmacist’s News Source

pharmacypracticenews.com

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Volume 40 • Number 11 • November 2013

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Printer-friendly versions available online

in this issue POLICY

7

A call for “public health problem solvers” at ASHP leadership meet.

OPERATIONS & MGMT

30

Building pharmacy’s brand to gain C-suite leverage.

CLINICAL

444

Myeloma genomics database a victory for personalized medicine.

LAST WORD

62

Transplant pharmacists can make a difference in organ donation.

TECHNOLOGY

66

How to boost the IQ of your smart IV pump launch.

EDUCATIONAL REVIEWS

Drug-Drug Interactions Between HIV and Non-HIV Medications See page 16.

Genomics, ID pharmacy advances

Practice-Changing Advances Fuel ASHP Lit Awards

Specialty Pharm ‘Carve-out’ May Be Eased by UHC Plan U

The reputation that Daniel Witt, PharmD, has gained as a leading expert in the field of anticoagulation therapy might possibly be matched

HC, a network of 1116 nonprofit academic medical center and 298 affiliated hospital members, announced that it will launch a program m by late 2013 or early 2014 to help those facilities gain n access to limited distribution specialty medicatio ons.

To be eligible, UHC C members will need to o sign a letter stating th hey will adhere to care protocols and guidelines being established by UHC to ensure consistent system-wide conformance to specialty pharmacy quality standards, according to Jake Groenewold, MBA, the senior vice president of supply chain at the Chiicago-based organization n.

Coupled with a toolkit to further promote such compliance, UHC members now have the puzzle pieces in place to become a major player in the specialty pharmacy arena, according to Mr. Groenewold. “We anticipate that 80% of our members should be able to participate,” he told Pharmacy Practice News.

see AWARDS, page 4

see UHC PLAN, page 35

A

rapid molecular diagnostic test for infectious disease that lowers mortality, hospital costs and time to appropriate drug therapy, and a pharmacogenomics algorithm that helps clinicians optimize warfarin dosing are two of several practicechanging advances by pharmacists who are recipients of this year’s Literature Awards issued by the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation.

Pharmacy Practice News spoke with the winners in advance of a ceremony honoring the awardees that will be held at the ASHP Midyear Clinical Meeting in Orlando, Fla.

Drug Therapy Research Award

•

Management of Hyperglycemia In Critically Ill Patients

•

See page 52.

REPORT Transforming the Pharmacy into a Strategic Asset See insert after page 34.

Corporate Spotlight MediDose/ EPS See page 51.

Benchmarking Tool Helps Keep Staff Cuts at Bay

D

evelopers of a new pharmacy benchmarking service say that health systems under financial pressure can use the analytical tool to fight off a common operational challenge: the unschooled consultant who recommends staff cuts to allegedly improve a hospital’s bottom line.

In such cases, pharmacy leaders need to champion their staff ’s ability to achieve optimal patient out-

•

see BENCHMARKING, page 26

Ibrutinib, a Juggernaut Therapy For CLL/MCL; Approval Nears

A

ll signs point to the imminent FDA approval of ibrutinib, the once-daily oral Bruton’s tyrosine kinase (BTK) inhibitor with impressive efficacy in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). At press time, the FDA was reviewing a New Drug Application (NDA) submitted by the drug’s manufacturer, Pharmacyclics, Inc., on July 10, 2013.

The NDA comes on the heels of findings published in The New England Journal of Medicine showing a 71% clinical response rate in difficult-to-treat CLL patients (2013;369:32-

42). The results have elicited nearly unanimous enthusiasm from those in the hematology/oncology community, including Nicole Lamanna, MD, an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Medical Center, in New York City.

“This is a huge [advance] for the field,” said Dr. Lamanna, who was not involved in research on the drug. “There is little doubt in most of our minds that ibrutinib will be used

•

see IBRUTINIB, page 41

New Products Pharmogistics® Software with IV compounding workflow management.

American Regent introduces a new IV iron replacement product.

See page 48.

See page 49.

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Grifols also provides operational solutions for compounding areas in pharmacy and diagnostic instrumentation, reagents, software and related products for the clinical laboratory.

Learn more about how Grifols can meet your hospital’s needs at www.grifols.com 1. Marketing Research Bureau data, June 2012

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Printed in USA.

April 2013

CO24-0413

Up Front 3

Pharmacy Practice News • November 2013

Capsules

surf

NOVEMBER 2013

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Doomsday for PharmD Grads or Alarmist Over-Reaction?

2. Juggernaut CLL/MCL Drug, Ibrutinib, En Route to FDA Approval 3. Top 5 Pharmacy News Articles from September 4. Compatibility of Commonly Used IV Drugs 5. Tips for Surviving “The Unthinkable” In Patient Safety Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘The transplant

pharmacy community [must promote] organ donation, because

first

without donation there simply is no transplantation.’

—Eric M. Tichy, PharmD, BCPS

See article, page 62

FDA Approves Perjeta for Early-Stage Breast Cancer

T

he FDA has approved a first-line chemotherapy for preoperative early-stage breast cancer, Genentech announced in a statement on Sept. 30. Pertuzumab (Perjeta) in combination with trastuzumab is the first bre east cancer treatment approved for use in a neoadjuvant setting. Perrtuzumab also is the first drug to meet accelerated approval using pathologic complete response (pCR) data.

“A new approval pathway has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible,” said Hal Barron, MD, the chief medical offficer of Genentech. “Together with the FDA, we’ve charted new territorry.”

In 2012, the FDA approved pertuzumab for metastatic,, late-stage HER2-positive breast cancer. Pertuzumab now also is intended for patients with HER2-positive early-stage, inflammatory or locally advanced breast cancer who are at risk for metastasis, relapse or death. Neoadjuvant therapy with Perjeta, which can range from nine to 18 weeks, would cost an estimated $27,000 to $49,000, according to a Genentech representative.

“We are seeing a significant shift in the treatment paradigm for early-stage breast cancer,” said Richard Pazdur, MD, the director of the FDA’s Office of Hematology and Oncology Products, in a press release. “By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences.”

The FDA based its approval on the results of a multicenter, randomized Phase II trial, NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation). Patients with HER2-positive early-stage, inflammatory or locally advanced breast cancer (N=417) were randomly assigned a 12-week regimen of one of four treatments: pertuzumab plus docetaxel; pertuzumab plus trastuzumab; trastuzumab plus docetaxel; or pertuzumab plus trastuzumab and docetaxel.

The primary end point of NEOSPHERE was the lack of detectable tumors in breast and lymph node tissue, or pCR. About 39% of patients receiving pertuzumab plus trastuzumab and docetaxel—the most efficacious treatment—achieved pCR, followed by 21% of patients who received trastuzumab and docetaxel (P=0.0063).

In the NEOSPHERE trial, adverse events included diarrhea, hair loss, nausea and a decrease in white blood cells. Anaphylaxis, decreased cardiac function, hypersensitivity and infusion-related reactions were other serious side effects. Additionally, the labeling for pertuzumab includes a warning that if it is used during pregnancy, it may cause birth defects or fetal death.

In 2013, the National Cancer Institute estimates there will be 232,300 new diagnoses of breast cancer and 39,600 women will die from the disease. Increased levels of HER2 protein are found in about 20% of breast cancer cases.

—Ben Guarino

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

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

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

Volume 40 • Number 11 • November 2013 • pharmacypracticenews.com

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

INTERNAL MEDICINE

EDITORIAL STAFF

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NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

BIOTECHNOLOGY

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ONCOLOGY

CARDIOLOGY

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C. Michael White, PharmD, Storrs, s CT

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CNS/PSYCHIATRY

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Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas

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4 Up Front

Pharmacy Practice News • November 2013

Research

AWARDS continued from page 1

by his “legendary” status as a Boy Scout leader of eight years.

“One of my favorite stories is when Dan took his group of young scouts on their first rafting trip on a river in Colorado,” recalled Dennis Helling, PharmD, Dr. Witt’s mentor and former supervisor and executive director emeritus for Pharmacy Operations and Therapeutics at Kaiser Permanente Colorado, in Aurora. “Due to unforeseen circumstances, the adventure turned into a whitewater survival test for his shivering and fearful

They found that the risk for thrombosis was 95% lower in the 58.8% of patients who resumed warfarin compared with those who discontinued the drug (hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.01-0.58). Additionally, the risk for death was 69% lower when treatment was restarted (HR, 0.31; 95% CI, 0.15-0.62).

Dr. Witt said he and his team were surprised to find that although the risk

‘We thought we’d see a much higher incidence of recurrent bleeding ...

Our findings suggest the benefits of resuming anticoagulant therapy outweigh the risks in many patients.’

—Daniel Witt, PharmD young scouts. I am not sure that many of them returned for more merit badges with their scout leader, the infamous Dan Witt.”

Although scouts tremble at the mere mention of his name, patients of Dr. Witt, the senior manager for clinical pharmacy research and applied pharmacogenomics at Kaiser Permanente Colorado, are certainly grateful for the work he has done to improve anticoagulation therapy safety. Among Dr. Witt’s accomplishments during the 20 years since he joined Kaiser Permanente Colorado is the establishment of an anticoagulation service, which has proven fruitful for his clinical as well as research pursuits.

“I’ve had lots of opportunities to do observational studies in the Kaiser system and to collaborate with others around the world,” he said.

For example, Dr. Witt recently cofounded the Warfarin-Associated Research Projects and other EnDeavors (WARPED) Consortium, an international, multidisciplinary collaboration that addresses “the real-world problems of anticoagulation care providers and patients.”

In the study for which he is receiving his award, Dr. Witt and his colleagues set out to address a common problem for clinicians treating patients with warfarin-related gastrointestinal (GI) bleeding: resume treatment and risk recurrent bleeding or stop treatment and risk thrombosis.

To this end, he and his team retrospectively analyzed a database of 442 patients who had experienced the complication and either discontinued or resumed treatment during the 90 days subsequent to GI bleeding treatment ((Arch Intern Med 2012;172:1484-1491).

for recurrent GI bleeding was higher among those who resumed treatment, the difference was not statistically significant (HR, 1.32; 95% CI, 0.50-3.57).

“We thought we’d see a much higher incidence of recurrent bleeding,” he said. “Our findings suggest the benefits of resuming anticoagulant therapy outweigh the risks in many patients.”

Dr. Helling said the findings are important and are deserving of an award—but so is the man. “I feel strongly about Dan,” he said. “He is an international expert and investigator in the field of anticoagulation while being an extremely humble person and a dedicated father and husband.”

Pharmacy Practice Research Award The essence of the award-winning research by Asad Patanwala, PharmD, can be distilled into a few words he shared with Pharmacy Practice News: “Moving the conversation beyond whether a pharmacist is effective in the emergency department [ED] to what a pharmacist should be doing to be as effective as possible.”

That is the overarching theme of much of Dr. Patanwala’s research into the effectiveness of ED pharmacists.

But in the award-winning study, “we

wanted to look at what activities lead to error interception,” said Dr. Patanwala, an associate professor at the University of Arizona’s College of Pharmacy, in Tucson. To that end, he and colleagues at four academic and community emergency EDs nationwide prospectively collected data from 364 medicationerror interceptions during 1,000 hours in their EDs. The findings, published in the Annals of Emergency Medicine (2012;59:369-373), revealed that more than 50% of all interceptions resulted from pharmacy consultative activities on the floor, whereas only 35% of errors were caught during order reviews.

“You have to be involved with the medical teams and be a visible and active part of the team to intercept the majority of errors,” Dr. Patanwala said.

“If you sit in a corner and just review orders on a computer screen, I’d say you aren’t as effective as somebody who’s responding to a variety of high-severity patients and actively talking to the team and to nurses about what’s going on.”

Dr. Patanwala’s focus on ED pharmacy emerged during his second year of critical care pharmacy residency at the University of Arizona, around the time the Joint Commission issued standards requiring ED orders be reviewed by a pharmacist—an irony that has not escaped Dr. Patanwala.

“Our study basically says that reviewing orders isn’t everything,” he said, adding that he is “excited and humbled to receive an award that has gone to some really good research endeavors.”

Since the Annals study was published, Dr. Patanwala has published other research honing in on more specific ED areas. “Our most recent publication found that critically ill ED trauma patients undergoing rapid-sequence intubation receive more appropriate drug therapy when a pharmacist is part of the resuscitation team,” he said ((Am J Health Syst Pharm 2013;70;1513-1517).

Michael C. Thomas, PharmD, an associate professor in the Department of Pharmacy Practice at South University, Savannah, Ga., co-author of the Annals paper, said Dr. Patanwala is “genuine, gregarious and productive.”

“Sid is a forward-thinking leader in the field of pharmacy and this award is an example of the impact he has made,” Dr. Thomas added. “This paper solidifies the cognitive value the emergency pharma-

‘[We are] moving the conversation beyond whether a pharmacist is effective in the emergency department to what a pharmacist should be doing to be as effective as possible.’

—Asad Patanwala, PharmD

cist can provide to health care providers in making patient care decisions.”

Award for Innovation In Pharmacy Practice During her postgraduate year 2 (PGY2) residency at Houston Methodist Hospital, Katherine Perez, PharmD, caught on to the importance of a new rapid molecular diagnostic test, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS).

“I realized this was going to be a game changer for how we treat infectious diseases, and I tried to figure out how I could be part of it,” said Dr. Perez, one of the hospital’s infectious diseases clinical pharmacy specialists.

As her award suggests, that has been working out quite well. Her study examined the effect of a protocol she helped develop, marrying the use of MALDITOF MS with near-real time antimicrobial stewardship ((Arch Pathol Lab Med 2013;137:1247-1254).

The protocol begins with a succession of specimen analyses, including MALDI-TOF MS for gram-negative isolates, as well as drug susceptibility testing. After examining the results as they emerge, an infectious disease pharmacist reviews the patient’s medical records and immediately contacts the treating physician to create a treatment plan. “This more prospective audit approach, where you’re actually presenting the prescriber with objective data, makes it harder to turn down a recommendation than using a restrictive model,” she said.

Indeed, use of the protocol was associated with fewer deaths (six of 107 vs. 12 of 112 before the intervention; P not significant), reduced hospital lengths of stay (mean 9.3 vs. 11.9 days; P=0.01), lower hospital costs (mean $26,162 vs. $45,709; P=0.009) and shorter times to appropriate treatment (36.5 vs. 73.2 hours; P=0.01), among other improvements.

Because she was the only infectious disease pharmacist actively involved in the study intervention, Dr. Perez was on call 24/7 for the duration of the fourmonth study. “I really believed in this and really thought it could make a huge difference—and it did!” said Dr. Perez, whose findings resulted in her full-time appointment as the hospital’s antimicrobial stewardship pharmacist.

Other institutions have contacted Dr. Perez, using her study to make a compelling case for purchasing a MALDITOF MS. “That’s really, really humbling and exciting,” she said.

Study co-author William Musick, PharmD, a clinical specialist in infectious diseases at the hospital, and the director of Dr. Perez’ PGY2 Pharmacy Residency in Infectious Diseases program, praised Dr. Perez for “working tirelessly

•

see AWARDS, page 7

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The burden of hyponatremia1,3 Hyponatremia occurs in up to 15% to 30% of hospitalized patients.4-6 Most cases are asymptomatic, and even when symptoms are present, they often overlap with other chronic comorbid conditions, making accurate assessment a challenge.3-6 Hyponatremia is known to complicate care, put patients with comorbid conditions at increased risk of mortality, and increase healthcare costs.1,3-5,7-9

Additionally, under current Congressional healthcare reform provisions, the Centers for Medicare and Medicaid Services has begun to both publically report hospital readmission rates and penalize hospitals for early readmissions.1,10

Increased risk for hospitals and patients11

A case-control study examining the incidence of falls among patients with asymptomatic chronic hyponatremia (126 ± 5 mEq/L) found that A 2009 retrospective cohort study (N=2047) examining the economic 21.3% (26/122) of hyponatremic patients experienced in-hospital falls impact of hyponatremia (≤134 mEq/L) vs 5.2% (13/244) of normonatremic The impact of hyponatremia on hospital resource utilization1 at admission found that hyponatremia patients.2 The Centers for Medicaid was associated with an additional Hospital Resource Utilization Hyponatremic Patients Normonatremic Patients and Medicare Services reported $2.5 million in hospital costs and Total length of stay (mean) 8.8 days 7.7 days in-hospital falls resulted in injuries, over 3400 additional bed days.7 The increased length of stay, malpractice ICU admission, N (%) 129,235 (23.1%) 123,502 (22.1%) 2011 overall cost of hyponatremia lawsuits, and >$4000 in excess ICU length of stay (mean) 5.5 days 4.9 days was estimated to be between $1.6 charges per hospitalization, a ICU cost (mean) $8525 $7597 and $3.6 billion.1,3 Responsibility liability for which Medicare has not 30-day all-cause 96,063 (17.5%) 87,058 (16.4%) readmission, N (%) for these costs falls primarily reimbursed hospitals since 2008.11 Total hospitalization cost (mean) $15,281 $13,439 to hospitals, which under most In response, The Joint Commission’s Adapted from Amin A, et al. J Hosp Med. 2012;7(8):634-639. reimbursement methodologies, often 2011-2012 National Patient Safety 7 cannot bill patients or payers for these additional h dditi l expenditures. dit Goals set reducing the risk of falls as Goal 9.12 And, hyponatremia A 2012 retrospective database analysis of over 700 hospitals found that can have serious consequences for some patients. A prospective hyponatremia was associated with increased length of stay, greater cohort study of 98,411 hospitalized patients found that even mild likelihood of ICU admission, greater chance of readmission, and higher hyponatremia (130-134 mEq/L) is associated with an increased risk total cost per admission vs normonatremic patients (see table).1 of in-hospital, 1-year, and 5-year mortality.9

What you don’t know can cost you

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References: 1. Amin A, Deitelzweig S, Christian R, et al. Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US. J Hosp Med. 2012;7(8):634-639. 2. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119:71.e1-71.e8.

3. Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Effect Resource Alloc. 2006;4(10):1-11. 4. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11A):S1-S21. 5. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatremia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant. 2006;21:70-76. 6. Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleveland Clin J Med. 2006:73(3):S4-S12.

7. Callahan MA, Do HT, Caplan DW, Yoon-Flannery K. Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study. Postgrad Med. 2009;121(2):186-191. 8. Adrogué HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol. 2005;25:240-249. 9. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med. 2009;122:857-865.

10. Congressional Record. Patient Protection and Affordable Care Act. 2010;156:1-906. 11. Inouye SK, Brown CJ, Tinetti M. Medicare nonpayment, hospital falls, and unintended consequences. N Engl J Med. 2009;360(23):2390-2393. 12. The Joint Commission. 2011-2012 National Patient Safety Goals. © Copyright 2012, The Joint Commission. ©2013 Otsuka America Pharmaceutical, Inc.

August 2013

0713A-8921C

Up Front 7

Pharmacy Practice News • November 2013

Research ‘I realized this was going to be a game changer for how we treat infectious diseases, and I tried to figure out how I could be part of it.’

—Katherine Perez, PharmD

AWARDS continued from page 4

on the project as we piloted our fledgling antimicrobial stewardship program. I’m confident it was her obvious dedication to patient care, her team spirit and her bubbly personality that helped the project succeed,” he said.

When she’s not dedicating herself to improving antimicrobial use, you can find Dr. Perez at her local karaoke bar, belting out a version of Neil Diamond’s “Sweet Caroline.” She also enjoys spending time with her boyfriend who, she gratefully pointed out, is not involved in health care. “It’s good to talk about things other than work.”

Student Research Award This year’s Student Research Award recipient’s mantra reflects the era of pharmacy practice that her generation is bringing to fruition: “the right drug for the right patient at the right dose.”

“We should all aim toward personalized medicine,” said Alga S. Ramos Morales, MS, from the University of Puerto Rico, Medical Sciences Campus, in San Juan. “We’ve come from a culture of ‘OK, this is a drug we give to everybody at the same dose,’ but we’re realizing that’s not the [best approach].”

Ms. Ramos Morales’s interest in personalized medicine developed after she

completed her undergraduate degree focusing on nuclear medicine. Entering her master’s studies, she contacted Jorge Duconge, PhD, an associate professor of pharmacokinetics and pharmacogenetics at the University’s Department of Pharmaceutical Sciences. The pair went on to collaborate on the study for which Ms. Ramos Morales is receiving the award, examining the pharmacogenetics of warfarin in Puerto Rico’s very distinct population ((Pharmacogenomics 2012;13:1937-1950). “We’re basically a mixture of three races: whites, West Africans and Amerindians,” the 21-year-old PharmD candidate said. “So we can’t follow the existing warfarindosing algorithms.”

tistical analyses suggested an algorithm based on several significant predictors would better identify the maintenance dose. The algorithm’s formula accounted for two VKORC1 gene variants, the presence of cytochrome P450 2C9, age, pulmonary embolism, concomitant use of amiodarone and a dose-adjusted international normalized ratio (INR) on day 3. In a modeling analysis, the algorithm accounted for 67.8% of the variance in therapeutic warfarin dose and the starting doses it predicted were an average of 1.22 standard deviations (SDs) away from the stable dose compared with 2.84 SDs using a solely clinical algorithm and 2.22 SDs using an ageadjusted fixed-dose approach ((P<0.001 for both comparisons).

The findings have led to a potential collaboration with the International Warfarin Pharmacogenomics Consortium, which may use these data in future analyses, Ms. Ramos Morales said.

Dr. Duconge, Ms. Ramos Morales’ mentor, professor, and research advisor

‘We’re basically a mixture of three races: whites, West Africans and Amerindians.

So we can’t follow the existing warfarindosing algorithms.’

—Alga S. Ramos Morales, MS Her team retrospectively examined genetic, clinical and demographic data from 163 racially mixed recipients of warfarin, most of whom had atrial fibrillation. The patients had achieved a stable dose after being administered an age-adjusted fixed initial dose. Sta-

and senior author of the study, referred to the award winner as “a very mature student” who is “skillful,” “hardworking,” “admirable” and “diligent.”

Ms. Ramos Morales and Dr. Duconge “spent about a month doing hands-on training in pharmacogenomics at the

Genetics Research Center, in Hartford, Conn.,” he recalled. He shared that one day after the training, they along with some “other colleagues in the lab, went to eat something and hang out downtown. It didn’t take too long before we had to deal with a kind of embarrassing situation once we were asked to show our IDs for admission to one of the city pubs. Just then we recalled that, despite her remarkable maturity and professionalism, [Ms. Ramos Morales] was still a teenager!”

Award for Sustained Contributions This is the second ASHP Literature Award that Marie Chisholm-Burns, PharmD, MPH, MBA, has received in the past three years. This latest award, for Sustained Contributions, is a testament to her vigorous curiosity—one that is unlikely to subside anytime soon.

“On any given day, I probably have around five questions that I look into, and they’re not necessarily pharmacy related,” said Dr. Chisholm-Burns, a dean and professor at the University of Tennessee Health Science Center’s College of Pharmacy in Memphis.

Dr. Chisholm-Burns has more than 260 publications to her credit and has received approximately $8 million in external funding as a principal investigator. Her work has focused on the value of pharmacists in patient care, health care access, medication adherence, solid organ transplantation and academic pharmacy/pharmacy education.

For more information on Dr. ChisholmBurns, please see her profile from the 2011 ASHP Literature Awards (bit. ly/17LbnfA).

—David Wild

POLICY

ASHP Fall Leadership Conference

Wanted: Public Health Problem Solvers Chicago—Know your health system’s strategy for health care reform; start living and breathing the delivery of pharmacy services across the continuum of care; and become an innovator in addressing major public health issues, the president of an academic medical center urged pharmacy leaders at the American Society of Health-System Pharmacists’ (ASHP) 2013 Fall Leadership Conference.

In his keynote address, Shane M. Cerone, the president of Beaumont Hospital, a 1,070-bed tertiary care institution in Royal Oak, Mich., painted a compelling portrait of a health care delivery system in serious need of reform. However, he said it remains to be seen whether the solutions proposed by the Affordable Care Act (ACA), notably, the accountable

care organization (ACO), will be enough to solve the problems of health care utilization and cost as an aging population, rising rates of obesity and associated diseases, and growing physician and nurse

shortages lead to unprecedented demand on the nation’s resources (sidebar).

“It is my estimation that there is absolutely no way for our current population base, given our current economy,

to maintain the same level of support in retirement as we have for previous generations unless there is some sort of massive magical fix to our industry,” Mr. Cerone said.

“For me, there’s a significant disconnect between what we have to do to lower costs of care for the nation and whether health reform and all of the initiatives taking place are going to have that effect,” he said. “We have to address and create a meaningful public health system and organizational structure in our country.”

Mr. Cerone called on pharmacy leaders to become innovators in this arena.

That message, he noted, can be conveyed by asking a few key questions: “How can

•

see PROBLEM SOLVERS, page 10

8 Policy

Pharmacy Practice News • November 2013

Reimbursement Matters

Billing for Waste: a Lost Revenue Opportunity T

he “crunch time” start date of the new fiscal year began on Oct. 1, 2013 and brought with it the realities of the updated Inpatient Prospective Payment System (IPPS). Although a few hospitals saw a bonus added to their payments as a result of the updates, a significant number felt the financial sting of penalties that subtracted from their earnings. The start of the Outpatient Prospective Payment System (OPPS) on Jan. 1, 2014, brings the next significant fiscal crunch.

“Reimbursement Matters” columns from the past few months have concentrated on providing background on reimbursement and how it affects the pharmacy as well as suggestions for billing and payment areas that may been overlooked or under-recognized for their revenue potential. Although pharmacists tend to concentrate on trying to bring down the cost of the medications and biologics that a health system purchases, and spend an inordinate amount of time on formulary management, they often tread lightly (if at all) when getting involved in the reimbursement picture.

When the stakes are high and your clinical program may be at risk for a funding decrease, it’s time to peer into every corner for lost dollars!

Billing for waste is in one of those corners. Unfortunately, the strategy is not applied universally, in part because few pharmacists and their colleagues in the billing department understand how to do it. In developing some basic pointers for reversing that knowledge gap, let’s use Medicare as a model because most private insurers follow the federal program’s lead in establishing payment terms. But remember to also think locally: The Medicare Administrative Contractor (MAC) that covers your area may have certain requirements as well.

As for Medicaid, what it does depends completely on the state in which your facility is located.

Oh, That’s Why Billing Units Matter!

Several years ago, Medicare created the ability to bill for expensive waste in the outpatient area shortly after moving to the concept of “billing units representing actual dose given” for reimbursement and away from the “whole vial” method of billing under OPPS. Medicare does not mandate billing for waste but makes it possible to recoup some lost dollars if you choose to bill for them—provided that you pay strict attention to the OPPS rules. The Table provides some important points to consider.

Recent discussions with colleagues have suggested that the current state of rather low implementation of waste

Table. Hints for Billing for Waste Only applies to Medicare unless your state’s Medicaid program also allows for waste billing Might apply to private pay depending on your negotiated contract Only applies to drugs that Medicare actually pays for that cost >$90/d (in 2014)

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health.

Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

These drugs are the ones listed on the quarterly ASP/NOC CMS updates.

Only applies to single-dose vials for these drugs The quarterly ASP NDC matched tables show you exactly how many billing units are in each vial so you can correctly calculate waste.

You can’t bill for overfill in the vials.

Each MAC/FI determines how they want waste billing to happen and what kind of documentation they require.

The MAC may require the use of the JW modifier to identify the drug amount discarded/not administered to any patient.

Don’t just copy from someone else if they’re not in the same MAC/FI as you.

You can do this if you break down the steps and make it as simple as possible You probably will end up billing for waste for only a very few expensive drugs and that’s worth the time it takes!

ASP, Average Sales Price; CMS, Centers for Medicare & Medicaid Services; FI, fiscal intermediary; MAC, maximum allowable cost; NDC, National Drug Code; NOC, not otherwise classified

‘Regardless of the rationale ..., the decision not to bill for outpatient [medication waste] is hurting everyone.’ billing is a result of a combination of factors that include knowledge gaps, a perceived low return on the effort, perceived resource constraints (too much complex work for the resulting yield), lack of information technology (IT) systems support for the required level of automation and documentation in the outpatient area, or a business risk assessment (the fear factor that a change in billing might lead to scrutiny), or some other set of circumstances.

Regardless of the rationale that may be paralyzing your facilities, the decision not to bill for outpatient waste is hurting everyone! And especially so, now that bundled payment models are in vogue.

Bundle payment calculations are based on “big data,” including the history of payment for separately payable medica-

tions and biologics, their drug administration costs and the payment for waste as well as the myriad of non-separately reimbursable products that are identified as being used. The decision to not implement waste billing (or to not bill for nonseparately reimbursable products) paints a deceptively inaccurately low picture of the true cost of medications being included in the bundled payment. Reconsider and respond!

Tips for Mastering Waste Case Study: The facility has an active outpatient area with specialty clinics including an infusion center supported by an outpatient pharmacy. The hospital has not yet extended electronic medication administration record (EMAR), electronic health records

Reading Material Topic: OIG letter on improper Herceptin payments Website: 1.usa.gov/1cZMAMV Topic: MM7095 - Discarded Drugs and Biologicals Policy at Contractor Discretion Website: go.cms.gov/1euxtZB Topic: MM6711 - Discarded Drugs and Biologicals Updates Website: go.cms.gov/1c02nf9

(EHR) or computerized prescriber order entry (CPOE) to the outpatient areas, although pharmacy uses the hospital’s pharmacy IT system. This system has the ability to print paper copies of pharmacy-generated MARs. Here are a few keys to how waste billing should proceed: Tip 1. Determine which drugs/biologics are targets for waste billing: • Only those in single-dose vials • Only those that cost more than $90 per day per average sales price reimbursement tables • Consider expensive chemotherapeutics, biologics and new uses of products like the explosion of botulism antitoxin product use in neurology and urology • Start with a manageable “top 10” list.

Tip 2. Create a new pharmacy drug master (PDM) description and corresponding charge description master (CDM) entry for each medication you’ve chosen to indicate wasted product and to ensure that the billing units assigned to this match those assigned to the corresponding drug PDM and CDM listing.

Don’t panic—this isn’t much work, and you’ll likely only have a very few expensive products to handle.

Tip 3. Get nursing to accept a pharmacy-generated paper MAR that will replace the handwritten one they’ve been using. This guarantees that documentation will be consistent and will accurately contain the information required for the facility’s billing and coding department to proceed with waste billing. This strategy also can help in amassing the documentation required for passing a potential audit.

(It also provides the opportunity to fix that annoying and perpetual problem of accurate documentation of drug administration start and stop times that may be compromising accurate reimbursement.)

Tip 4. At order-entry time, determine if waste billing will apply (e.g., that’s the only Medicare patient that day who will be receiving the drug, which comes in a single-dose vial). If so, enter both the order for the drug as well as a separate order for the waste.

Tip 5. Provide both the product and the MAR to the clinic area.

■

10 Policy

Pharmacy Practice News • November 2013

Leadership

PROBLEM SOLVERS continued from page 7

you and your organizations sponsor and support creativity? How do we take on the challenge of obesity? What are we going to do to manage the costs of care for the elderly? How are we changing our approach to the end of life? My estimation is that there’s so much value you can provide as pharmacists and as leaders.”

According to Mr. Cerone, for pharmacists, “the future skill set is going to be thinking about minimizing [medication]

substitutions and disruptions. We’re going to have to think about our formulary approach in a very different way” to reduce the costs of care, he said. He encouraged pharmacy leaders to work closely with physicians on this problem.

New Areas of Expertise Needed Mr. Cerone said pharmacists also need to know how to: Capture revenue. “We have to know that we’re collecting payment for all the care we provide,” he said. “As leaders, it’s critical that you understand

ACO Basics

I

n his speech at the ASHP meeting, Mr. Cerone reviewed some of the solutions proposed by the ACA to reduce costs and improve health care quality. Chief among these is the ACO, which holds providers accountable for quality and costs for a defined patient population. The two basic ACO models are the Pioneer and Shared Savings programs.

With the potentially more rewarding, but riskier and less common Pioneer

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approach, the ACO receives fee-forservice payments for care at half the normal rate. The remainder of the funding comes through a per-member, per-month payment methodology based on performance against a risk-adjusted target.

In 2012, after the initial year of implementation under a program coordinated by the Centers for Medicare & Medicaid Services (CMS), seven of the 32 participating organizations shifted to the less risky Shared Savings approach and two left the project completely.

Only 13 (40%) produced savings to share with CMS. The total savings for Medicare was $33 million, only about 3.5% of the total projected savings of $940 million. Two of the 32 organizations suffered losses totaling $4 million. Currently, there are 23 Pioneer ACOs in the country (Modern Healthcare, July 16, 2013).

“The eventual departure of several of these Pioneer programs has signaled that the critical cost-containment approach is not as simple as some of the initial members had thought,” Mr. Cerone said.

The more prevalent Shared Savings program requires the ACO to serve at least 5,000 Medicare beneficiaries. The Shared Savings program rewards ACOs that reduce growth in health care costs compared with calculated expected expenditures. At present, 228 organizations are participating in this program.

The program has two tracks: 1) a reward-only track in which the organization cannot lose reimbursements in years 1 and 2 but is financially at risk in year 3 if the cost of care is higher than expected; and 2) a two-sided risk-and-reward structure for years 1, 2 and 3.

Patients under a Shared Savings ACO are assigned based on the terms of the contract with CMS. The ACO bills normally for fee-for-service. The total cost of care for the assigned population is then compared with a risk-adjusted target.

The ACO’s performance against that target determines whether savings are distributed to the ACO. Three tiers of increasing financial risk and return are available in the Shared Savings program. Payment systems gradually transition from fee-for-service to bundled payments as well, with some shared savings and bonuses if per-beneficiary spending is below agreed-on targets in tier 1; more shared savings and bonuses if per-beneficiary spending is below agreed-on targets and some risk if spending is above agreed-on targets in tier 2; and the highest level of shared savings and bonuses if per-beneficiary spending is below agreed- on targets but greatest amount of risk if spending is above agreed on targets in tier 3 (Health Afff 2010;7:29).

—S.B.

ADR 2000-0713

Policy 11

Pharmacy Practice News • November 2013

Leadership your revenue cycle.”

Bend the cost curve. “What are you doing to lower costs on admission rates?

What are you doing to lower overall utilization? We’re going to have to do more with less within our hospitals and within our clinic structure.”

Understand pharmacy services across all settings. With the expansion of bundled payments, “we’re leaving the days where you’re paid based on your environment. Those payments are going to start to blend. So it’s going to be critical that we understand care across the continuum. That’s going to take us outside the walls of our day-to-day enterprise,” Mr. Cerone said.

Have realistic expectations. “I’m not sure all ACO structures, clinical integration strategies and changed marketplaces are going to fundamentally change public health programs,” he said. “I don’t think they’re going to change how we care for people in their elder years when they consume so many resources.”

‘Why should we fragment patient care by changing medications every time a patient has an encounter with a hospital or if their physician switches them from one drug to another?’

—Rita R. Shane, PharmD two particularly acute problems in elder care—medication overuse and medication adherence—are major public health issues that merit special attention from

pharmacists. On that point, Dr. Shane urged pharmacists to collaborate with the health care team to ensure that a drug regimen for a given patient is not

only effective and safe but also necessary. Although that strategy can be an important tool for reducing potentially harmful polypharmacy in elderly patients, it’s also something to strive for in alll patients, she pointed out.

“My overarching belief,” said Dr. Shane, “is that the role of pharmacists should always include evaluating whether patients need to be on all the medications they’re taking as well as identifying the medications they may need that they’re not taking.”

—Susan Birk

A Pharmacy Director’s Take Rita R. Shane, PharmD, FASHP, FCSHP, the director of pharmacy services at Cedars-Sinai Medical Center, in Los Angeles, said she agreed with Mr. Cerone’s call for an alternative to the current model of substituting medications to meet hospital formularies.

A new approach would go a long way toward reducing medication errors and avoidable readmissions, she noted in an interview with Pharmacy Practice News.

‘There’s a significant disconnect between what we have to do to lower costs of care for the nation and whether health reform and all of the initiatives taking place are going to have that effect.’

—Shane M. Cerone “Why should we fragment patient care by changing medications every time a patient has an encounter with a hospital or if their physician switches them from one drug to another?” Dr. Shane asked. “Why don’t we try to keep the patient at the center and keep the drug list accurate and consistent?” (Dr. Shane presented her views on the problems associated with medication substitutions in her Harvey A.K. Whitney Lecture at the ASHP 2012 Summer Meeting.)

Dr. Shane also echoed Mr. Cerone’s call for a more rational approach toward elder care. Indeed, she stressed that

LEADERS ARE NEVER AFRAID TO GO FIRST

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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. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy.

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 fi 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. Clinically significant fi hypotension during infusions was seen most often in the first several hours of treatment and appeared to be related to the rate of infusion. 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.

• Elevations of blood hepatic enzyme values ALT, AST, GGT are commonly seen in patients with immediately life-threatening VT/VF. / 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. • Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. 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.

• There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings included pulmonary infi filtrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. Two percent (2%) of patients were reported to have acute respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary toxicity including pulmonary fifibrosis is a well-recognized complication of long-term amiodarone use.

• 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 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.

• 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. 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%).

• 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. HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required.

• Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in effi ficacy. 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.

The institution of antithyroid drugs, Ƶ-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland.

Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism.

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.

Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients.

5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics.

Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri

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.

Respiratory: y 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

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.

Thyroid: d thyroid nodules/thyroid cancer

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.

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.

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%).

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

Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Body as a whole Fever Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia Digestive System Liver function tests normal Nausea

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

24 (2.9%) 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 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

Pancreatic: pancreatitis Renal:l renal impairment, renal insufficiency, acute renal failure

Vascular: r vasculitis 7 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.

HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.

Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required.

Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy.

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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D Reproductive and teratology studies performed in rabbits and rats at doses of up to 100 mg/kg per day (about 1.4 times the maximum recommended human dose on a body surface area basis) revealed no evidence of embryotoxicity at 5 mg/kg and no teratogenicity was observed at any dosage in rabbits.

Maternal toxicity and embryotoxicity were observed in rats in the 100 mg/kg group.

Use NEXTERONE during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

8.2 Labor and Delivery It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects.

8.3 Nursing Mothers Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug.

8.4 Pediatric Use The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended.

8.5 Geriatric Use Clinical studies of amiodarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carefully consider dose selection in an elderly patient.

10 OVERDOSAGE There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of intravenous amiodarone include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity.

Treat hypotension and cardiogenic shock by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Monitor hepatic enzyme concentrations closely. Amiodarone is not dialyzable.

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

Cardiovascular: r hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema

Sourced from: 07-19-68-241 Rev. January 2012

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:l myopathy, muscle weakness, rhabdomyolysis

111923 04/13

16 Clinical

Pharmacy Practice News • November 2013

Educational Review

The Art of Managing

Drug–Drug Interactions Between HIV And Non-HIV Medications ROSHNI S. PATEL, PHARMD Assistant Professor Jefferson School of Pharmacy Philadelphia, Pennsylvania

NEHA SHETH PANDIT, PHARMD Assistant Professor Department of Pharmacy Practice and Science University of Maryland School of Pharmacy Baltimore, Maryland

CHARMAINE ROCHESTER, PHARMD Associate Professor Department of Pharmacy Practice and Science University of Maryland School of Pharmacy Baltimore, Maryland

O

ver the past decade, there have been numerous advancements in the treatment of HIV infection. New antiretroviral i l agents t have been introduced into the market and are proving to be effective, safe, and

more convenient than older agents.1 These new options for antiretroviral therapy (ART) have contributed to decreased HIV-related morbidity and mortality, as well as increased

life expectancy. However, patients who live longer often develop other comorbidities that require treatment, increasing the risk for drug–drug interactions (DDIs).1

Uncovering DDIs with ART may appear to be a difficult feat, given the multiple drug classes available for HIV management, but clinicians can easily review drug regimens to identify DDIs by understanding the basic mechanisms through which DDIs can occur. The intent of this article is to guide clinicians through a stepwise approach to identifying and managing DDIs involving ART, while providing examples of common and clinically important DDIs.

Step 1. Identify how the potentially interacting agents are metabolized.

Most DDIs involving ART occur through effects on hepatic drug metabolism, and specifically on enzymes belonging to the cytochrome P450 (CYP450) superfamily.2 Therefore, it is especially important to identify the CYP isoenzyme involved in the metabolism of specific antiretroviral agents. Certain agents also are activators of the pregnane X receptor (PXR).

Text continues on page 18

Case Study History of Present Illness MB is a 47-year-old man who presented to the pharmacy clinic after being referred by his physician for medication management. He had been diagnosed with HIV 8 years before and was initially started on a regimen of lopinavir 200 mg/ ritonavir 50 mg (Kaletra, Abbvie) 4 tablets orally once daily and emtricitabine 200 mg/tenofovir 300 mg (Truvada, Gilead) 1 tablet orally once daily. Over the past 8 years, MB has been intermittently nonadherent with this ART regimen.

Recently, he was hospitalized for 3 weeks with a chief complaint of chest pain. When he presented to the emergency department, MB informed the health care team that he had been off his ART for the past 6 months. During this admission, a transesophageal echocardiogram revealed a left ventricular thrombus and he was started on warfarin therapy. However, international normalized ratio (INR) management was challenging because MB was unable

to achieve a therapeutic INR; he was switched to rivaroxaban (Xarelto, Janssen) 20 mg orally daily.

Past Medical History HIV Ischemic cardiomyopathy Left ventricular thrombus Hyperthyroidism Depression Social History Smokes half pack of cigarettes/d Cocaine use approximately 3 times/wk Denies alcohol use Medications Furosemide 20 mg orally/d Lisinopril 2.5 mg orally/d Dapsone 100 mg orally/d (for Pneumocystis cariniii pneumonia prophylaxis) Aspirin 81 mg orally/d Methimazole 10 mg orally/d Text continues on page 21

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18 Clinical

Pharmacy Practice News • November 2013

Educational Review Table 1. Metabolism of Antiretroviral Drug Classes Text continued from page 16

This receptor is a transcription factor that, when activated, increases gene expression of CYP3A4,3 making more CYP3A4 enzyme available to metabolize agents. Transporter proteins, such as P-glycoprotein (Pgp), also may affect drug metabolism. Pgp is an energy-dependent efflux transporter and is present in both the liver and kidney, where it works to increase the clearance of drugs by moving molecules into the bile and urine.4 Finally, drug metabolism also can occur through glucuronidation involving enzymes such as uridine diphosphate (UDP)-glucuronosyltransferases (UGT).5 Currently, there are 6 classes of antiretroviral agents. These classes, however, have important differences in their metabolic pathways, resulting in a varying degree of DDI potential. Table 1 lists the primary modes of metabolism for the ART classes used in the treatment of HIV infection.2,6-8

Antiretroviral Class

Metabolism of Class or Agent

Nucleoside/nucleotide reverse transcriptase inhibitors

Metabolism does not involve the CYP pathway and excretion occurs through renal elimination

Non-nucleoside reverse transcriptase inhibitors

Metabolized by the CYP3A4 isoenzyme

Protease inhibitors

Metabolized by the CYP3A4 isoenzyme

Integrase strand transfer inhibitors

Raltegravir (Isentress, Merck) metabolized via glucuronidation; elvitegravir (component of Stribild, Gilead) metabolized via glucuronidation and by the CYP3A4 isoenzyme

CCR5 antagonists

Metabolized by the CYP3A4 isoenzyme and Pgp

Fusion inhibitors

Catabolism to amino acids

CCR5, C-C chemokine receptor type 5; CYP, cytochrome P450; Pgp, P-glycoprotein Based on references 2 and 6-8.

Table 2. Metabolic Effects of ART on Cytochrome P450 Isoenzymes Predicted Enzyme Effect Antiretroviral

3A4

2B6

2C9

2C19

2D6

1A2

Atazanavir (Reyataz, Bristol-Myers Squibb)

I

—

I

—a

—

I

Darunavir (Prezista, Janssen)

I

D

D

D

—a

D

—

—

PIs

Fosamprenavir (Lexiva, VIIV)

I/D

D

—

—

a

Step 2. Identify additional inhibition or induction effects of the ART involved.

Indinavir (Crixivan, Merck)

I

—

—

—

—

Lopinavir/ritonavir (Kaletra, Abbvie)

I

D

D

D

—a

D

It is important to recognize that many antiretroviral agents demonstrate additional CYP inhibition or induction properties, themselves.

This can, in turn, affect other agents metabolized by the CYP450 system.

For example, most protease inhibitors (PIs) exhibit CYP3A4 inhibition, whereas non-nucleoside reverse transcriptase inhibitors (NNRTIs) tend to be CYP3A4 inducers. Although CYP3A4 is the most common isoenzyme affected by ART, clinicians should be aware of the effect of ART on other CYP isoenzymes as well.

Table 2 shows the metabolic activity of antiretroviral agents on specific CYP isoenzymes.6,7,9,10

Nelfinavir (Viracept, VIIV)

I/D

—

D

D

—

D

Ritonavir (Norvir, AbbVie)

I

D

D

D

I

D

—

—

—

—

Saquinavir (Invirase, Genentech)

I

—

—

Tipranavir (Aptivus, Boehringer Ingelheim)

I

D

D

D

I

D

Efavirenz (Sustiva, Bristol-Myers Squibb)

D

D

I

D

I

I

Etravirine (Intelence, Janssen)

D

D

I

I

—

—

Nevirapine

D

D

D

—

—

—

Rilpivirine (Edurant, Janssen)

D

D

?

D

?

D

Raltegravir (Isentress, Merck)

—

—

—

—

—

—

Elvitegravir (component of Stribild, Gilead)

I

?

D

?

?

?

I

—

—

—

I

—

NNRTIs

INSTIs

Other

Step 3. Determine the potential effect of the DDI. As shown in Table 1, the CYP3A4 enzyme metabolizes both PIs and NNRTIs. Therefore, when these agents are combined with those that are CYP3A4 inducers, theoretically, a decrease in ART concentration can be expected. Such interactions can raise concern regarding decreased efficacy of the HIV regimen, resistance, and even virologic failure. Conversely, when PIs and NNRTIs are combined with CYP3A4 inhibitors, a theoretical increase in ART concentration is the likely outcome, resulting in a possible heightened risk for adverse events.

a

a

Cobsicistatb (component of Stribild, Gilead)

ART, antiretroviral therapy; D, induction; I, inhibition; I/D, mixed inhibition/induction; INSTIs, integrase strand transfer inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; ?, unknown a

Enzyme not affected at clinically relevant ART concentrations

b

Cobicistat is a CYP3A4 inhibitor that acts to “boost” elvitegravir to achieve therapeutic concentrations

Based on references 6, 7, 9, and 10.

Step 4. Select the most appropriate action to circumvent or manage the DDI. There are a variety of resources available to clinicians that offer guidance on managing DDIs. Drug compendia that include drug interaction checkers such as MICROMEDEX or LEXICOMP often are used as first-line

Tables continue on page 21

resources to identify potential DDIs. However, these sources also identify DDIs that may not be clinically significant. Therefore, clinicians should become familiar with the most up-todate HIV guidelines provided by the Department of Health and Human Services (DHHS), which offer specific recommendations and strategies for the management of clinically

important DDIs.2 The full prescribing information of specific antiretroviral agents also provides a host of information on DDIs. The case study shows the application of this stepwise approach.11,12 Clinically important DDIs with ART usually will warrant a recommendation to avoid a particular agent and Text continues on page 22

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Sandoz now offers Enoxaparin Sodium Injection, USP

WARNING: SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Please see brief summary of full prescribing information including boxed warning on following page.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. www.us.sandoz.com © 2013 Sandoz Inc., a Novartis company. All rights reserved.

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Enoxaparin Sodium Injection,USP WARNING: SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning.

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

- - - - - - INDICATIONS AND USAGE - - - - - Enoxaparin sodium injection, USP is a low molecular weight heparin [LMWH] indicated for: • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness • Inpatient treatment of acute DVT with or without pulmonary embolism • Outpatient treatment of acute DVT without pulmonary embolism • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI] • Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI] - - - - - - DOSAGE AND ADMINISTRATION - - - - - Indication

Dose

DVT prophylaxis in abdominal surgery

40 mg SC once daily

DVT prophylaxis in knee replacement surgery

30 mg SC every 12 hours

DVT prophylaxis in hip replacement surgery

30 mg SC every 12 hours or 40 mg SC once daily

DVT prophylaxis in medical patients

40 mg SC once daily

Inpatient treatment of acute DVT with or without pulmonary embolism

1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily*

Outpatient treatment of acute DVT without pulmonary embolism

1 mg/kg SC every 12 hours *

Unstable angina and non-Q-wave MI

1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration]

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients ≥75 years of age

0.75 mg/kg SC every 12 hours (no bolus) (with aspirin)

• See recommended durations for enoxaparin sodium injection therapy • *See recommendations regarding transitioning to warfarin therapy • Adjust the dose for patients with severe renal impairment

- - - - - - DOSAGE FORMS AND STRENGTHS - - - - - 100 mg/mL concentration: Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL 150 mg/mL concentration: Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/mL - - - - - - CONTRAINDICATIONS - - - - - Active major bleeding Thrombocytopenia with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium Hypersensitivity to enoxaparin sodium Hypersensitivity to heparin or pork products Hypersensitivity to benzyl alcohol [for multi-dose formulation only] - - - - - - WARNINGS AND PRECAUTIONS - - - - - Increased risk of hemorrhage: Use with caution in patients at risk Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage History of heparin-induced thrombocytopenia: Use with caution Thrombocytopenia: Monitor thrombocytopenia closely Interchangeability with other heparins: Do not exchange with heparin or other LMWHs Pregnant women with mechanical prosthetic heart valves and their fetuses may be at increased risk and may need more frequent monitoring and dosage adjustment

- - - - - - ADVERSE REACTIONS - - - - - Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea and nausea To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

- - - - - - DRUG INTERACTIONS - - - - - Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium injection or conduct close clinical and laboratory monitoring - - - - - - USE IN SPECIFIC POPULATIONS - - - - - Severe renal impairment: Adjust dose for patients with creatinine clearance <30 mL/min Geriatric patients: Monitor for increased risk of bleeding Patients with mechanical heart valves: Not adequately studied Hepatic Impairment: Use with caution Low-weight patients: Observe for signs of bleeding

Manufactured by Baxter Pharmaceutical Solutions LLC for Sandoz Inc., Princeton, NJ 08540 Rev. June 2013

Clinical 21

Pharmacy Practice News • November 2013

Educational Review Table 3. Examples of DDI Management Involving PIs ART

Interacting Agent(s)

ATV

PPIs

ATV/r

PPIs

All RTVboosted PIs

Mechanism of DDI

Effect

Management

Absorption interaction Atazanavir (Reyataz, BristolMyers Squibb) requires an acidic environment for absorption more so than the other PIs

Decrease in ATV absorption

PPIs are not recommended for use in patients receiving unboosted ATV; alternative acid-lowering therapy is recommended.

Fluticasone (inhaled or intranasal)

Metabolism interaction PIs are CYP3A4 inhibitors and fluticasone is a CYP3A4 substrate

Increase in fluticasone concentrations, which may result in adrenal suppression and Cushing syndrome

Use an alternative corticosteroid that is not a CYP3A4 substrate, such as beclomethasone (Qvar, Teva).

All PIs

St. John’s wort

Metabolism interaction St John’s wort is a substrate for the activation of PXR, which promotes availability of the CYP3A4 enzyme to metabolize PIs

Decrease in PI concentration, which may lead to resistance and virologic failure

Concomitant use of these agents is contraindicated.

All PIs

Simvastatin, lovastatin

Metabolism interaction PIs are CYP3A4 inhibitors and simvastatin and lovastatin are CYP3A4 substrates

Increase in HMG-CoA concentration, which is associated with a risk for statin-induced myopathy or rhabdomyolysis

Use an alternative statin that is not metabolized by the CYP3A4 isoenzyme (eg, fluvastatin is metabolized by the CYP2C9 isoenzyme, and pravastatin, rosuvastatin [Crestor, AstraZeneca], and pitavastatin [Livalo, Kowa] do not use the CYP450 pathway to a significant degree).

All PIs

Salmeterol

Metabolism interaction PIs are CYP3A4 inhibitors and salmeterol is a CYP3A4 substrate

Increase in salmeterol concentration is possible, resulting in an increased risk for salmeterol-associated cardiovascular events

Use an alternative long-acting β2 agonist that is not metabolized by CYP3A4; formoterol, a minor substrate of 2C9, is a reasonable option.

All PIs

Midazolam, triazolam

Metabolism interaction PIs are CYP3A4 inhibitors and midazolam and triazolam are CYP3A4 substrates

Increase in midazolam and triazolam concentrations

Use an alternative benzodiazepine, such as lorazepam, oxazepam, or temazepam; these agents are not metabolized via the CYP450 pathway and, therefore, have less of a DDI potential.

PPIs should not exceed a dose equivalent to omeprazole 20 mg daily in PI-naive patients; additionally, PPIs should be administered at least 12 h before ATV/r.

ATV, atazanavir; ATV/r, atazanavir boosted with ritonavir; CYP, cytochrome P450; DDI, drug–drug interaction; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; PIs, protease inhibitors; PPIs, proton pump inhibitors; PXR, pregnane X receptor; RTV, ritonavir

Text continued from page 16

Azithromycin 600 mg orally Tuesday and Thursday (for Mycobacterium avium complex prophylaxis) Rivaroxaban 20 mg orally/d Tramadol 50 mg orally q6h prn Most Recent Laboratory Data HIV RNA: 140,000 copies/mL CD4: 14 (1%) cells/mm3 Discussion MB’s CD4 count was significantly decreased, placing him at a high risk for opportunistic infections, so the health care team restarted ART to reduce the risk for AIDS-related mortality. The health care team wanted to restart the patient’s previous daily oral regimen of lopinavir 200 mg/ritonavir 50 mg (4 tablets) and emtricitabine 200 mg/tenofovir 300 mg (1 tablet). The team asked the pharmacist to assess for the appropriateness of this ART regimen, considering the patient’s history of nonadherence and to assess his current medication list for any DDI potential. The pharmacist used the stepwise approach to identify any DDIs with this medication regimen.

Step 1. Identify how the potentially interacting agents are metabolized. The PIs lopinavir and ritonavir are primarily metabolized by the CYP3A4 isoenzyme. Agents metabolized by this particular isoenzyme are commonly involved in DDIs.

Conversely, the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) emtricitabine and tenofovir are not metabolized by the CYP450 system and are less commonly involved in DDIs. Of the other non-HIV agents on the patient’s medication list, rivaroxaban also is a CYP3A4 substrate.11 Step 2. Identify additional inhibition or induction effects of the ART involved. Both lopinavir and ritonavir exhibit additional properties of inhibition and induction on CYP isoenzymes. In particular, both agents demonstrate CYP3A4 inhibition effects.

Step 3. Determine the potential effect of the DDI. The information gathered in steps 1 and 2 indicated that concomitant use of lopinavir and ritonavir with rivaroxaban may result in an increased effect of the direct factor Xa inhibitor through inhibition of the CYP3A4-mediated metabolism of the anticoagulant. This can increase the risk for bleeding associated with rivaroxaban.

Step 4. Select the most appropriate action to circumvent or manage the DDI. To avoid a heightened risk for bleeding for MB, the pharmacist created an alternative HIV regimen that did not pose this DDI. The standard of care is for ART regimens to comprise 2 NRTIs in addition to another agent from one of the other ART classes, most commonly with an NNRTI, a PI, or an integrase strand transfer inhibitor (INSTI).2 As noted above, using a PI will result in a DDI, so the agent selected should be from a different antiretroviral class. Because NNRTIs are CYP3A4

inducers, using an agent from the NNRTI class may result in a reduced anticoagulant effect of rivaroxaban and potentially could put the patient at an increased risk for a recurrent thrombotic event. Therefore, the pharmacist decided to avoid using the NNRTIs, and turned to the integrase inhibitors. The newest agent introduced to the market, Stribild, seemed appealing because it is formulated as a single tablet that combines elvitegravir with 3 other agents: cobicistat, emtricitabine, and tenofovir. Using “one tablet once daily” would simplify an HIV regimen and can promote improved adherence,12 but both elvitegravir and cobicistat exhibit CYP3A4 inhibition properties, which would result in a similar DDI mechanism as the one resulting in the DDI identified between PIs and rivaroxaban.

Raltegravir (Isentress, Merck), however, the first agent of the integrase class, is neither metabolized by the CYP450 system nor exhibits metabolic effects on CYP isoenzymes.

Treatment The pharmacist recommended initiation of raltegravir 400 mg orally twice daily in addition to emtricitabine 200 mg/tenofovir 300 mg 1 tablet orally daily. This new regimen presented no clinically meaningful DDIs with the patient’s other medications. After 2 weeks on the new regimen, the patient’s viral load decreased to 480 copies/mL and after an additional 4 weeks, his viral load became undetectable.

22 Clinical

Pharmacy Practice News • November 2013

Educational Review age, and concomitant medications. select alternative therapy or to make Therefore, the prudent pharmacist a dose adjustment. Table 3 describes should review all medications for some common and clinically impor- HIV patients to prevent or circumtant DDIs and includes various man- vent these interactions. Patients also agement strategies.2,3,13-20 Choosing should be encouraged to proactivean appropriate management strate- ly seek out pharmacists to review all gy helps to ensure both safety and of their over-the-counter and herbal efficacy of drug therapy. supplements in addition to their prescription medications to determine Conclusion DDI potential with their ART. The effect of DDIs may vary from patient to patient depending References on comorbidities, genetic factors, 1. Soodalter J, Sousa M, Boffito M. Drug-drug Text continued from page 18

interaction involving new antiretroviral drugs and drug classes. Curr Opin Infect Dis. 2009;22(1):18-27.

2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/ lvguidelines/AdultandAdolescentGL.pdf.

Accessed October 15, 2013.

3. Moore LB, Goodwin B, Jones SA, et al.

St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA. 2000;97(13):7500-7502.

4. Yu DK. The contribution of P-glycoprotein

to pharmacokinetic drug-drug interactions.

J Clin Pharmacol. 1999;39(12):1203-1211.

5. Williams JA, Hyland R, Jones BC, et al.

Drug-drug interactions for UDPglucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCI/AUC) ratios.

Drug Metab Dispos. 2004;32(11):1201-1208.

6. Isentress (raltegravir) [package insert].

Whitehouse Station, NJ: Merck & Co., Inc; August 2013.

7.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) [package insert]. Foster City, CA: Gilead Sciences, Inc; October 2013.

8. Fuzeon (enfuvirtide)[package insert].

South San Francisco, CA: Genentech; August 2012.

9. Rathbun RC, Liedtke MD. Antiretroviral drug interactions: overview of interactions involving new and investigational agents and the role of therapeutic drug monitoring for management.

Pharmaceutics. 2011;3(4):745-781.

10. Shah BM, Schafer JJ, Priano J, Squires KE. Cobicistat: a new boost for the treatment of human-immunodeficiency virus infection.

Pharmacotherapy. 2013;33(10):1107-1116.

What if those costs could be reduced?

11. Xarelto (rivaroxaban) [package insert].

Titusville, NJ: Janssen Pharmaceuticals; August 2013.

12. Airoldi M, Zaccarelli M, Bisi L, et al. Onepill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects.

Patient Prefer Adherence. 2010;4:115-125.

13. Falcon RW, Kakuda TN. Drug interactions between HIV protease inhibitors and acid-reducing agents. Clin Pharmacokinet.

2008;47(2):75-89.

Adverse drug events created by mistakes in a hospital pharmacy are expensive and can be fatal – especially when they involve IV medications.

Measurable costs for ADEs, such as extended hospitalizations and emergency intervention, can be thousands of dollars per event. And that doesn’t include the cost of litigation.

Unfortunately, mistakes are not infrequent. Manual IV Unfortuna compound compounding has numerous risk points that can result in ADEs – wro wrong drug, dose or concentration, incorrect labeling, contamination contam due to improper aseptic practices, cross contamination…

14. Tseng A, Foisy M. Important drug-drug interactions in HIV-infected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Rep. 2012;14(1):67-82.

15. Josephson F. Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A4 inhibition. J Intern Med. 2010;268(6):530-539.

16. Serevent Diskus (salmeterol xinafoate) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; January 2012.

17. Foradil Aerolizer (formoterol fumarate) [package insert]. Kenilworth, NJ: Schering Corporation; September 2012.

18. Ray GM. Antiretroviral and statin drug-drug interactions. Cardiol Rev. 2009;17(1):44-47.

19. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS. 2002;16(4):569-577.

Because of the high cost of mistakes, we created RIVA. With unmatched accuracy, accurac repeatability and multiple technologies to ensure the safety of every dose, RIVA helps reduce the cost of IV medication mistakes. Plus, RIVA lowers the cost-per-dose of medication, and reduces outsourcing and waste – savings that can provide an ROI of less than three years.

Because RIVA enhances safety, productivity and efficiency, pharmacy costs are more controllable than you thought.

™ RIVA is a technology of Intelligent Hospital Systems

Contact 1-888-778-RIVA (7482) | www.intelligenthospitals.com

20. Schachter M. Chemical, pharmacokinetic, and pharmacodynamic properties of statins: an update. Fundament Clin Pharmacol. 2005;19(1):117-125.

In our next issue, look for stories from The 2013 ASHP Conference for Leaders in Health-System Pharmacy

Policy 23

Pharmacy Practice News â&#x20AC;˘ November 2013

Oncology

IOM Report Warns of Impending Cancer Care Crisis

T

he growing demand for cancer care, combined with increasingly complex treatments, a shrinking workforce and rising costs, now constitutes â&#x20AC;&#x153;a crisisâ&#x20AC;? for the field, according to a new report from the Institute of Medicine (IOM).

Although the IOM report cited many deficiencies, one statement summed up its key conclusions: â&#x20AC;&#x153;[Cancer] care often is not patient-centered; many patients do not receive palliative care to manage their symptoms and side effects from treatment; and decisions about care often are not based on the latest scientific evidence,â&#x20AC;? the report stated.

Matthew Farber, the director of provider economics and public policy at the Association of Community Cancer Centers (ACCC), commented that â&#x20AC;&#x153;none

of the problems or solutions listed in the report are incredibly shocking,â&#x20AC;? but the study nevertheless â&#x20AC;&#x153;is a call to arms.â&#x20AC;?

The report proposes a conceptual framework for making improvements, outlines 10 goals and issues several recommendations (Table). Tom Smith, MD, one of the reportâ&#x20AC;&#x2122;s authors, and an oncologist and the director of palliative care at John Hopkinsâ&#x20AC;&#x2122; Sidney Kimmel Comprehensive Cancer Center in Balti-

more, said the following recommendations may make the most impact: that patients have written care plans; that clinicians provide detailed information to patients about benefits, risks and costs of treatment; and that any seriously ill patient has access to palliative care alongside usual oncology care. â&#x20AC;&#x153;Palliative care is the home run of American medicine,â&#x20AC;? Dr. Smith said. â&#x20AC;&#x153;First, people have better symptom

management and quality of life. Second, people have fewer hospital days and hospitalizations at the end of life.

Third base is people live at least as long, if not longer, with both hospice and palliative care. And fourth, it is care that we can actually afford.â&#x20AC;?

Removing reimbursement barriers to team-based care also is sorely needed, the IOM report noted. Some insurance

â&#x20AC;˘

see IOM REPORT, page 24

NOW AVAILABLE

Table. IOM Cancer Care Goals Provide patients with understandable information on cancer prognosis, treatment benefits and harms, palliative care, psychosocial support and estimates of total and out-of-pocket costs.

For adult patients with iron deficiency anemia (IDA) of various etiologies

Provide end-of-life care consistent with patientsâ&#x20AC;&#x2122; needs, values and preferences.

Ensure members of the cancer care team coordinate with one another and with primary/geriatric and specialist care teams to implement patient care plans and deliver comprehensive, efficient and patient-centered care.

Ensure the cancer care team has core competencies.

Expand breadth of cancer research data collected on cancer interventions for older adults and individuals with multiple comorbid conditions.

Expand the depth of data available for assessing interventions.

Develop an ethically sound health care information technology system that can â&#x20AC;&#x153;learnâ&#x20AC;? by enabling real-time analysis of data from cancer patients in a variety of care settings.

Develop a national quality-reporting program for cancer care as part of a learning health care system.

Reduce disparities in access to cancer care among vulnerable and underserved populations.

Improve the affordability of cancer care by leveraging existing efforts to reform payment and eliminate waste.

IMPORTANT SAFETY INFORMATION INDICATIONS/CONTRAINDICATIONS InjectaferÂŽ (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. InjectaferÂŽ is contraindicated in patients with hypersensitivity to InjectaferÂŽ or any of its inactive components.

WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving InjectaferÂŽ. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after InjectaferÂŽ administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer InjectaferÂŽ when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving InjectaferÂŽ. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.

In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each InjectaferÂŽ administration.

In the 24 hours following administration of InjectaferÂŽ, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in InjectaferÂŽ.

ADVERSE REACTIONS In two randomized clinical studies, a total of 1775 patients were exposed to InjectaferÂŽ, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by â&#x2030;Ľ2% of InjectaferÂŽ-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).

The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

InjectaferÂŽ is an iron replacement product indicated for the treatment of IDA in adult patients1 t X IP IBWF JOUPMFSBODF UP PSBM JSPO PS IBWF IBE VOTBUJTGBDUPSZ response to oral iron t XIP IBWF OPO EJBMZTJT EFQFOEFOU DISPOJD LJEOFZ EJTFBTF

Up to 750 mg can be delivered in a single dose*1 t Give 2 doses separated by at least 7 days for a total cumulative

dose of 1500 mg t " ENJOJTUFS JOUSBWFOPVTMZ CZâ&#x20AC; â&#x20AC;&#x201C; Infusion over at least 15 minutes â&#x20AC;&#x201C; Slow push injection at the rate of approximately 100 mg (2 mL) per minute over at least 7.5 minutes * For patients weighing 50 kg (110 lb) or more, give each dose as 750 mg. For patients weighing less than 50 kg (110 lb), give each dose as 15 mg/kg body weight. â&#x20AC;

When administered via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not <2 mg of iron per mL and administer over at least 15 minutes. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 mL) per minute.

NDC 0517-0650-01 For more information, please call American Regent Customer Service at 800-645-1706 or visit Injectafer.com For reimbursement assistance, please call the Reimbursement Hotline at 877-4-IV-IRON REFERENCE: 1. InjectaferÂŽ [package insert]. Shirley, NY: American Regent, Inc.; 2013.

InjectaferŽ is manufactured under license from Vifor (International) Inc., Switzerland. Š2013 American Regent, Inc. Printed in USA FCM002 Rev. 09/2013

Please see Brief Summary of the Full Prescribing Information on the following page.

24 Policy

Pharmacy Practice News â&#x20AC;˘ November 2013

Oncology

IOM REPORT

â&#x20AC;&#x2DC;[Cancer] care often is not patient-centered; many patients do not receive palliative care to manage their symptoms and side effects from treatment; and decisions about care often are not based on the latest scientific evidence.â&#x20AC;&#x2122;

continued from page 23

companies do not pay for a patient to see more than one physician per day, when oftentimes the ideal is to meet with a team of caregivers. Dr. Smith said new care models may remedy this, including bundled payments, accountable care organizations and oncology patient-centered medical homes.

To align clinical trial populations with those most commonly seen in a community clinic, the IOM recom-

Brief Summary of Full Prescribing Information

INJECTAFERÂŽ (ferric carboxymaltose injection)

â&#x20AC;&#x201D;Institute of Medicine mends rewarding companies with a six-month patent extension when they conduct drug trials in older patients or individuals with multiple comorbidi-

Rx Only

INDICATIONS AND USAGE: InjectaferÂŽ (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deďŹ ciency anemia in adult patients: s WHO HAVE INTOLERANCE TO ORAL IRON OR WHO HAVE HAD UNSATISFACTORY RESPONSE TO ORAL IRON

s WHO HAVE NON DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE DOSAGE AND ADMINISTRATION: &OR PATIENTS WEIGHING KG LB OR MORE 'IVE )NJECTAFERÂŽ in TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE &OR PATIENTS WEIGHING LESS THAN KG LB 'IVE )NJECTAFERÂŽ IN TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG KG BODY WEIGHT FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE InjectaferÂŽ TREATMENT MAY BE REPEATED IF IRON DElCIENCY ANEMIA REOCCURS Administer InjectaferÂŽ INTRAVENOUSLY EITHER AS AN UNDILUTED SLOW INTRAVENOUS PUSH OR BY INFUSION 7HEN ADMINISTERING AS A SLOW INTRAVENOUS PUSH GIVE AT THE RATE OF APPROXIMATELY MG M, PER MINUTE 7HEN ADMINISTERED VIA INFUSION DILUTE UP TO MG OF IRON IN NO MORE THAN M, OF STERILE SODIUM CHLORIDE INJECTION 530 SUCH THAT THE CONCENTRATION OF THE INFUSION IS NOT LESS THAN MG OF IRON PER M, AND ADMINISTER OVER AT LEAST MINUTES )NSPECT PARENTERAL DRUG PRODUCTS VISUALLY FOR THE ABSENCE OF PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION 4HE PRODUCT CONTAINS NO PRESERVATIVES )NJECTAFERÂŽ IS A SINGLE USE VIAL $ISCARD UNUSED PORTION !VOID EXTRAVASATION OF )NJECTAFERÂŽ SINCE BROWN DISCOLORATION OF THE EXTRAVASATION SITE MAY BE LONG LASTING -ONITOR FOR EXTRAVASATION )F EXTRAVASATION OCCURS DISCONTINUE THE )NJECTAFERÂŽ ADMINISTRATION AT THAT SITE DOSAGE FORMS AND STRENGTHS: 3INGLE USE VIALS CONTAINING MG ELEMENTAL IRON PER M, IN THE FOLLOWING PRESENTATION MG IRON M, CONTRAINDICATIONS: (YPERSENSITIVITY TO )NJECTAFERÂŽ OR ANY OF ITS INACTIVE COMPONENTS WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving InjectaferÂŽ. Patients may present with shock, clinically signiďŹ cant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after InjectaferÂŽ administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer InjectaferÂŽ when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. )N CLINICAL TRIALS

SERIOUS ANAPHYLACTIC ANAPHYLACTOID REACTIONS WERE REPORTED IN OF SUBJECTS RECEIVING InjectaferrÂŽ /THER SERIOUS OR SEVERE ADVERSE REACTIONS POTENTIALLY ASSOCIATED WITH HYPERSENSITIVITY WHICH INCLUDED BUT NOT LIMITED TO PRURITUS RASH URTICARIA WHEEZING OR HYPOTENSION WERE REPORTED IN OF THESE SUBJECTS Hypertension: )N CLINICAL STUDIES HYPERTENSION WAS REPORTED IN OF SUBJECTS IN CLINICAL TRIALS AND 4RANSIENT ELEVATIONS IN SYSTOLIC BLOOD PRESSURE SOMETIMES OCCURRING WITH FACIAL mUSHING DIZZINESS OR NAUSEA WERE OBSERVED IN OF SUBJECTS IN THESE TWO CLINICAL TRIALS 4HESE ELEVATIONS GENERALLY OCCURRED IMMEDIATELY AFTER DOSING AND RESOLVED WITHIN MINUTES -ONITOR PATIENTS FOR SIGNS AND SYMPTOMS OF HYPERTENSION FOLLOWING EACH )NJECTAFERÂŽ ADMINISTRATION Laboratory Test Alterations: )N THE HOURS FOLLOWING ADMINISTRATION OF )NJECTAFERÂŽ LABORATORY ASSAYS MAY OVERESTIMATE SERUM IRON AND TRANSFERRIN BOUND IRON BY ALSO MEASURING THE IRON IN InjectaferÂŽ ADVERSE REACTIONS Adverse Reactions in Clinical Trials: "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REmECT THE RATES OBSERVED IN CLINICAL PRACTICE )N TWO RANDOMIZED CLINICAL STUDIES A TOTAL OF PATIENTS WERE EXPOSED TO )NJECTAFERÂŽ MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON !DVERSE REACTIONS REPORTED BY t OF TREATED PATIENTS ARE SHOWN IN THE FOLLOWING TABLE 4ABLE !DVERSE REACTIONS REPORTED IN t OF 3TUDY 0ATIENTS IN #LINICAL 4RIALS AND

/RAL IRON InjectaferÂŽ 0OOLED #OMPARATORSa . . .

.AUSEA

Hypertension

&LUSHING (OT &LUSH

"LOOD 0HOSPHORUS $ECREASE

$IZZINESS

6OMITING

)NJECTION 3ITE $ISCOLORATION

Headache

Alanine Aminotransferase Increase

$YSGEUSIA

Hypotension

#ONSTIPATION

a Includes oral iron and all formulations of IV iron other than InjectaferÂŽ 4RANSIENT DECREASES IN LABORATORY BLOOD PHOSPHORUS LEVELS MG D, HAVE BEEN OBSERVED IN OF PATIENTS IN CLINICAL TRIALS 4ERM

ties. This is a tool used to encourage trials in pediatric populations.

Another important recommendation is for payers to implement payment models

Adverse Reactions from Post-marketing Experience: 4HE FOLLOWING SERIOUS ADVERSE REACTIONS HAVE BEEN MOST COMMONLY REPORTED FROM THE POST MARKETING SPONTANEOUS REPORTS WITH )NJECTAFERÂŽ: URTICARIA DYSPNEA PRURITUS TACHYCARDIA ERYTHEMA PYREXIA CHEST DISCOMFORT CHILLS ANGIOEDEMA

BACK PAIN ARTHRALGIA AND SYNCOPE /NE CASE OF HYPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A SUBJECT WHO RECEIVED MG OF )NJECTAFERÂŽ EVERY WEEKS FOR A TOTAL OF WEEKS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ DRUG INTERACTIONS: &ORMAL DRUG INTERACTION STUDIES HAVE NOT BEEN PERFORMED WITH )NJECTAFERÂŽ USE IN SPECIFIC POPULATIONS Pregnancy 0REGNANCY #ATEGORY # !DEQUATE AND WELL CONTROLLED STUDIES IN PREGNANT WOMEN HAVE NOT BEEN CONDUCTED )NJECTAFERÂŽ SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENElT JUSTIlES THE POTENTIAL RISK TO THE FETUS Nursing Mothers: ! STUDY TO DETERMINE IRON CONCENTRATIONS IN BREAST MILK AFTER ADMINISTRATION of InjectaferÂŽ N OR ORAL FERROUS SULFATE N WAS CONDUCTED IN LACTATING WOMEN WITH POSTPARTUM IRON DElCIENCY ANEMIA -EAN BREAST MILK IRON LEVELS WERE HIGHER IN LACTATING WOMEN RECEIVING )NJECTAFERÂŽ THAN IN LACTATING WOMEN RECEIVING ORAL FERROUS SULFATE Pediatric Use: 3AFETY AND EFFECTIVENESS HAS NOT BEEN ESTABLISHED IN PEDIATRIC PATIENTS Geriatric Use: /F THE SUBJECTS IN CLINICAL STUDIES OF )NJECTAFERÂŽ WERE YEARS AND OVER WHILE WERE YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE SUBJECTS AND YOUNGER SUBJECTS AND OTHER REPORTED CLINICAL EXPERIENCE HAS NOT IDENTIlED DIFFERENCES IN RESPONSES BETWEEN THE ELDERLY AND YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT OVERDOSAGE: %XCESSIVE DOSAGES OF )NJECTAFERÂŽ MAY LEAD TO ACCUMULATION OF IRON IN STORAGE SITES POTENTIALLY LEADING TO HEMOSIDEROSIS ! PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS DEVELOPED HEMOSIDEROSIS WITH MULTIPLE JOINT DISORDER WALKING DISABILITY AND ASTHENIA (YPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ DESCRIPTION: Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1ŕľş4)-O-Ë&#x17E;-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately 150,000 Da. InjectaferÂŽ FERRIC CARBOXYMALTOSE INJECTION IS A DARK BROWN STERILE AQUEOUS ISOTONIC COLLOIDAL SOLUTION FOR INTRAVENOUS INJECTION %ACH M, CONTAINS MG IRON AS FERRIC CARBOXYMALTOSE IN WATER FOR INJECTION 3ODIUM HYDROXIDE AND OR HYDROCHLORIC ACID MAY HAVE BEEN ADDED TO ADJUST THE P( TO 4HE VIAL CLOSURE IS NOT MADE WITH NATURAL RUBBER LATEX CLINICAL PHARMACOLOGY Mechanism of Action: &ERRIC CARBOXYMALTOSE IS A COLLOIDAL IRON ))) HYDROXIDE IN COMPLEX WITH CARBOXYMALTOSE A CARBOHYDRATE POLYMER THAT RELEASES IRON Pharmacodynamics: 5SING POSITRON EMISSION TOMOGRAPHY 0%4 IT WAS DEMONSTRATED THAT RED CELL UPTAKE OF Fe and Fe from InjectaferÂŽ RANGED FROM TO )N PATIENTS WITH IRON DElCIENCY

RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS )NJECTAFERÂŽ DOSE )N PATIENTS WITH RENAL ANEMIA RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS )NJECTAFERÂŽ DOSE Pharmacokinetics: !FTER ADMINISTRATION OF A SINGLE DOSE OF )NJECTAFERÂŽ OF TO MG OF IRON IN IRON DElCIENT PATIENTS MAXIMUM IRON LEVELS OF ÂŤG M, TO ÂŤG M, WERE OBTAINED RESPECTIVELY AFTER MINUTES TO HOURS POST DOSE 4HE VOLUME OF DISTRIBUTION WAS ESTIMATED TO BE , 4HE IRON INJECTED OR INFUSED WAS RAPIDLY CLEARED FROM THE PLASMA THE TERMINAL HALF LIFE RANGED FROM TO HOURS 2ENAL ELIMINATION OF IRON WAS NEGLIGIBLE NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility: #ARCINOGENICITY STUDIES HAVE NOT BEEN PERFORMED WITH FERRIC CARBOXYMALTOSE &ERRIC CARBOXYMALTOSE WAS NOT GENOTOXIC IN THE FOLLOWING GENETIC TOXICOLOGY STUDIES in vitro MICROBIAL MUTAGENESIS !MES ASSAY in vitro CHROMOSOME ABERRATION TEST o IN HUMAN LYMPHOCYTES

in vitroo MAMMALIAN CELL MUTATION ASSAY IN MOUSE LYMPHOMA , 9 4+ CELLS in vivoo mouse MICRONUCLEUS TEST AT SINGLE INTRAVENOUS DOSES UP TO MG KG )N A COMBINED MALE AND FEMALE FERTILITY STUDY FERRIC CARBOXYMALTOSE WAS ADMINISTERED INTRAVENOUSLY OVER ONE HOUR TO MALE AND FEMALE RATS AT IRON DOSES OF UP TO MG KG !NIMALS WERE DOSED TIMES PER WEEK ON $AYS

AND 4HERE WAS NO EFFECT ON MATING FUNCTION FERTILITY OR EARLY EMBRYONIC DEVELOPMENT 4HE DOSE OF MG KG IN ANIMALS IS APPROXIMATELY OF THE HUMAN DOSE OF MG BASED ON BODY SURFACE AREA CLINICAL STUDIES: 4HE SAFETY AND EFlCACY OF )NJECTAFERÂŽ for treatment of iron deďŹ ciency anemia WERE EVALUATED IN TWO RANDOMIZED OPEN LABEL CONTROLLED CLINICAL TRIALS 4RIAL AND 4RIAL )N THESE TWO TRIALS )NJECTAFERÂŽ WAS ADMINISTERED AT DOSE OF MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON PATIENT COUNSELING INFORMATION s 1UESTION PATIENTS REGARDING ANY PRIOR HISTORY OF REACTIONS TO PARENTERAL IRON PRODUCTS s !DVISE PATIENTS OF THE RISKS ASSOCIATED WITH )NJECTAFERÂŽ s !DVISE PATIENTS TO REPORT ANY SIGNS AND SYMPTOMS OF HYPERSENSITIVITY THAT MAY DEVELOP DURING AND FOLLOWING )NJECTAFERÂŽ ADMINISTRATION SUCH AS RASH ITCHING DIZZINESS LIGHTHEADEDNESS SWELLING AND BREATHING PROBLEMS InjectaferÂŽ IS MANUFACTURED UNDER LICENSE FROM 6IFOR )NTERNATIONAL )NC 3WITZERLAND

that incentivize discussions about clinical options, cost of care and end-of-life care issues. Robert Arnold, MD, the chief of palliative care and medical ethics at the University of Pittsburgh School of Medicine, says physicians who have endof-life care discussions currently bill their time under general counseling Current Procedural Terminology, or CPT, codes.

He thinks having specific CPT codes for an end-of-life conversation will help. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s an uncomfortable conversation and itâ&#x20AC;&#x2122;s a financial loser, so everything is against it,â&#x20AC;?

Dr. Arnold said. â&#x20AC;&#x153;I think if you tell doctors we support it [by having a specific code], the symbolism is really important. It says, â&#x20AC;&#x2DC;this is something from a societal point of view that we want you to do.â&#x20AC;&#x2122;â&#x20AC;?

According to Virginia Vaitones, MSW, the president of the ACCC, educating patients about all aspects of chemotherapy treatment takes at least an hour. It is not reimbursable if undertaken by nurses and only partially reimbursable when done by doctors. She thinks having more thorough discussions up front will save money in the long run, and she sees the new codes coming to fruition within the next five years. A precedent for having specialized consultation codes has been setâ&#x20AC;&#x201D;an existing diabetes management code can be used as an example.

Many clinicians hope the reportâ&#x20AC;&#x2122;s focus on patient-centered care will encourage research in this area. Current clinical trials are rarely designed to provide information to a patient who is going to live with treatment-related side effects and long-term sequelae. â&#x20AC;&#x153;The older oncology literature is really focused on things like survival and recurrence,â&#x20AC;? said Benjamin Smith, MD, an oncologist at University of Texas MD Anderson Cancer Center in Houston. â&#x20AC;&#x153;Those are helpful, but they donâ&#x20AC;&#x2122;t tell the whole story of the way a patient experiences an illness.â&#x20AC;?

Dr. Smith, who also is a health services researcher, believes the IOM report will make waves. â&#x20AC;&#x153;I think IOM reports carry quite a bit of weight,â&#x20AC;? he said. As evidence, he pointed to a 1999 IOM report that concluded the gaps in cancer care need further study. â&#x20AC;&#x153;There has been a dramatic proliferation of cancer-related health services research between the time that report was published and the present day,â&#x20AC;? he said. â&#x20AC;&#x153;Given there is a historical precedent, I am hopeful that this IOM report will have an impact.â&#x20AC;?

)SS

â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke

Policy 25

Pharmacy Practice News • November 2013

Medication Safety

Tygacil Gets Black Box Warning on Increased Risk for Death

T

he FDA has issued a black box warning label for the IV antibiotic tigecycline because patients receiving the drug have an increased mortality risk.

In 2010, the FDA issued a safety alert linking tigecycline (Tygacil, Pfizer) to an increased risk for death, but the agency did not add a warning label until now.

Dorothy McCoy, PharmD, BCPS-ID, a clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers University, in Piscataway, N.J., said the antibiotic’s risks are well known to many infectious disease pharmacists. “This is not surprising.”

For the watchdog organization Public Citizen, the label change is not only unsurprising, but it comes a few years too late. “The requirement for a black box warning was a step in the right direction,” said Michael Carome, MD, the director of Public Citizen’s Health Research Group.

“But it was not timely, in our view.”

In October 2011, the Health Research Group petitioned the FDA to add a warning label to the antibiotic, stating that tigecycline “should be used only as a last-resort antibiotic in the treatment of serious infections, and then only in com-

bination with one or more bactericidal antibiotics.” Dr. Carome said Public Citizen isn’t seeking the removal of the drug by the FDA but wants the agency to make sure providers are aware of its risks.

The FDA based its latest decision on a meta-analysis of 10 studies that showed increased mortality among patients receiving tigecycline. According to the FDA review, of 2,640 patients who received tigecycline, 2.5% died, versus 1.8% of 2,628 patients who were given other antibiotics. The adjusted risk difference for death was 0.6% (95% confidence interval [CI], 0.0-1.2%). The FDA attributed the majority of deaths to infection complications, worsening infections and other underlying medical conditions.

“This information is the same information the FDA had three years ago,” Dr. Carome said. “The trend has been a consistent signal since 2010.” The FDA made no comment on this point.

A previous meta-analysis of 13 Phase III and IV trials, cited by the FDA in its 2010 statement, also demonstrated an increased risk for death. Among 3,788 patients who received tigecycline, 148 deaths occurred (4% mortal-

ity), compared with 106 deaths among 3,646 patients (3% mortality) who were administered other antimicrobials, resulting in an adjusted risk difference of 0.6% (95% CI, 0.1%-1.2%) (FDA Drug Safety Communication, 2010).

“The higher death rate in some populations of patients with severe illness has been known with Tygacil monotherapy,” according to Gary Stein, PharmD, a professor of medicine and pharmacology in the Division of Infectious Diseases at Michigan State University, East Lansing.

When the FDA approved tigecycline in 2005, the drug was the first glycylcycline, a tetracycline derivative, available for use in a clinical setting. Tigecycline binds to the 30S subunit of microbial ribosomes and disrupts protein translation inside bacteria. The antibiotic is indicated for complicated skin and skin structure infections, complicated intraabdominal infections and community-acquired bacterial pneumonia.

The FDA has not approved tigecycline for diabetic foot infection or hospitalacquired pneumonia, including ventilator-associated pneumonia.

Although Public Citizen welcomed

the FDA’s addition of a black box warning label to tigecycline, Dr. Carome said he would like to see Pfizer release a Dear Doctor letter. “It’s most important that the physician prescribers understand this risk,” he said.

At Hackensack University Medical Center, in New Jersey, where Dr. McCoy practices, tigecycline is listed as a restricted antibiotic under the institution’s antibiotic stewardship program.

Infectious disease clinicians prescribe other agents first, reserving tigecycline for cases of allergic reactions or multidrug resistance. “If you have a resistant gram-negative organism, when you can’t use the first-, second- or third-line choices,” Dr. McCoy said, “you might [still] look to use this agent. That’s probably how most people have used it, and that’s why the warning might not change [practice] much.”

—Ben Guarino Drs. Carome and McCoy reported no relevant financial conflicts of interest. Dr. Stein reported receiving research grants from Pfizer.

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26 Operations & Management

Pharmacy Practice News • November 2013

Quality Improvement

BENCHMARKING continued from page 1

comes and downstream savings. Unfortunately, “pharmacists are often not well positioned to develop a business case for their current services,” said Ernest R. Anderson Jr., MS, RPh, a former director of pharmacy at two multihospital systems in Massachusetts who is helping with the launch of the new comparison tool, called BenchmaRx. “Often we see clinical services being challenged when [assessed using] outdated productivity metrics by nonpharmacist consultants who have little understanding of the bigger picture,” Mr. Anderson said. “As hospitals cut pharmacy staff, oftentimes the utilization of expensive but easier-toprepare drugs increases.”

What is the disconnect that leads to such ill-conceived decision making?

“I think part of the problem is that some consultants don’t understand a very basic but important fact about pharmacy departments,” Mr. Anderson said. “Unlike other hospital departments where staffing accounts for the bulk of expenses, 75% to 80% of hospital pharmacy spending is drug-related,” he explained. “So if you cut staff, you actually impede the ability of that staff to manage those drug costs effectively.

It’s a very shortsighted approach that I have seen actually increase overall hospital-wide costs.”

To fight off hasty personnel cuts, “you can’t just go into the C-suite with a strongly worded argument in support of your staffing levels,” he said. “You need data to make the case that your department not only saves money but actually contributes to the hospital’s bottom line via its clinical and operational interventions—and that you’re doing so at a high level compared to other facilities. BenchmaRx can help you make that case.”

Factoring Outcomes BenchmaRx collects data on drug utilization, 30-day hospital readmission rates, the use of pharmacy residents and other key areas of pharmacy operations. Although other benchmarking tools measure those criteria, the new initiative has several crucial points of differentiation, according to its developers, not the least of which is the ability to correlate these performance areas with patient outcomes.

“What we ultimately want to be able to say is ‘if you want to achieve the best clinical and financial outcomes, these are the staffing skills, in-hospital positioning and other metrics that you want to target to achieve your ideal outcomes,” said BenchmaRx founder Richard Ptachcinski, PharmD. “Identifying these targets is the struggle we’ve

Patient complexity, as measured by a hospital’s Case Mix Index (CMI), can have a significant effect on drug utilization. CMI therefore can be used to normalize the data when comparing hospitals with different patient acuity levels. In this sample report from BenchmaRx, a hospital’s purchases are being compared at the 25th and 50th percentiles, which indicate when the hospital is doing better or worse than other facilities in the database and where opportunities for improvement exist.

‘Our vision is to create a benchmarking tool that is the national standard for hospital pharmacies. We believe such a product will help the profession of pharmacy advance.’

—Ernest R. Anderson Jr., MS, RPh faced for the last 30-odd years.”

Another important distinguishing feature of BenchmaRx is the scope of its comparative database, said Dr. Ptachcinski, who is also the president of American Pharmacotherapy, LLC, based in Windermere, Fla. The comparison tool, he noted, measures operational efficiencies and other metrics culled from a nationwide sampling of institutions that employ a variety of technologies, staffing and distribution models. Participating hospitals contract with group purchasing organizations (GPOs) and wholesalers on a similarly nationwide basis.

As of mid-October, the BenchmaRx database included approximately 60 hospital pharmacies from across the

country, according to its developers.

That broadly representative client base is something that the developers hope to continue to attract, they said, because it would be an improvement over the databases of other benchmarking services, which typically include data from hospital pharmacies in a single GPO, wholesaler or health system. “Benchmarking services owned by wholesalers or GPOs pretty much only include their own price data set and it is obviously not in their best interest to tell you someone else is offering a better price,” Dr. Ptachcinski said.

He added that internal BenchmaRx analyses have found there can be significant pricing variability between hospitals, even if they are in the same health

‘If a pharmacy falls above the median for a drug or therapeutic category, we use that as a first step to look for opportunities for potential savings.’

—Richard Ptachcinski, PharmD

This graph from the BenchmaRx service depicts potential opportunities for cost savings by therapeutic class.

system and under the same contract.

Moreover, BenchmaRx’s price analyses are comprehensive, matching a department’s drug prices to national drug codes, generic product identifiers and generic product packaging codes. “With these matches, we’re sure that we’re truly doing a fair comparison,” he said.

Additionally, BenchmaRx’s cost analyses take any institutional volumebased drug rebates into account, tying purchase volumes and market share data into the analyses and also grouping hospitals according to 340B eligibility, Dr. Ptachcinski explained. The data from all hospitals are aggregated into percentile categories and an individual department can get a sense of where it stands in relation to the mixed nationwide sampling.

Kaiser Sees Value W. Perry Flowers, RPh, MS, the vice president of acute and transitional care, national pharmacy programs and services at Kaiser Permanente, headquartered in Oakland, Calif., said that a national database with broadly representative pricing information is something even large organizations like his, with its substantial purchasing power, would welcome. “The thing we’re all after, and that has eluded the vast majority of health care systems, is drug pricing benchmarking data, and it’s this kind of data that is by far the single hardest thing to obtain in a way that yields a critical mass of information that produces a fair comparison,” said Mr. Flowers, who is not involved with the BenchmaRx initiative.

GPOs and wholesalers—the ultimate source of drug pricing data—are, of course, protective of these numbers, Mr. Flowers said. He added that BenchmaRx’s clients may represent most of the major GPOs and wholesalers, but the database would need to grow substantially in numbers of participating entities to reach the truly representative critical mass to which he alluded.

Drug Utilization The drug utilization benchmarking included in the new initiative is based on analyzing data by site of care, including inpatient, outpatient and ambulatory care—a feature most benchmarking systems do not include, Dr. Ptachcinski noted. “The overall economic end points are very different for these settings,” he said. “Reimbursement, cost and margin must be considered in the outpatient and ambulatory care settings.”

The BenchmaRx tool calculates utilization trends based on several interrelated criteria, including patient acuity, patient days in the hospital, an overall case mix index and total utilization costs, with the resultant utilization trends

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28 Operations & Management

Pharmacy Practice News • November 2013

Quality Improvement

BENCHMARKING continued from page 26

plotted on a monthly, quarterly, semiannual and annual basis. BenchmaRx includes suggestions for drug alternatives in the same therapeutic category or in the grouping of medications used for the same disease state, Dr. Ptachcinski noted. “If a pharmacy falls above the median for a drug or therapeutic category, we use that as a first step to look for opportunities for potential savings,” he said, noting that clients are asked to

submit data on a monthly basis.

BenchmaRx’s utilization metrics are strong, Mr. Flowers noted, although he pointed out that other benchmarking services use the same ones. Still, such metrics “are absolutely necessary when looking at the total cost of care for health systems.”

Dr. Ptachcinski reiterated that BenchmaRx does, in fact, have an important distinguishing feature—it can be used by facilities to correlate a wide variety of performance metrics with quality outcomes. The operational met-

rics they look at include departmental staff numbers, ratios of pharmacists to support personnel, the presence of pharmacy residents, distribution and clinical models, the technologies used, multihospital integration and educational programs. Quality outcomes include a hospital pharmacy’s placement on the Pharmacy Practice Model Initiative, their hospital care quality information from the Consumer Perspective survey scores and their 30-day readmission rates, as well as the total cost of care per patient.

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At the time of this writing, the BenchmaRx team was still collecting these operational data and had not yet identified correlations between operational factors and quality outcomes.

Challenges Ahead One challenge BenchmaRx is facing in creating the correlative model is that operational metrics are defined differently across institutions, Mr. Anderson noted. Mr. Anderson said he and Dr. Ptachcinski hope to work with the American Society of Health-System Pharmacists (ASHP), the American College of Clinical Pharmacy and other organizations to identify those operational metrics that best represent current practice and to create standard definitions for them.

“Our vision is to create a benchmarking tool that is the national standard for hospital pharmacies,” Mr. Anderson said.

“We believe such a product will help the profession of pharmacy advance.”

Standardized operational measures are something the hospital pharmacy practice industry needs, Mr. Flowers agreed. “Health care organizations don’t always classify patient days the same way, for example,” he said. “So the efforts that Mr. Anderson and Dr. Ptachcinski are making to work with ASHP and the ACCP and establish standardized nationwide definitions would be beneficial.”

In the interim, Marianne Ivey, PharmD, MPH, a professor of pharmacy practice at the University of Cincinnati, who is not involved with BenchmaRx, said the service’s current metrics are “very good ones that I have included on my pharmacy performance dashboard in the past.” Regarding whether the BenchmaRx service is a nationally representative database, she said, “while 60 hospitals is a nice number, I would need to see details on the number of hospitals [with] different bed size, hospital types, geographic spread and other characteristics.”

Other benchmarking options include Premier Inc.’s Spend Advisor and VHA Pharmacy’s Spend Analytics.

—David Wild Mr. Flowers reported no relevant financial conflicts of interest. Dr. Ivey reported that she is on the Executive Alliance Advisory Board of McKesson. Mr. Anderson reported that he is a consultant with BenchmaRx.

Comment? * In prescriptions of unbranded generics per IMS, June 2012

a mn ea l. com Copyright © 2012 Amneal Pharmaceuticals, All Rights Reserved - AMN-PPN-1012

Which hi h b benchmarking h ki tools l d do you use to ensure optimal pharmacy performance?

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Q & A 29

Pharmacy Practice News • November 2013

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30 Operations & Management

Pharmacy Practice News • November 2013

Leadership

Build Pharmacy’s ‘Brand’ To Gain C-suite Leverage Chicago—Hospital and health-system pharmacies are well positioned to become major strategic decision makers within their organizations, with more chief pharmacy officers at the helm. But to win influence and possibly even a position among senior leadership, they need to take ownership of what they do, tell the story of who they are, and develop a brand identity as both a business and a comprehensive clinical service line, according to a health care consultant presenting at the Fall 2013 meeting of the Hematology/Oncology Pharmacy Association (HOPA).

The current health care environment, in which medication is playing an increasingly central role and pharmacies often manage huge budgets, offers a golden opportunity for pharmacies to become key influencers, said James A. Jorgenson, RPh, FASHP, the chief operating officer of Visante, Inc., a Minneapolis-based consulting group specializing in medicines management and pharmacy. Actually getting to that point, however, requires first overcoming the common perception of pharmacy as a mere commodity or an ancillary service. That entails aggressively communicating with senior leaders about the business of pharmacy, and how that business aligns and resonates with the core issues of finance and patient safety/clinical quality that are foremost in health care decision makers’ minds, Mr. Jorgenson said.

The pharmacy brand should exude quality, Mr. Jorgenson added, “so that when the going gets tough, leadership comes to us.” Most hospitals and health systems now have chief nursing officers because nurses have the highest head counts of any clinical care group and play a critical role in patient care.

A comparable awareness of pharmacy’s clinical contributions and role as a leading revenue generator through medications is still lacking in many institutions. As a result, pharmacy typically is not present at the C-suite table, even though it’s a critical player in the care delivery process, he said. “We need to educate the C-suite on the value that we bring. They see the resources going in, but they don’t understand what’s coming out for the investment.”

A Stepwise Plan For Gaining Access To generate that awareness, build a brand and communicate persuasively with senior leadership, Mr. Jorgenson encouraged pharmacies to use these approaches: Look for crisis opportunities. This can be done by stepping forward, delivering under pressure, becoming known

for clinical and financial competencies, and showing that you understand the larger issues around safety, quality and cost. For example, pharmacies need to continually demonstrate to the C-suite the financial consequences of lapses in safety related to medication errors and how pharmacy is instrumental in preventing those errors.

Increase pharmacy’s visibility by producing an annual report. “You need to let leaders know on an annual basis what you do,” Mr. Jorgenson said.

As chief pharmacy officer of Indiana University Health, in Indianapolis, he distributed a 60-page pharmacy report to the board of directors every year.

Each of these reports began with a compelling patient story.

Develop a strategic plan. “How do you know where you’re going if you don’t have a plan?” he said. Modified every three to five years, the plan should support the organization’s larger goals and objectives, and involve everyone in the pharmacy service line. This plan can serve as a tool for conversations with senior leaders.

Create a marketing plan. “What do you do to market the business of pharmacy?” Mr. Jorgenson said. Whether on a website, through a blog or with some other combination of communication channels, “you have to keep sending the message about what you do,” he said. At his institution, Mr. Jorgenson published a patient story every month highlighting pharmacy’s role. Pharmacy staff also participated in a monthly radio show on medication-related topics of community interest. “Whatever you do, do it regularly,” he advised.

your message acro oss to them in 100 word ds or less?” he said.

Jettison the jargon. Frame your presentations and interactions around your audience’s schema, whether it i is financial, regulatory or something else. Avoid “pharm macyspeak.” Use the lan nguage your audience understands. erstands.

Know Your Audience Andrew J. Donnelly, PharmD, MBA, the director of pharmacy at the University of Illinois Hospital and Health Sciences System, in Chicago, echoed the importance of keeping the audience’s frame of reference in mind. “The information I present to the chief financial officer about a particular initiative will be different from what I provide to the chief medical officer,” he said.

In presenting to senior executives, Mr. Jorgenson advised pharmacists to: Ask for what you want. Let them know right up front what you want to accomplish. Example: Pharmacy has no regular full-time presence in one of the adult oncology clinics and in the pediatric oncology clinic, so I am requesting full-time clinical pharmacy services for both of those locations.

Dr. Donnelly also stressed the importance of clarity and brevity. “When I meet with our CEO, I bring an agenda listing current issues that need to be addressed. This helps the meeting stay

‘We need to educate the C-suite on the value that we bring. They see the resources going in, but they don’t understand what’s coming out for the investment.’

—James A. Jorgenson, RPh, FASHP Tell a story. Because pharmacies often lack decision-making authority within the senior ranks, make skillful use of influence and advocacy, particularly through storytelling, in communicating with senior leadership. “Stories create understanding; they’re believable; and they get the listener engaged,” he said. Tell a relevant patient story to illustrate your point.

Less is more. To communicate persuasively with senior executives, focus on what your C-suite wants to know, and be concise about it. “Can you get

focused and the discussion relevant to the issues presented,” he said.

Use experts to bolster support for your position. An example would be a position paper by the chief of hematology/oncology detailing the risks to patients of an inconsistent pharmacy presence in the oncology clinics.

Use data to support your case.

Example: Chemotherapy is being administered to 10 to 12 patients daily without prior authorization. This is costing more than $2 million annually in collectable revenue. “The success of

any request made to senior leadership, whether it is for additional staffing or new technology, will depend in large part on the data yyou present,” addeed Dr. Donnelly. “As such, it needs to be as crredible and comprehensivve as possible.”

Incorp porate an emotional component. componen Example: These are very powerful drugs with severe side effects that must be administered very carefully. These drugs are among our most expensive and need special handling. No one is better equipped to manage these tasks than pharmacy.

Refer to a track record that they know and trust. Example: This proposal is very similar to the cardiology enhancements that we successfully implemented last year.

Stress the time-sensitive nature of your proposal to create a sense of urgency. Example: Every day that we delay in having these patients seen by pharmacy further increases our financial and clinical risk profile.

Use reliable and familiar external data sources. Example: Our collection rate for percentage of billed charges is significantly lower than that of comparator organizations. We are writing off $11 million in potential appeals annually where pharmacy could help.

Close the deal. End your presentation by asking for a commitment. Example: Given all of the evidence for improving the care of this high-risk population and the cost savings associated with it, can we move forward with creating additional pharmacy oncology positions?

Dr. Donnelly said when he receives a commitment, he also offers to help move it forward. “Given how busy senior administration is, this can help prevent a delay in realizing what was approved,” he said.

Health care faces some major problems, particularly related to balancing demands concerning quality, safety and cost, Mr. Jorgenson said. “Pharmacy needs to step up and be a solution to these problems. We make a lot of things look easy, but we don’t get credit for it.

We’re only relevant when something bad happens. We need to position ourselves so we are seen as key to the concerns that are keeping senior leaders up at night.”

—Susan Birk Mr. Jorgenson and Dr. Donnelly reported no relevant financial conflicts of interest.

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32 Ops & Mgmt

Hospital Medicine

BRIEF SUMMARY

Adenosine Injection USP FOR INTRAVENOUS INFUSION ONLY INDICATIONS AND USAGE Intravenous adenosine is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately (see WARNINGS).

CONTRAINDICATIONS Intravenous adenosine injection should not be administered to individuals with: 1. Second- or third-degree AV block (except in patients with a functioning artificial pacemaker).

2. Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker).

3. Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma).

4. Known hypersensitivity to adenosine.

WARNINGS Fatal Cardiac Arrest, Life Threatening Ventricular Arrhythmias, and Myocardial Infarction Fatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and nonfatal myocardial infarction have been reported coincident with adenosine infusion. Patients with unstable angina may be at greater risk. Appropriate resuscitative measures should be available.

Sinoatrial and Atrioventricular Nodal Block Adenosine injection exerts a direct depressant effect on the SA and AV nodes and has the potential to cause first-, second- or third-degree AV block, or sinus bradycardia. Approximately 6.3% of patients develop AV block with adenosine, including firstdegree (2.9%), second-degree (2.6%), and thirddegree (0.8%) heart block. Adenosine can cause sinus bradycardia. Adenosine should be used with caution in patients with pre-existing first-degree AV block or bundle branch block and should be avoided in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Adenosine should be discontinued in any patient who develops persistent or symptomatic high-grade AV block. Sinus pause has been rarely observed with adenosine infusions.

Hypotension Adenosine injection is a potent peripheral vasodilator and can cause significant hypotension. Patients with an intact baroreceptor reflex mechanism are able to maintain blood pressure and tissue perfusion in response to adenosine by increasing heart rate and cardiac output. However, adenosine should be used with caution in patients with autonomic dysfunction, stenotic valvular heart disease, pericarditis or pericardial effusions, stenotic carotid artery disease with cerebrovascular insufficiency, or uncorrected hypovolemia, due to the risk of hypotensive complications in these patients. Adenosine should be discontinued in any patient who develops persistent or symptomatic hypotension.

Hypertension Increases in systolic and diastolic pressure have been observed (as great as 140 mm Hg systolic in one case) concomitant with adenosine infusion; most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours.

Bronchoconstriction Adenosine injection is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis. Approximately 28% of patients experience breathlessness (dyspnea) or an urge to breathe deeply with adenosine. These respiratory complaints are transient and only rarely require intervention.

Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release. These effects have not

been observed in normal subjects. Adenosine has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenosine should be discontinued in any patient who develops severe respiratory difficulties.

Atrial Fibrillation Atrial fibrillation has been reported in patients (with and without a history of atrial fibrillation) undergoing myocardial perfusion imaging with adenosine infusion. In these cases, atrial fibrillation began 1.5 to 3 minutes after initiation of adenosine, lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm.

PRECAUTIONS Drug Interactions Intravenous adenosine injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine should be used with caution in the presence of these agents.

The vasoactive effects of adenosine are inhibited by adenosine receptor antagonists, such as methylxanthines (e.g., caffeine and theophylline).

The safety and efficacy of adenosine in the presence of these agents has not been systematically evaluated.

The vasoactive effects of adenosine are potentiated by nucleoside transport inhibitors, such as dipyridamole. The safety and efficacy of adenosine in the presence of dipyridamole has not been systematically evaluated.

Whenever possible, drugs that might inhibit or augment the effects of adenosine should be withheld for at least five half-lives prior to the use of adenosine.

Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of adenosine injection. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.

Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

Fertility studies in animals have not been conducted with adenosine.

Pregnancy Teratogenic Effects Pregnancy g y category g yC Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. Because it is not known whether adenosine can cause fetal harm when administered to pregnant women, adenosine should be used during pregnancy only if clearly needed.

Pediatric Use The safety and effectiveness of adenosine in patients less than 18 years of age have not been established.

Geriatric Use Clinical studies of adenosine did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently.

Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients. Greater sensitivity of some older individuals, however, cannot be ruled out.

ADVERSE REACTIONS The following reactions with an incidence of at least 1% were reported with intravenous adenosine among 1421 patients enrolled in controlled and uncontrolled U.S. clinical trials. Despite the short half-life of adenosine, 10.6% of the side effects occurred not with the infusion of adenosine but several hours after the infusion terminated. Also, 8.4% of the side effects that began coincident with the infusion persisted for up to 24 hours after the infusion was complete. In many cases, it is not possible to know whether these late adverse events are the result of adenosine infusion.

Flushing 44% Chest discomfort 40% Dyspnea or urge to breathe deeply 28% Headache 18% Throat, neck or jaw discomfort 15% Gastrointestinal discomfort 13% Lightheadedness/dizziness 12% Upper extremity discomfort 4% ST segment depression 3% First-degree AV block 3% Second-degree AV block 3% Paresthesia 2% Hypotension 2% Nervousness 2% Arrhythmias 1% Adverse experiences of any severity reported in less than 1% of patients include: Body as a Whole Back discomfort; lower extremity discomfort; weakness Cardiovascular System Nonfatal myocardial infarction; life-threatening ventricular arrhythmia; third-degree AV block; bradycardia; palpitation; sinus exit block; sinus pause; sweating; T-wave changes; hypertension (systolic blood pressure > 200 mm Hg) Central Nervous System Drowsiness; emotional instability; tremors Genital/Urinary System Vaginal pressure; urgency Respiratory System Cough Special Senses Blurred vision; dry mouth; ear discomfort; metallic taste; nasal congestion; scotomas; tongue discomfort Postmarketing Experience (See WARNINGS.) The following adverse events have been reported from marketing experience with adenosine.

Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, (3) strength of causal connection to the drug, or a combination of these factors.

Body as a Whole Injection site reaction Central Nervous System Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness Digestive Nausea and vomiting Respiratory Respiratory arrest, throat tightness

Teva Pharmaceuticals USA Sellersville, PA 18960 Rev. B 9/2012

Obese Patients Use More Resources Perioperatively

P

atients who are morbidly obese use more hospital resources in the perioperative period, including longer operating room (OR) times and more time spent under anesthesia, a pair of new studies shows.

Although more research is needed eeded to tease out the reasons for the iincrease, experts said, hospitals may want w to consider booking additio onal OR time for patients who o are morbidly obese or havee more personnel on hand to help position these patients for surgery. Both studies were presented at the 2013 annuall meeting of the American Sociiety of Anesthesiologists (ASA).

In the first study (absttract 2056), researchers from Weilll Cornell Medical College and the Hospital for Special Surgery, both in New York City, reviewed records from 131,541 patients undergoing anesthesia at NewYork Presbyterian Hospital (part of the Cornell campus) from December 2007 to February 2013, looking at comorbidities, time spent in the OR and blood pressure.

They divided patients by body mass index (BMI), with 56,776 patients in the normal range of 18.5 to 24.9 kg/m2; 43,925 patients considered overweight with BMI of 25 to 29.9 kg/m2; 25,407 patients considered obese with BMI of 30 to 39.9 kg/m2; and 5,433 patients considered morbidly obese with BMI of at least 40 kg/m2.

More obese patients (28%) had hypertension—a measure of health before surgery—than overweight patients (23%) or those with a BMI in the normal range (16%; P<0.0001). Obese patients were more likely to be ranked as ASA class 3 (31% vs. 24% for overweight patients and 21% for normal BMI patients; P<0.0001). Obese and overweight patients also were more likely than patients with a normal BMI to have inpatient rather than ambulatory procedures. Among patients who were obese, 42% had inpatient procedures and 51% were treated on an outpatient basis; among overweight patients 40% were inpatients, whereas 53% were outpatients; and among patients in the normal BMI range, 30% had inpatient procedures whereas 65% were treated on an outpatient basis ((P<0.0001).

Obese patients also had longer overall operating time (96.8 vs. 89.8 minutes for overweight patients and 74.5 minutes for patients with a normal BMI; P<0.0001) and spent more time under anesthesia (176 vs. 168 minutes for overweight patients and 131 minutes

Operations & Management 33

Pharmacy Practice News • November 2013

Hospital Medicine for the normal BMI group; P<0.0001).

“Although we cannot conclude this from our specific data, longer OR times have been associated with higher infection rates, for example,” said Stavros Memtsoudis, MD, PhD, a clinical professor of anesthesiology and public health at Weill Cornell, who helped conduct the study.

In a smaller study (abstract 2270), researchers at Stanford Medical Center, in Stanford, Calif., found that patients who w o are a e morbidly obese and undergoing prim mary hip arthroplasty required significantly more OR time than did d patients with normal BMI. The investigators reviewed ccharts from 1,332 patients scheduled for primary hip arthroplasty at the medical center from February 2008 tto Jan. 1, 2013. The morbidly ob bese group had a total OR tim me of 168 minutes compared with 1146 minutes for obese patients and 139 m minutes for the normal BMI cohort (Table). Patients who were morbidly obese also had longer operation times—103 versus 86 minutes for those with a normal BMI—and longer induction times, 28 versus 24 minutes for obese patients and 21 minutes for patients with normal BMI. Prospective research is needed to investigate what factors account for these differences, said Dr. Memtsoudis, who also is an attending anesthesiologist at the Hospital for Special Surgery, in New York City. Anesthesia and OR times might be longer for morbidly obese patients because of difficulty performing various procedures, positioning them for surgery or higher rates of complications, Dr. Memtsoudis said.

But it could be instead that the health care team is being more careful with this population to avoid adverse events.

Paradoxically, previous reports have suggested that obese patients have better outcomes following surgery, he said, although it’s not clear why.

Nevertheless, “these studies are important because they help us understand that these patients use resources,” Dr. Memtsoudis said. He and his colleagues screen obese patients more thoroughly “to make sure there are no surprises” during surgery. And the hospital ensures more staff members are available to help with patient positioning.

Two authors from the Stanford study, Bassam Kadry, MD, a clinical assistant professor of anesthesiology, perioperative and pain medicine, and Christopher Press, MD, a second-year anesthesiology resident, also called for research to determine which procedures require extra time for obese patients. A linear relationship between procedure duration and obesity does not necessarily exist, Dr. Kadry said,

Table. Rising Obesity Linked to Prolonged Surgeries and Hospital Stays BMI Range

30-34.9 (n=275) 35-39.9 (n=113) 40-50 (n=70)

Variables

Mean

Mean

Mean

Total time in OR, min

146.3

156.3

167.9

Induction time, min

23.7

26.3

28.2

Operation time, min

90.3

97.6

103.0

Emergence time, min

9.2

9.5

10.9

Recovery time, min

167.7

184.9

174.6

Total hospital stay, days

3.5

3.6

3.9

but understanding the connection “can potentially be used to more accurately predict procedure duration.”

For now, the Stanford Medical Center has modified the surgery schedule to allow more time for some operations on obese patients. For hospitals that treat a high percentage of obese patients, Dr. Kadry said, “it’s worth considering creating dedicated service lines to help with transportation, positioning and peripheral IV placement for morbidly obese patients.”

—Karen Blum

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34 Operations & Management

Pharmacy Practice News • November 2013

Practice Pearl Lean Process Improvement Initiative:

Identifying a Safe Medication Order Verification Rate Mark Heelon, PharmD

START

Medication Safety Coordinator

Log In

Malgorzata Szerszen, PharmD

Enter assigned workstation

a

Postgraduate Year 1 Residentt

Karen Johnson, RN

Step 1

Sean Illig, PharmD Manager, Inpatient Pharmacy Operations

Erin Taylor, PharmD Assistant Director, Inpatient Pharmacy Services Baystate Health Springfield, Massachusetts

W

ith the demands for clinical pharmacy services increasing and personnel resources continuing to be stretched, we wanted to find a realistic and comprehensive metric to help illustrate pharmacy workflow to ensure that our pharmacists are working efficiently and safely. We performed peer surveys and literature searches to identify commonly used productivity metrics, especially those focusing on inpatient pharmacy and order verification rates.

The results demonstrated a wide variability in collected and reported data, and ultimately, a lack of any true “goldstandard” or “benchmark” metric.

As a result, we led a lean process improvement initiative to assess the clinical order verification processes at Baystate Medical Center (BMC) and to identify an internal benchmark for safe order verification rates. Specific objectives included the development of a benchmark for BMC clinical order review to define accountability (quality of order review and documentation) as well as identification and assessment of inefficiencies (ie, “nonproductive” time) in daily practices to streamline and optimize workflow.

A multidisciplinary verification process improvement team (VPIT) consisting of the medication safety coordinator, 11 clinical pharmacists, 3 pharmacy technicians, and 3 nurses was created.

Members of VPIT directly observed pharmacist workflow and verification processes within the inpatient pharmacy. They sought to understand the steps of order verification, as well as to quantify and identify pharmacist inter-

Look at Priority Order

Step 2

Director, Performance Improvement Studies

Sort Orders

Select patient View profile: • Age • Sex • Weight • Nursing unit • Problem list • Reason for visit • Medication list/history • Labs • Allergies • Order-dependent start/stop dates • Duplicate medications • Interactions • Patient notes

Drug-Specific Review

(STAT, ASAP, routine, etc)

Step 3

Check: patient’s own, investigational, nonformulary medications

Step 4

Proceed to order Product selection

Step 5

Allergy warning

• Dose • Clinical dosing (renal, hepatic) • Route of administration • Frequency/duration • Comments tab • Duplication • Determine unknown • Multiple product selection • Complete required fields • Adding IV fluid to med/2nd product selection • Hit OK to verify (Submit) or reject (Step 6)

Interaction

Select Verify

Dose calculator Dose range checking

Step 6 Reject Order • Hit key to reject • Call RN and/or MD • Obtain provider response

Discontinue verify

Step 7 Document Intervention • Enter patient profile • Enter ad hoc charting • Select type of intervention • Manually type medication name and/or select from drop-down box • Select clinical importance • Find contact name • Pharmacy intervention time • Add information (optional) • Click the check mark upper left for completion

MD or RPh change order

No change • Verify and include explanation note • Document Repeat Rx interverification vention process (Step 7)

END (Verification)

Figure. Order verification process.

ruptions, workflow inefficiencies, and order verification times to define an order verification rate benchmark. Multidisciplinary team meetings employed value stream mapping exercises to delineate the order verification process (Figure) and to identify waste. Value stream mapping is a lean technique used to assess and analyze the flow of materials and information.

The VPIT calculated a rate of 35 orders per hour per pharmacist as the maximum rate that allowed safe and accurate clinical review of medication orders at BMC. This was calculated through pharmacist observation of an average cycle time (time to verify one medication order) of 1.7 minutes with interruptions. Identified inefficiencies were associated mainly with breaches in workflow, including difficulties in medication information retrieval and nonclinical disruptions during the verification process. Changes were implemented to help mitigate these inefficiencies and achieve and sustain a safer order verification rate in the absence of additional pharmacy staff.

Interventions included the development of pharmacist workstations with dual-screen displays, pharmacist and technician workflow redesigns, and a phone call tree system to reduce interruptions of pharmacists with nonclinical calls (ie, automated dispensing cabinet drawer jams).

Internally, the order verification metric has been used to assist in planning for BMC’s pharmacy practice model redesign and has established minimum staffing levels. The order verification rate benchmark also has been helpful when strategizing for the addition of clinical initiatives to pharmacist workflows and has provided an opportunity for pharmacy managers to discuss productivity with individual pharmacists. Now that BMC has reduced inefficiencies in its workflows and added clinical activities to them, plans are to replicate this activity with the current model to accurately reflect health system productivity. a At the time of the project, Dr. Szerszen was a postgraduate year 1 resident, but she has since graduated and is now a clinical pharmacist at UMass Medical Center, in Worcester, Massachusetts.

Operations & Management 35

Pharmacy Practice News • November 2013

Finance

UHC PLAN

‘Academic medical centers can improve [specialty pharmacy] patients’ overall care experience by providing benefits investigation, prior authorization, patient monitoring, education and prescription services, all from the same location.’

continued from page 1

Help With Data Aggregation One of the traditional knocks against hospitals or health systems providing specialty pharmacy services is the channel’s inability to provide robust clinical data aggregation—a major requirement of many specialty drug contracts. UHC is addressing that perceived shortcoming by running a central data repository that tracks patient outcomes, Mr. Groenewold noted. As for the toolkit that is being developed for members, it will help facilities manage Risk Evaluation and Mitigation Strategies (REMS) compliance, supply-chain integrity, time to first dose, regimen adherence, around-the-clock clinical support, patient counseling and monitoring of patient experience. Typically, each hospital’s main pharmacy will administer the program.

To placate smaller manufacturers with niche drugs, UHC has a single distribution point in mind. From this hub, UHC would redistribute specialty medications to participating hospitals.

Doug Smith, PharmD, the senior director of UHC’s capital resource program and supply chain services, said that “smaller manufacturers told us if they were to include UHC in their distribution, they’d want one UHC-level contract that would encompass all participating members.”

Idea Floated at Armada UHC members were instrumental in developing the main components of the new specialty pharmacy network, Dr. Smith noted. Andy Pulvermacher, RPh, the specialty services supervisor at the University of Wisconsin Hospital and Clinics, in Madison, and Kevin Colgan, RPh, MA, FASHP, the corporate director of pharmacy at Rush University Medical Center, in Chicago, played key roles.

“They went to [the] Armada [Specialty Pharmacy Summit meeting] with me last spring,” Dr. Smith said. “We spoke with 13 specialty drug manufacturers there about our idea, and asked, ‘is this on point?’ Our program reflects their input” as well as input from other manufacturers “with mature specialty programs” that UHC members have contacted.

Mr. Colgan stressed that a main impetus for the UHC program is “to reduce fragmentation of care in the current [specialty pharmacy] model” and to cut confusion for patients and caregivers when they try to access specialty pharmaceuticals.

“Academic medical centers can improve [specialty pharmacy] patients’ overall care experience by providing benefits investigation, prior authorization, patient monitoring, education and prescription services, all from the same location.”

Currently, UHC sees many instances in

—Kevin Colgan, RPh, MA, FASHP

Table. 2016 Projected Top 10 Medications

a

a

then can’t control for high-risk patients.”

Taking a more direct role in the provision of specialty pharmacy care is the major focus of the UHC initiative, Mr. Pulvermacher noted. “Our members will want to assure that utilization of specialty pharmaceuticals is appropriate, and will want to manage that risk themselves using their own specialty pharmacy programs,” he said. “Our focus is on our ability to manage patients and our financial liability going forward as ACO participants.”

Drug

Revenue (Billions)

Indication

Rituxan

$3.57

Oncology

Humira

$3.54

Rheumatoid arthritis

Avastin

$3.45

Oncology

Januvia/Janumet

$3.42

Diabetes

Advair

$3.27

Asthma, COPD

Revlimid

$2.95

Oncology

Lantus

$2.80

Diabetes

Explosive Market Growth

Enbrel

$2.78

Autoimmune disorders

Remicade

$2.62

Rheumatoid arthritis

Atripla

$2.56

HIV

Better patient care is certainly an important driver of the UHC initiative.

But market forces are also at play in this move by hospitals to grab a piece of the specialty pharmacy pie. By 2016, seven of the top 10 drugs are projected to move through specialty channels (Table), and the script volume for these medications is projected to grow by more than 20% annually. Thus, hospitals urgently want to be in specialty drug networks.

“The gold rush is on,” said Gary Cohen, BSPharm, RPh, CSP, the CEO of the National Association of Specialty Pharmacy. That should not be surprising, he noted, “with new patients in the system, new [specialty] drugs in the pipeline, mounting care needs and the evolving ACO model.” Indeed, Mr. Cohen sees specialty “becoming the norm for all pharmacies.”

Although not commenting specifically on the UHC initiative, Ali McBride, MS, BCPS, clinical coordinator of hematology/oncology at The University of Arizona Cancer Center (UACC), in Tucson, said that it makes perfect sense for health systems to have some strategy in place for gaining access to specialty pharmacy networks. This issue has become even more critical due to the explosive growth of oral chemotherapy agents that hospitals often cannot dispense due to exclusionary specialty pharmacy contracts, Mr. McBride said.

Coupled with a loss of revenue from IV infusions that has been occurring due to increased competition from infusion centers, being cut out of those contracts “is just not sustainable from a revenue standpoint,” he said. “And of course there is the issue of continuity of care and patient outcomes.”

As a result, the days of sending specialty pharmacy patients to Walgreens, CVS or some other big-box specialty pharmacy “are all but over,” he stressed. “And

Color denotes specialty drug.

COPD, chronic obstructive pulmonary disease Source: CVS/Caremark Insights 2012 report

which outpatients want a UHC member facility to dispense a specialty drug and care for them, but the patients must first call an 800 number to have an authorized distributor directly ship them the drug, which they bring in with them for treatment. This “white-bagging” process leaves obvious gaps in clinical care, potentially disrupts the assurance of supply-chain integrity, and makes it far more difficult to bolster and document regimen adherence (related story, page 1). UHC could deliver continuity of care with greater access to specialty drugs, and that would improve patient safety and compliance, Mr. Groenewold noted.

JoAnn Stubbings, BSPharm, the assistant director of specialty pharmacy services at University of Illinois at Chicago, a UHC member, agreed that continuity of care is crucial. “It certainly was an important driver in our decision several years ago to seek access to specialty pharmacy contracts,” she said. Outsourcing those services, she added, was not a viable option “because it doesn’t really make as much sense in light of health [care] reform and ACOs [accountable care organizations], where the health system assumes risk for transitions in care. It’s tough to do that when you’re locked out of limited-distribution networks for specialty drugs and

‘Specialty Drug’—What’s in a Name?

T

here is no standard industry definition of “specialty drug.” The Centers for Medicare & Medicaid Services (CMS) define a drug as specialty if it costs more than $600 per month. Industry data from a large survey of health plans indicate that 80% of plans define a drug as specialty if the average monthly cost is more than $1,200 per month. Facilitation of appropriate benefit design and distribution often determines whether a drug is defined as specialty.

However, by and large, most health care organizations apply a set of criteria that includes: • Very expensive drugs that can range from $6,000 to $750,000 per year • Injectable or infusion drugs—although oral agents that meet additional criteria are often included • Drugs that treat complex chronic and/or rare diseases • Drugs that have significant side-effect and/or risk profiles • Drugs with special handling requirements • Drugs with unique distribution management requirements • Drugs that require a high degree of ongoing patient assessment, monitoring and management Source: CVS/Caremark Insights 2012 report

•

see UHC PLAN, page 36

36 Operations & Management

Pharmacy Practice News • November 2013

Finance A hassle for health systems?

‘White Bagging’ of Specialty Drugs Draws Some Ire Boston—With the growing number of patients using specialty pharmacy medications, hospitals and clinics that are not part of the limited-distribution networks for those drugs face serious financial and operational challenges.

One of the most problematic is the practice of “white bagging,” in which a specialty pharmacy delivers the product directly to a clinic or practice for use by a specific patient. Stakeholders say the practice can result in the loss of a significant amount of potential revenue for an institution, not to mention the drug-handling hassles it can cause.

Network (OPEN) meeting, held before the Association of Community Cancer Centers National Oncology Conference.

Moreover, when drugs come through specialty pharmacy, hospitals and clinics need to manage the logistics of acting as a courier service, often without compensation. Maintaining a patientspecific supply of those drugs requires working with numerous specialty pharmacies, sometimes for the same drug, as well as dealing with varying requirements from different insurance companies. On top of the financial burden of those efforts, health-system

‘Health care systems that are not participating in specialty pharmacy are caught in a funnel of missed opportunities, where profit leaks from [the facility].’

of those drugs, and you don’t get any reimbursement for doing all the logistics.”

(Mr. Anderson pointed out that white bagging should not be confused with brown bagging, which occurs when a patient brings medicines to a clinic that they acquired through a specialty pharmacy or a store. Most hospitals don’t allow brown bagging, so it’s not a major financial or operational concern.)

Jim Smeeding, RPh, MBA, the executive director of the National Association of Specialty Pharmacy (NASP), who was a co-presenter during the OPEN session on white bagging, put the financial hit in even more stark terms. “Health care systems that are not participating in specialty pharmacy are caught in a funnel of missed opportunities, where profit leaks from [the facility],” he said.

Operational Hassles

—Jim Smeeding, RPh, MBA One of the biggest challenges posed by white bagging is the complex nature of the specialty pharmaceuticals involved.

The drugs often require special handling, temperature-control monitoring and product-specific support services, noted Ernie Anderson Jr., MS, RPh, a Brockton, Mass.–based health care consultant who discussed the white bagging of specialty medications during the recent Oncology Pharmacy Education

pharmacies have to absorb the cost of providing ancillary supplies (e.g., needles, syringes) and managing unused drugs because a patient has died or a dose has changed.

“When I was at Steward Health Care and Lahey Clinic, we had a whole section on the shelf that contained specialty medications,” said Mr. Anderson, who worked at both Massachusetts facilities. “It’s a lot of work to keep track

UHC PLAN

and complex patients—and the attendant revenue—to specialty pharmacies due to limited distribution contracts. A spokesperson for ExceleraRx told Pharmacy Practice News that the group will be ready to announce an update regarding its efforts in mid-November.

Mr. Cohen said it is logical for hospitals and health systems to enter the specialty pharmacy market. Nationwide, “they are moving in the direction of being able to provide specialty pharmacy services on an outpatient basis,” he said. “With the development of the ACO model [where money flows through health systems and hospitals], initiatives like ExceleraRx and UHC will proliferate.”

Mr. Cohen cited several reasons why hospitals are well positioned to become players in the specialty pharmacy arena.

“Hospitals already have the ability to transfer specialty patients from inpatient to outpatient services,” he said, adding that those patient acquisition skills are “the key part of the triangle that includes access to specialty drugs and contracts for reimbursement.”

The financial benefit of this strat-

continued from page 35

that is a trend I see beginning to gain real traction throughout the country.”

Mr. McBride added a final rationale for holding on to specialty pharmacy patients. To retain those patients, many hospitals need to expand the scope of their outpatient pharmacies—a process that can add significantly to a hospital’s revenue stream, he noted. “So the opportunity to add even more to that, via a partnership with a specialty pharmacy network, is something that really deserves some consideration.”

Non-Profits Not Alone UHC is not the only organization to try and forge a specialty pharmacy network. In spring 2012, a national network of hospital pharmacies named ExceleraRx, LLC launched, with the aim of uniting at least 20 large, integrated health systems in an effort to win specialty share. At the time, they told Pharmacy Practice News that their hospitals lost 30% to 40% of their most vulnerable

In addition to causing financial hardships for hospitals and clinics, white bagging can have a negative effect on continuity of patient care and patient safety if it becomes unclear who is taking responsibility for caring for the patient. Other challenges include biomedical verification of devices for medication administration, verification of drug integrity/pedigree, and ensuring that Risk Evaluation and Mitigation Strategies requirements are met.

The issue of drug pedigree and liabil-

egy also should not be overlooked, Mr. Cohen stressed. “Hospitals now realize they don’t have to abdicate revenue to outside [specialty] pharmacy services, especially when they already have the skill sets and medical records to serve complex patients.”

But what about established specialty pharmacy providers’ take on this trend? Although not specifically addressing UHC’s announced strategy, Phil Hagerman, RPh, the CEO of Diplomat Specialty Pharmacy, said his company has a track record of welcoming hospitals into the fold. “Over the past several years, Diplomat has created leading products to support some of the nation’s top retailers and hospitals in developing their specialty pharmacy strategy,” he said. “We are excited and proud to be supporting many of the nation’s top hospital systems in that build-out.”

A Specious Argument?

Several other large specialty pharmacy providers declined to comment on the UHC initiative, either specifically

ity can be particularly vexing for hospitals, Mr. Anderson noted. “Who is assuring the integrity of the specialty pharmacy and who is legally responsible if something is wrong with the drug?” he asked. “Institutions don’t get reimbursed for mixing the whitebagged specialty pharmacy drugs, but they assume all of the liability for it.”

Mr. Anderson cited yet another concern: If a health system stops buying drugs because of white bagging, under some wholesale distribution contracts, it may end up having to pay increased prices for other drugs.

Some health systems are responding to this trend by pushing back during the prior authorization process, when requested to use a specialty pharmacy, and have not allowed white bagging under any circumstances. Other pharmacies have told insurers they want to be paid for managing white bagging, but few have been successful. Mr. Anderson emphasized that clinicians must bill zero dollars for the product along with an administration fee to collect a fee for administering specialty medications.

For IV drugs, clinicians should mark down a start and stop time to be accurately reimbursed, he noted.

If commercial insurance companies are using average sales price (ASP)-based reimbursement, pharmacies should

•

see WHITE BAGGING, page 38

or in broad strokes. But Ms. Stubbings said she has heard all of the claimed reasons why health systems are ill-suited to enter the specialty pharmacy market— and doesn’t buy them.

“It’s been suggested by key players in the specialty pharmacy arena that health systems ‘can’t do REMS or meet the other criteria,’ and I would ask them for specific reasons or proof why not,” she said. “It is a claim that is completely unsubstantiated. Health systems are in a better position than all of those other entities to implement and execute REMS, especially because we have access to the [patient’s] electronic medical record.

“At our institution, I know we have several partners in specialty pharmacy who are very happy with our performance, including the most important partner—the patient.”

—Al Heller, with additional reporting by David Bronstein Sources disclosed no relevant financial conflicts of interest.

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38 Operations & Management

Pharmacy Practice News â&#x20AC;˘ November 2013

Finance

WHITE BAGGING continued from page 36

request a fee of +25% to 30% over ASP to include pharmacy overhead, Mr. Anderson said. That number is supported by a 2005 Medicare Payment Advisory Commission study that revealed the actual costs of administering and preparing drugs. If a pharmacy ends up after negotiations with +15% or 20%, that is still a whole lot better than +6%, the current rate of payment set for hospitals.

A few years ago, Blue Cross and Blue

Shield of Massachusetts required that 30 self-injectable drugs come through specialty pharmacy. At the time, Mr. Anderson was system vice president at Steward. â&#x20AC;&#x153;Rather than say â&#x20AC;&#x2DC;we will not accept white bagging,â&#x20AC;&#x2122; what we said was â&#x20AC;&#x2DC;if we are going to do white bagging, here are some of the criteria that we are looking for to make sure that we ensure the integrity of the product.â&#x20AC;&#x2122;â&#x20AC;?

Alternatively, a hospital can take the plunge and become a specialty pharmacy provider. In Massachusetts, six hospitals have gained access to specialty phar-

macy contracts, and more are anticipated to do the same, Mr. Anderson noted.

Elsewhere, hospitals and health systems throughout the country, including Cleveland Clinic, the University of Illinois at Chicago and Duke University have formed their own specialty pharmacies, either individually or as part of recently launched networks (see story, page 1).

Skills Needed To Join Specialty Networks There is a checklist of several capabilities that hospitals have to master

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before establishing a specialty pharmacy, the speakers noted. They must, for example, have authorization by a third party and the ability to bill and adjudicate claims; maintain an inventory of specialty products; establish a variety of policies and procedures; and have a call center 24/7, 365 days per year. Becoming a specialty pharmacy also involves creating a delivery service with a tracking system; quality assurance; compliance and accreditation; provision of patient education materials; and meeting the standards from the FDA, National Comprehensive Cancer Network and compendia listing.

If a hospital doesnâ&#x20AC;&#x2122;t want to become a specialty pharmacy, it should consider the partnership option, Mr. Smeeding suggested. â&#x20AC;&#x153;Partnering can offer some established care protocols, data management and infrastructure, payor contracting, pharma contracting and central distribution options.â&#x20AC;?

Whether hospitals and clinics decide to get in the game or try to get paid for white bagging, they have to do something. Specialty pharmacy drugs represent a small percentage of prescriptions, perhaps 2%, but they can account for greater than 30% of expenditures, Mr. Smeeding pointed out. Moreover, â&#x20AC;&#x153;50% of the top 100 drugs and eight of the top 10 will be specialty pharmaceuticals by 2016.â&#x20AC;?

Help Is at Hand Hospitals and clinics struggling with how to deal with specialty pharmacy will have help soon. The American Society of Health-System Pharmacists is expected to release guidelines on coordinating patient care with specialty pharmacy services in December 2013 or early 2014. â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke Mr. Smeeding and Mr. Anderson reported no relevant ďŹ nancial conďŹ&#x201A;icts of interest.

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Clinical 39

Pharmacy Practice News • November 2013

Infectious Disease

Gloves and Gowns Decrease MRSA, but not VRE, Transmission

G

loves and gowns may help prevent the spread of methicillin-resistant Staphylococcus aureus (MRSA), but they do not stop vancomycin-resistant enterococci (VRE) transmission, researchers at the University of Maryland recently found. The combined rate of MRSA and VRE infections in ICUs also remained unaffected by these contact precautions.

“We thought this was a fairly aggressive intervention, which had been only tested before during outbreaks,” said Daniel J. Morgan, MD, MS, a professor at the University of Maryland School of Medicine, Baltimore, and the senior author of the study, which was published online in the Journal of the American Medical Association (doi:10.1001/jama.2013.277815).

“The results were a bit surprising.”

Taken together, MRSA and VRE cause more than 100,000 infections and 12,000 deaths each year in the United States, according to the Centers for Disease Control and Prevention (CDC). “In intensive care units, infections are a leading cause of death and morbidity,” Dr. Morgan said.

To determine the effect of gloving and gowning, the researchers randomly divided 20 medical and surgical ICUs into two groups. The control group (n=10) followed CDC recommendations, wearing gloves and gowns only during interactions with patients who had clinically identified MRSA or VRE. Health care workers in the intervention group (n=10), on the other hand, donned gloves and gowns whenever they had patient contact or entered patients’ rooms.

Over a three-month baseline period and a nine-month study period, clinicians collected more than 92,200 swabs from 26,180 patients in ICUs. Researchers grew MRSA and VRE cultures from the swabs and used polymerase chain reaction to detect antibiotic resistance genes. Wearing gowns and gloves during all patient contact did not significantly reduce MRSA or VRE acquisition compared with the control measures.

In the intervention group, total acquisitions reduced from a baseline of 21.35 to 16.91 per 1,000 patient-days over the course of the study compared with 19.02 to 16.29 acquisitions per 1,000 patientdays for control ((P=0.57).

For MRSA acquisitions alone, however, the additional contact precautions significantly decreased transmission rates compared with the control group (10.03 to 6.00 acquisitions per 1,000 patient-days vs. 6.98 to 5.94 acquisitions per 1,000 patient-days, respectively; P=0.046). The intervention did not have a significant effect on VRE transmission in comparison with the control (15.18 to 13.59 acquisitions per 1,000 patient-days vs. 14.37 to 11.88 acquisitions per 1,000 patient-days, respectively; P=0.70).

Gowns and gloves may have been more effective barriers to MRSA than VRE because the organisms inhabit separate areas of the body. MRSA resides primarily in the nose and on the skin, Dr. Morgan said, whereas VRE colonizes the gastrointestinal tract. If a health care worker is wearing gloves and a gown, the potential for MRSA to spread via skin-to-skin contact is reduced, but transmission of gutdwelling VRE may remain unaffected.

Additionally, errors in determining baseline VRE infections may have influenced the results, noted Preeti N. Malani, MD, a professor of internal medicine at the University of Michigan, Ann Arbor, in an accompanying editorial.

An effective way to reduce transmission of MRSA and VRE, according to Dr. Morgan, is to bathe patients with chlorhexidine. A recent study found that chlorhexidine baths significantly reduce

MRSA-positive cultures in ICUs (N ( Engl J Med 2013;368:2255-2265). And, compared with putting on gowns and gloves before patient contact, a chlorhexidine bath “is a lot easier, and it’s only done once a day,” Dr. Morgan said. “If implemented, gloving and gowning should be just part of an overall strategy that includes efforts to optimize hand hygiene and prudent use of antimicrobials.”

—Ben Guarino

40 Clinical

Pharmacy Practice News • November 2013

Oncology

Bev + Cap ‘Optimal’ for Treating Elderly mCRC Patients San Francisco—In a rare trial that focused on elderly patients with metastatic colorectal cancer, the addition of bevacizumab to capecitabine significantly improved progression-free survival (PFS) compared with capecitabine alone. In patients who received the combination therapy, PFS reached a mean of 9.1 months—four months longer than in patients who received capecitabine alone, representing a 47% decrease in risk

for progression (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P<0.001).

“Based on the efficacy and safety results, bevacizumab plus capecitabine might be an optimal treatment approach to improve outcomes in elderly patients,” said lead author David Cunningham, MD, a consultant medical oncologist and head of the gastrointestinal unit at the Royal Marsden Hospital, in London, England. He presented the trial results

at the 2013 Gastrointestinal Cancers Symposium (abstract 337).

This is the first Phase III trial to prospectively evaluate the use of a biologic in an elderly patient population.

Elderly patients are woefully underrepresented in clinical trials, with one study suggesting that patients over the age of 65 years account for less than one-third of trial participants ((J Clin Oncol 2003;21:1383-1389).

In this open-label trial, known as AVEX, 280 patients with a mean age of 76 years were randomized to receive first-line capecitabine (Xeloda, Genentech) 1,000 mg/m2 daily for two weeks followed by a one-week break or capecitabine in combination with bevacizumab (Avastin, Genentech) 7.5/kg given every 21 days.

The combination therapy nearly doubled the overall response rate from 10% to 19.3% ((P=0.042). The effect was seen across all recognized subsets, including those based on sex, age, performance status, site of disease and location of the primary tumor.

Patients in the combination group remained on bevacizumab for a median of 5.8 months—1.5 months longer than patients in the capecitabine-alone group remained on that drug. Following the study presentation, several commentators noted that patients’ PFS significantly exceeded the length of time on treatment. Dr. Cunningham explained that patients were taken off treatment for reasons other than disease progression and were rechallenged if they continued to show a response.

Grade 3 or higher adverse events (AEs) occurred more frequently in patients in the combination arm: 59% versus 44.1%.

However, grade 5 AEs were more common in the capecitabine-alone arm: 11.8% versus 8.2%. AEs associated with bevacizumab included bleeding/hemorrhage (25.4%), hypertension (19.4%), venous thromboembolic events (11.9%), proteinuria (7.5%), arterial thromboembolic events (4.5%), wound healing complications (1.5%), pulmonary hemorrhage/ hemoptysis (0.7%) and fistulae (0.7%).

“I was certainly impressed at how well tolerated this approach was,” Dr. Cunningham said.

In a comment that downplayed the significance of the finding, however, Robert A. Wolff, MD, a professor at the University of Texas MD Anderson Cancer Center, in Houston, said other studies have shown that improvements in survival are “quite modest” when using more active cytotoxic agents and bevacizumab.

On Jan. 23, 2013, the FDA approved bevacizumab for use in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-containing regimen.

—Christina Frangou Dr. Cunningham reported research funding from Amgen, AstraZeneca, Celgene, Merck, Novartis, and Roche. Dr. Cunningham’s coauthors included employees of Roche.

Clinical 41

Pharmacy Practice News • November 2013

Oncology

IBRUTINIB continued from page 1

in some fashion as first-line therapy for CLL, with the potential of sparing some patients a number of treatments that otherwise might be too toxic.”

Along with previously published findings, the NEJM results also have impelled the FDA to apply three Breakthrough Drug Designations to ibrutinib and to place it on a fast track for approval. In an email to Pharmacy Practice News, the FDA would not comment on the timing of the drug’s approval.

The NEJM M data, initially presented at last year’s American Society of Hematology (ASH) annual meeting, in Atlanta, included outcomes from 85 CLL patients with refractory or relapsed disease, who were randomized to receive 420 or 840 mg of the drug daily. The participants had undergone a median of four prior therapies; 33% had 17p deletions and 36% had 11p deletions, both predicting poor treatment response. Patients were a median 66 years of age and were followed for a median of 21 months.

Led by John Byrd, MD, the director of the Division of Hematology at Ohio State University Wexner Medical Center, in Columbus, the researchers reported that 71% of patients in each group experienced a clinical response.

Since most had some evidence of continuing disease, their response was considered partial. The estimated progression-free survival and overall survival rates were 75% and 83%, respectively, over 26 months, and the likelihood of response was independent of clinical and patient characteristics.

The investigators found that 78% of the partial responders experienced transient lymphocytosis in the early part of treatment. However, an additional 20% in the low-dose group and 15% in the higherdose group had persistent lymphocytosis despite significant reductions in tumor size, and, therefore, were classified as nodal partial responders.

What Can Pharmacists Expect?

Informing physicians of the potential for transient lymphocytosis early in the course of treatment will be a key role for pharmacists, said Lindsay Hladnik, PharmD, BCOP, a clinical pharmacist for Hematologic Malignancies/Stem Cell Transplantation at Barnes-Jewish Hospital, in St. Louis. “It will be important for them to know that this is likely due to the drug’s mechanism of action and not to disease progression,” said Dr. Hladnik, who was not involved in the research.

According to the NEJM M study, the most common adverse events (AEs) were grade 1-2 diarrhea (47% of both

‘There is little doubt … that ibrutinib will be used in some fashion as first-line therapy for CLL, with the potential of sparing some patients a number of treatments that otherwise might be too toxic.’

—Nicole Lamanna, MD groups), grade 1-2 fatigue (28%) and grade 1-2 upper respiratory tract infections (33%). Grade 3-4 AEs included pneumonia (12%), dehydration (6%), neutropenia (15%), pyrexia (5%), hyper-

tension (5%) and sinusitis (5%). Most infections occurred early in the course of treatment.

Two patients in the 420 mg group and four patients in the 840 mg group

discontinued treatment because of AEs, the investigators reported.

Robert C. Wolf, PharmD, the hematology/oncology pharmacotherapy coordinator and program director of the Pharmacy Practice Residency in Oncology at Mayo Clinic College of Medicine, in Rochester, Minn., said ibrutinib’s “specific role and place in therapy will be better defined over the ensuing months to years as clinical trial results evolve.”

Pharmacists can expect to provide the usual range of care to patients receiving

•

see IBRUTINIB, page 42

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42 Clinical

Pharmacy Practice News • November 2013

Oncology

continued from page 41

ibrutinib, noted Dr. Wolf, who has not been involved in research on the drug.

“While not necessarily unique to ibrutinib, issues of access, adherence, follow-up for efficacy and safety, drug interactions and affordability will need to be addressed,” he said.

Dr. Hladnik agreed that having knowledge of the available patient access programs for ibrutinib and being able to direct physicians to these resources will be critical, “especially since patients will take ibrutinib continuously until disease progression or unacceptable toxicity. This could potentially be a very expensive treatment and patient access could become a real issue. Hopefully, there will be good patient access programs in place.”

Access to ibrutinib isn’t only an issue for patients; because the drug will likely

go the specialty pharmacy route, hospitals may need to grapple with getting into limited distribution networks for the drug, according to Ali McBride, MS, BCPS, clinical coordinator of hematology/oncology at The University of Arizona Cancer Center, in Tucson.

Assuming such logistical issues can be worked out, the primary challenge in managing patients on ibrutinib will be clinical. For her part, Dr. Lamanna said, “I wonder about the long-term unexpected toxicity with ibrutinib, [because] this will likely be prolonged therapy. Also, will this drug need to be used indefinitely ... if patients who respond eventually achieve complete responses or MRD [minimal residual disease] negativity?”

Dr. Hladnik said ibrutinib appeared to be straightforward to administer and manage. “The once-daily oral dosing will definitely help with patient compliance, although we could play a key role in verifying patient compliance and evaluating

Ibrutinib’s Effect on Transplants

A

t Ohio State’s College of Medicine Wexner Medical Center in Columbus, Leslie Andritsos, MD, went from conducting approximately 15 CLL-related hematopoietic stem cell transplants (HSCT) annually before 2011, to seven transplants in that year and down to none in 2012.

“The change has coincided with the availability of ibrutinib through clinical trials,” said Dr. Andritsos, who is the clinical director of the Blood and Marrow Transplantation Program at the medical center.

Dr. Andritsos said the drug has changed the way she approaches treatment of patients with CLL. “For those with access to ibrutinib trials, I would rather put them on the drug and only transplant them if they fail to respond to therapy,” she said.

Although the drug’s availability has eliminated the need for many transplants for now—unarguably a huge step for CLL treatment—Dr. Andritsos struck a cautious note, pointing out that 25% of patients in the ibrutinib trial published in NEJM M did not experience clinical remission. “I think we’ll start to see some refractory patients showing up again for transplant, although there will be far fewer transplants than before,” she said.

Robert C. Wolf, PharmD, the hematology/oncology pharmacotherapy coordinator at Mayo Clinic College of Medicine in Rochester, Minn., noted that HSCT is positioned differently in the treatment algorithm for mantle cell lymphoma (MCL), for which ibrutinib also has received a Breakthrough Drug Designation from the FDA. He said HSCT is used as a last resort in patients with CLL, but, “in general, when HSCT is adopted in MCL, it is generally done earlier in the course of the disease as a consolidative therapy during first remission.

“Thus, even if ibrutinib demonstrated value in front-line therapy for MCL, I don’t think it would necessarily immediately impact the decision on autologous HSCT in these patients.”

—D.W.

Drs. Andritsos and Wolf reported no relevant financial conflicts of interest.

Source: Susan O’Brien, MD. Reprinted with permission

IBRUTINIB

‘The once-daily oral dosing will definitely help with patient compliance, although we could play a key role in verifying patient compliance and evaluating and managing any adverse events, [such as] diarrhea, so that patients can stay on the medication.’

Lindsay Hladnik, PharmD, BCOP and managing any adverse events, [such as] diarrhea, so that patients can stay on the medication,” she noted.

She said that she was not aware of any information on any ibrutinib dosing adjustments, drug–drug and drug– food interactions and adverse-event monitoring.

Dr. Hladnik added a caveat regarding ibritinib’s place in the regulary stream. “When it comes to oncology drugs, you can get an agent approved based on Phase 2 studies if there is an unmet clinical need, but outcomes can be different once it’s studied in Phase 3 studies.” At press time, seven of the 31 registered clinical trials of ibrutinib were Phase 3 studies. A number of the head-to-head trials among these studies are examining use of ibrutinib in combination with other established

treatments and for a range of B-cell leukemias.

Dr. Lamanna said she is awaiting updated findings slated for presentation at this year’s ASH annual meeting and at the International Workshop on CLL in Germany, where she expects favorable results on the durability of CLL clinical response with ibrutinib.

“As more data on this drug from ongoing clinical investigation emerges,” Dr. Lamanna said, “lots of exciting new questions in terms of how best to use the drug will, hopefully, be answered.”

—David Wild Dr. Byrd reported receiving research funding from Pharmacyclics and Janssen.

Drs. Wolf, Lamanna and Hladnik reported no relevant financial conflicts of interest.

Send us your news Pharmacy Practice News appreciates news tips and suggestions for coverage from readers.

All submissions will be considered for publication.

Write to editorial director David Bronstein at davidb@mcmahonmed.com

For patients with invasive fungal infections who are refractory to, or intolerant of conventional amphotericin B therapy

ABELCET saves time

*

*Abelcet is supplied in a ready-to-use vial and does not require reconstitution thereby saving drug preparation time. With invasive fungal infections (IFIs) being a leading cause of morbidity and mortality in the most vulnerable immunocompromised patients, polyenes offer effective fungicidal therapy.1,2,3 Abelcet is a key treatment for patients with IFIs who are refractory to, or intolerant of conventional amphotericin B (CAB) therapy. Contact your Abelcet national account manager to learn about Abelcet.

1

Fridkin SK. The changing face of fungal infections in health care settings. Clin Infect Dis. 2005;41:1455-1460.

Manavathu EK, Ramesh MS, Baskaran I, Ganesan LT, Chandrasekar PH. A comparative study of the postantifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans. J Antimicrob Chemother. 2004; 53:386-389.

3 Moosa MYS, Alangaden GJ, Manavathu E, Chandrasekar PH. Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis. J Antimicrob Chemother. 2002;49:209-213.

2

**For additional information, please see full prescribing information at abelcet.com.

abelcet.com** To contact an Abelcet National Account Manager please call 1-800-447-0169, select option 1 and enter 572.

Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B- containing drugs (<0.1% incidence rate with Abelcet). Despite generally less nephrotoxicity of Abelcet observed at a dose of 5 mg/kg/d compared with CAB therapy at a dose range of 0.6 mg/kg/d to 1 mg/kg/d, dose-limiting renal toxicity may still be observed with Abelcet. Renal toxicity of doses greater than 5 mg/ kg/d of Abelcet has not been formally studied.

The adverse events most commonly reported with Abelcet are transient chills and/or fever during infusion of the drug. Š 2013 Sigma-Tau Pharmaceuticals, Inc.

ABL-172P-0813

44 Clinical

Pharmacy Practice News • November 2013

Oncology

Open Access to Genomics May Spur Myeloma Therapy New York—With the click of a mouse, doctors and researchers worldwide can now access clinical and genomic data for hundreds of patients with multiple myeloma (MM). The Multiple Myeloma Research Foundation (MMRF) believes this new database, called the Researcher Gateway, will revolutionize precision medicine for this challenging malignancy. Launched in late September, the freely avail-

‘If great is the enemy of good, [the Researcher Gateway initiative] is a wonderful example of trying to be good on our way to being great.’

—Howard McLeod, PharmD able data set is a collaborative effort between the MMRF and academia, clinicians, industry and patients.

“With this kind of data set, you get

I-101-41-US-N ®

ABELCETT (Amphotericin B Lipid Complex Injection) BRIEF SUMMARY (SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION) INDICATIONS AND USAGE ABELCETT® is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See DESCRIPTION OF CLINICAL STUDIES IN FULL P.I.).

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properrties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipidcomplexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products.

DOSAGE AND ADMINISTRATION The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCETT® should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.

Renal toxicity of ABELCETT®, as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.

Preparation of Admixture for Infusion: Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of ABELCETT® from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with ABELCET® and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of ABELCETT®, since no bacteriostatic agent or preservative is present.

DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET® with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCETT®, or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER. The diluted ready-for-use admixture is stable for up to 48 hours at 2$ to 8$C (36$ to 46$F) and an additional 6 hours at room temperature.

CONTRAINDICATIONS ABELCETT® is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.

WARNINGS Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCETT® with an incidence rate of <0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCETT®.

PRECAUTIONS General: As with any amphotericin B-containing product, during the initial dosing of ABELCETT®, the drug should be administered under close clinical observation by medically trained personnel.

Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCETT®.

These reactions are usually more common with the first few doses of ABELCETT® and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.

Laboratory Tests: Serum creatinine should be monitored frequently during ABELCETT® therapy (see ADVERSE REACTIONS).

It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts.

Drug Interactions: No formal clinical studies of drug interactions have been conducted with ABELCET®. However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCETT®: Antineoplastic agents: Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET® with great caution.

Corticosteroids and corticotropin (ACTH): Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCETT®, serum electrolytes and cardiac function should be closely monitored.

Cyclosporin A: Data from a prospective study of prophylactic ABELCETT® in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCETT® within several days of bone marrow ablation may be associated with increased nephrotoxicity.

Digitalis glycosides: Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCETT®, serum potassium levels should be closely monitored.

Flucytosine: Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCETT® with caution.

Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitroo and in vivoo animal studies. The clinical significance of these findings has not been determined.

Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCETT® should not be given concurrently.

Other nephrotoxic medications: Concurrent use of amphotericin B and agents such as aminoglycosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCETT® only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications.

Skeletal muscle relaxants:: Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with ABELCETT®, serum potassium levels should be closely monitored.

Zidovudine:: Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET® (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCETT®, renal and hematologic function should be closely monitored.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:: No long-term studies in animals have been performed to evaluate the carcinogenic potential of ABELCETT®. The following in vitroo (with and without metabolic activation) and in vivo studies to assess ABELCETT® for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivoo mouse micronucleus assay. ABELCETT® was found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET® had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).

more than just clinical information; you get the annotation of genomics,” said Sagar Lonial, MD, a professor at Emory Winship Cancer Institute, in Atlanta,

ADVERSE REACTIONS The total safety data base is composed of 921 patients treated with ABELCETT® (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were ADVERSE EVENTSa WITH AN INCIDENCE OF *3% (N=556) treated in open-label, non-comparative studies; and 556 patients were treated Adverse Event Percentage (%) of Patients in an open-label, emergency-use Chills 18 program. Most had underlying hemaFever 14 tologic neoplasms, and many were reIncreased Serum Creatinine 11 ceiving multiple concomitant medicaMultiple p Organ g Failure 11 tions. Of the 556 patients treated with Nausea 9 ABELCETT®, 9% discontinued treatment Hypotension yp 8 due to adverse events regardless of Respiratory p y Failure 8 presumed relationship to study drug.

Vomitingg 8 In general, the adverse events most Dyspnea yp 7 commonly reported with ABELCETT® Sepsis p 7 were transient chills and/or fever durrDiarrhea 6 ing infusion of the drug.

Headache 6 Cardiac Arrest Hypertension yp Hypokalemia yp Infection Kidneyy Failure Pain Thrombocytopenia y p Abdominal Pain Anemia Hyperbilirubinemia yp Gastrointestinal Hemorrhage g Leukopenia p Rash Respiratory p y Disorder Chest Pain Nausea and Vomitingg

6 5 5 5 5 5 5 4 4 4 4 4 4 4 3 3

The following adverse events have also been reported in patients using ABELCETT® in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCETT® is uncertain.

Body as a whole:: malaise, weight loss, deafness, injection site reaction including inflammation Allergic:: bronchospasm, wheezing, asthma, anaphylactoid, and other allergic reactions a The causal association between these adverse events and ABELCET® is Cardiopulmonary:: cardiac failure, uncertain. pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation Dermatological:: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme Gastrointestinal:: acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, venoocclusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis Hematologic:: coagulation defects, leukocytosis, blood dyscrasias including eosinophilia Musculoskeletal:: myasthenia, including bone, muscle, and joint pains Neurologic:: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms Urogenital:: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria Serum electrolyte abnormalities:: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia Liver function test abnormalities:: increased AST, ALT, alkaline phosphatase, LDH Renal function test abnormalities:: increased BUN Other test abnormalities:: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc., at 1-888-393-4584 or by email at drugsafety@sigmatau.com or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Special Populations Hepatic Impairment:: The effect of hepatic impairment on the disposition of ABELCETT® is not known.

Renal Impairment:: The effect of renal impairment on the disposition of ABELCETT® is not known. The effect of dialysis on the elimination of ABELCETT® has not been studied; however, amphotericin B is not removed by hemodialysis when administered as amphotericin B desoxycholate.

Pediatric and Elderly Patients: The pharmacokinetics and pharmacodynamics of pediatric patients ()16 years of age) and elderly patients (*65 years of age) have not been studied.

Pregnancy:: There are no reports of pregnant women having been treated with ABELCETT®. Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of ABELCETT® up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCETT® should be used during pregnancy only after taking into account the importance of the drug to the mother.

Nursing Mothers:: It is not known whether ABELCETT® is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:: One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET® at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of ABELCETT®. No serious unexpected adverse events have been reported.

Geriatric Use:: Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET® at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.

OVERDOSAGE Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of ABELCETT® between 7-13 mg/kg. None of these patients had a serious acute reaction to ABELCETT®. If an overdose is suspected, discontinue therapy, monitor the patient’s clinical status, and administer supportive therapy as required. ABELCETT® is not hemodialyzable.

I-101-41-US-N

Manufactured by Sigma-Tau PharmaSource, Inc., Indianapolis, IN 46268.

Distributed by Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878.

and a speaker at the MMRF conference launching the database. By taking genetic data into account, Dr. Lonial said, a treatment that shows success in a few patients can become “more than just an anecdote.”

The clinical and genetic patient data that form the basis of the Researcher Gateway are provided by an ongoing clinical study, CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), which is sponsored by the MMRF. The goal of CoMMpass, which began in 2011, is to classify 1,000 patients with MM by their molecular profiles and clinical characteristics.

These clinical characteristics are important, according to Howard McLeod, PharmD, the medical director of the Personalized Medicine Institute at Moffitt Cancer Center, in Tampa, Fla., because genomic profiles alone aren’t enough to offer therapeutic improvement. The more challenging part, he noted, is phenotype— a patient’s physical characteristics and clinical condition. “You can get an amazingly pristine genome sequence, and not be any wiser” without such additional information, he said.

CoMMpass Amassing Data From 100 Patients Out of the 300 patients enrolled in CoMMpass, the cancer genomes of about 100 have been sequenced, including transcriptomes and exomes, and subsequently uploaded to the MMRF database.

The Researcher Gateway also provides information on patient demographics, medical history, treatment responses and observed side effects.

“I wouldn’t be shocked if this proves to be the model for all cancers,” said Eric Lander, PhD, the director of the Broad Institute of Massachusetts Institute of Technology and Harvard University, both in Boston. Dr. Lander was a prin-

Clinical 45

Pharmacy Practice News • November 2013

Oncology ‘I wouldn’t be shocked if this proves to be the model for all cancers.’

—Eric Lander, PhD

cipal researcher in the Human Genome Project, which provided the basis for research in genome sequencing.

Access to the Researcher Gateway is not limited to doctors and researchers involved in CoMMpass. Upon verification, any clinician may add data for her or his patients, and the MMRF has contracted a third-party research organization to validate data entries.

According to Walter Capone, the chief operating officer of the MMRF, normal somatic sequences are scrubbed and patients are made anonymous, conforming to HIPAA standards.

Additionally, all academic institutions and corporations affiliated with the database have forgone intellectual property rights.

A Boost for Personalized Medicine As the database grows, the MMRF’s goal in collecting this information will be to improve personalized medicine.

“It’s knowing the genomic profile of an individual patient and tailoring therapy to meet this patient’s needs” that is such a compelling aspect of the initiative, said Keith Stewart, MB, ChB, a professor at Mayo Clinic in Phoenix, during the MMRF conference. “It’s using the right drug, for the right patient, at the right time.”

Paired with the genomic data, the clinical outcomes can give patients an idea of what to expect from certain therapies.

“New patients are going to be able to walk in and see me,” Dr. Lional said, “and I can say, ‘I’m going to propose to give you treatment X, and this is what happened to the 150 or 200 patients who

had your genomic profile. And this is how they did, compared to all the other potential treatments.’”

Dr. Lonial estimates, broadly, that it could cost patients with MM between

$5,000 and $10,000 to get viable sequencing data. According to a representative for Aetna, insurance policies may cover genetic testing when “tests are medically necessary to plan and monitor treatment,” although specifics for members with MM were not provided.

Additionally, clinicians may encounter patients who would like to have their genomes sequenced but aren’t expressing enough of the disease to get results.

“That’s not a bad thing, because it means they’re in remission,” Dr. Lional said.

And even in cases when patients can

receive these tests, he said, not every mutation discovered will be informative or actionable.

“If great is the enemy of good,” Dr. McLeod said, “this is a wonderful example of trying to be good on our way to being great.”

—Ben Guarino Dr. Stewart reported that he is a consultant for Celgene and Millennium, and is engaged in clinical trials with GlaxoSmithKline, Onyx and Genentech. Dr. McLeod reported that he is on the board of directors of Gentris.

Now Available

For Uncompromised Living™ BIVIGAM® [Immune Globulin Intravenous (Human), 10% Liquid] is indicated for the treatment of primary humoral immunodeficiency (PI).

• 64% of study participants did not miss any days of work or school1 • 2.3 days/patient/year out of school or work1 • Sugar-free, 10% liquid preparation • BIVIGAM is manufactured in the USA for US providers and patients • First newly approved IVIG* product with a validated thrombin generation assay (TGA) Customer Support: 1-800-458-4244 BIVIGAM Cares Program and BIVIGAM CareLine 1-855-248-4426 (1-855-BIVIGAM) Reimbursement specialists to assist patients with insurance issues and ensure that BIVIGAM users can continue BIVIGAM treatment in the event of a lapse in private insurance

insPIred support for the PI community® Program www.BIOTESTinspired.com Supports PI patients, caregivers, and healthcare professionals with education and resources WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE See full Prescribing Information for complete boxed warning.

• Thrombosis may occur with immune globulin intravenous (IGIV) products, including BIVIGAM. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, a history of venous or arterial thrombosis, the use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.

• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with the administration of Immune Globulin Intravenous (Human) (IGIV) products in predisposed patients.

• Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. BIVIGAM does not contain sucrose.

• For patients at risk of thrombosis, renal dysfunction, or renal failure, administer BIVIGAM at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Please read the summary of full Prescribing Information on the adjacent page. © 2013 Bi Biotest t t Ph Pharmaceuticals ti l C Corporation. ti

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BIOTEST and the BIOTEST & Design marks are trademarks and/or registered trademarks of BIOTEST AG. BIVIGAM is a trademark of Biotest Pharmaceuticals Corporation.

This information is intended only for residents of the United States. *IVIG is also known as IGIV, Immune Globulin Intravenous (Human)

Reference: 1. Wasserman RL, Church JA, Stein M, et al. Safety, efficacy and pharmacokinetics of a new 10% liquid intravenous immunoglobulin (IVIG) in patients with primary immunodeficiency.

J Clin Immunol. 2012. doi:10.1007/s10875-012-9656-5.

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www.BIVIGAM.com 10/13

10190-90-IGG-040312_R03 10190 90 IGG 040312 R03

46 Clinical

Pharmacy Practice News • November 2013

Critical Care

Keeping an Eye on Anesthesia Drug Costs Washington—Anesthesia costs can differ by as much as 10-fold between similar cases, suggesting significant variability in how clinicians handle medications in the operating room, new research has found.

The wide variations in drug use, and consequent costs, among anesthesia providers during similar cases are both an opportunity to minimize waste and a teaching opportunity, according to the researchers.

Doug Hester, MD, an assistant professor of anesthesiology at Vanderbilt University Medical Center, in Nashville, Tenn., said the study began as part of a multicenter effort aimed at decreasing the average cost of anesthesia for surgery at two large academic medical centers.

The investigators created an automated cost calculator for medications administered during surgical cases, then identified both the median drug cost for any

Rx only BIVIGAM® [Immune Globulin Intravenous (Human), 10% Liquid] Brief summary: Consult the full Prescribing Information for complete product information WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE Thrombosis may occur with immune globulin (IGIV) products, including BIVIGAM. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, a history of venous or arterial thrombosis, the use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, has been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death1,2.

Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. BIVIGAM does not contain sucrose. For patients at risk of thrombosis, renal dysfunction, or renal failure, administer BIVIGAM at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Indication and Usage: BIVIGAM is an Immune Globulin Intravenous (Human), 10% Liquid, indicated for the treatment of primary humoral immunodeficiency (PI).

Contraindications: BIVIGAM is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. BIVIGAM is contraindicated in IgA deficiency patients with antibodies to IgA and a history of hypersensitivity.

Warnings and Precautions: Thrombosis: Thrombosis may occur following treatment with IGIV products, including BIVIGAM. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer BIVIGAM at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Hypersensitivity: Severe hypersensitivity reactions may occur with IGIV products, including BIVIGAM. In case of hypersensitivity, discontinue BIVIGAM infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

BIVIGAM contains trace amounts of IgA ( 200 micrograms per milliliter). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. BIVIGAM is contraindicated in IgA deficient patients with antibodies against IgA and a history of hypersensitivity reaction. Acute Renal Dysfunction and Acute Renal Failure: Acute renal dysfunction/failure, osmotic nephrosis, and death may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering BIVIGAM. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing BIVIGAM. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer BIVIGAM at the minimum infusion rate practicable. Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia: Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy, including BIVIGAM. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events. Aseptic Meningitis Syndrome (AMS): AMS may occur infrequently with IGIV treatments including BIVIGAM. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting.

Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Hemolysis: IGIV products, including BIVIGAM, may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration,13 and acute hemolysis, consistent with intravascular hemolysis, has been reported. Monitor patients for clinical signs and symptoms of hemolysis. If these are present after BIVIGAM infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. Transfusion-Related Acute Lung Injury (TRALI): Noncardiogenic pulmonary edema may occur in patients following IGIV treatment including BIVIGAM. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti- neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. Transmissible Oct 2013 [10760-90-IGG-032013_R01]

given procedure as well as the degree of variability attributable to different anesthesia providers. “So, in order to effect behavioral change, we need to educate those providers about their costs for any given case,” Dr. Hester said. “And in order to do that, we need to create a good system to deliver that cost to them.”

The researchers began by obtaining acquisition costs of all intraoperative medications from the institutions’ phar-

Infectious Agents: Because BIVIGAM is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Biotest Pharmaceuticals Corporation at 1-800-458-4244. Before prescribing BIVIGAM, the physician should discuss the risks and benefits of its use with the patient. Monitoring Laboratory Tests: Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis with IGIV treatment, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If signs and/or symptoms of hemolysis are present after an infusion of BIVIGAM, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. Interference with Laboratory Tests: After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

ADVERSE REACTIONS: Serious adverse reactions observed in clinical trial subjects receiving BIVIGAM were vomiting and dehydration in one subject. The most common adverse reactions to BIVIGAM (reported in 5% of clinical study subjects) were headache, fatigue, infusion site reaction, nausea, sinusitis, blood pressure increased, diarrhea, dizziness, and lethargy. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice. In a multicenter, open-label, non-randomized clinical trial, 63 subjects with PI, on regular IGIV replacement therapy, received doses of BIVIGAM ranging from 254 to 1029 mg/kg (median dose 462.8 mg/kg) every 3 weeks or 4 weeks for up to 12 months (mean 317.3 days; range 66 – 386 days). The use of pre-medication was discouraged; however, if subjects required pre-medication (antipyretic, antihistamine, or antiemetic agent) for recurrent reactions to immune globulins, they were allowed to continue those medications for this trial. Of the 746 infusions administered, 41 (65%) subjects received premedication prior to 415 (56%) infusions. Fifty-nine subjects (94%) had an adverse reaction at some time during the study. The proportion of subjects who had at least one adverse reaction was the same for both the 3- and 4-week cycles. The most common adverse reactions observed in this clinical trial were headache (32 subjects, 51%), sinusitis (24 subjects, 38%), fatigue (18 subjects, 29%), upper respiratory tract infection (16 subjects, 25%), diarrhea (13 subjects, 21%), cough (14 subjects, 22%), bronchitis (12 subjects, 19%), pyrexia (12 subjects, 19%), and nausea (9 subjects, 14%). Adverse reactions (ARs) are those occurring during or within 72 hours after the end of an infusion. In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of BIVIGAM infusions with one or more temporally associated adverse reactions was 31%. The total number of adverse reactions was 431 (a rate of 0.58 ARs per infusion).

Seven subjects (11.1%) experienced 11 serious ARs. Two of these were related serious Table: Adverse Reactions (ARs) (within 72 hours after the end of a BIVIGAM infusion) in 5% of Subjects No. Subjects No. Infusions With ARs Reporting ARs ARs (% of Subjects) (% of Infusions) [n=63] [n=746] Headache 27 (43%) 115 (15.4%) Fatigue 15 (24%) 59 (7.9%) Infusion Site Reaction 5 (8%) 5 (0.7%) Nausea 5 (8%) 8 (1.1%) Sinusitis 5 (8%) 5 (0.7%) Blood Pressure Increased 4 (6%) 5 (0.7%) Diarrhea 4 (6%) 4 (0.5%) Dizziness 4 (6%) 4 (0.5%) Lethargy 4 (6%) 4 (0.5%) Back Pain 3 (5%) 3 (0.4%) Blood Pressure Diastolic 3 (5%) 5 (0.7%) Decreased a Fibromyalgia 3 (5%) 17 (2.3%) Migraine 3 (5%) 8 (1.1%) Myalgia 3 (5%) 4 (0.5%) Pharyngolaryngeal Pain 3 (5%) 3 (0.4%) a Symptoms occurring under pre-existing fibromyalgia ARs (vomiting and dehydration) that occurred in one subject. One subject withdrew from the study due to ARs related to BIVIGAM (lethargy, headache, tachycardia and pruritus). All 63 subjects enrolled in this study had a negative direct antiglobulin (Coombs’) test at baseline.

During the study, no subjects showed clinical evidence of hemolytic anemia. No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. During the clinical trial no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). There was a single positive finding for parvovirus (B19 virus) during the study. This subject came in contact with acute B19 virus from working at a school greeting children where a child was reported to have symptomatic Fifth's disease. There was no cluster (no other cases in other subjects) of B19 virus transmission with the IGIV batch concerned.

DRUG INTERACTIONS Live Virus Vaccines Immunoglobulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella, and varicella because the continued presence of high levels of passively acquired antibody may interfere with an active antibody response. The immunizing physician should be informed of recent therapy with BIVIGAM so that appropriate measures may be taken.

macies. They then developed a series of database queries to automatically obtain and calculate cost-per-case totals using the facility’s anesthesia information management system. Data were extracted regarding the amount of drug given by bolus, infusion or inhalation.

These amounts were then indexed with the drug’s acquisition cost, providing a total cost per case and cost per minute.

“We had to create a process that would calculate costs in real time and be delivered to the anesthesia provider in the room,” said Dr. Hester, who presented the findings at the annual meeting of the American Society of Anesthesiologists (abstract 165). “This info is not typically known by providers.”

Dr. Hester and his colleagues presented data from the first set of diagnostic codes analyzed, total knee arthroplasty.

They found that median cost for 449 cases was $22.98, $24.29 at institution A (229 cases) and $20.23 at institution B

Statement of Ownership

Clinical 47

Pharmacy Practice News • November 2013

Critical Care ‘It does make sense to compare costs across the different hospitals in a system and use best practices when containing costs.’

—Tricia A. Meyer, MS, PharmD

(220 cases). Perhaps more importantly, anesthetic costs ranged widely among providers, from $7.99 to $81.77.

“The idea is to then communicate with providers both the mean cost and their specific cost for any particular [diagnostic] code,” Dr. Hester explained.

“And we are hoping that this would spur behavioral changes regarding the stewardship of pharmacologic costs, assuming it doesn’t affect outcomes.”

The investigators also plan to combine this information with quality indicators to quantify value in anesthetic care. “If we could save $10 on every case we do, we would save about half a million dollars every year,” he said.

therefore delaying treatment. So this is an important challenge for both patients and facilities that vigilant

pharmacists can help meet.”

In fact, “hospitals have already managed the ‘low-hanging fruit’ as far as cost savings,” she noted. “Therefore, any new ideas or strategies that show savings should be considered, evaluated

high in botic risk is When throm thrombin deficiency ti hereditary an

—Michael Vlessides, with additional reporting by David Bronstein

To learn more, visit www.thrombate.com

FELY PROCEED SA

Pharmacists Can Help Asked to comment on the study, Tricia A. Meyer, MS, PharmD, FASHP, the senior director of the Department of Pharmacy at Scott & White Healthcare, in Temple, Texas, said that “it would be helpful to know exactly which drugs the researchers used to calculate spending; local anesthetics, antiemetics, pain medications, metoclopramide, gases, metoprolol, etc., all could be a target of potential analysis and subsequent cost-control efforts.”

That caveat aside, “this is an interesting, highly relevant and hot topic. It does make sense to compare costs across the different hospitals in a system and use best practices when containing costs.”

At Scott & White, Dr. Meyer said, “we periodically will take the top 10 to 20 drugs used by anesthesia along with the acquisition cost and set it up in a table format, and place copies inside the lid of the anesthesia kit so everyone (anesthesia providers) can see current prices. It is a good practice to keep everyone aware of the costs because they change frequently with different manufacturers, or we switch from a branded to generic product, or a drug shortage occurs and the compounded price is typically considerably higher.”

There’s no one best way to analyze and manage pharmacy spending, noted Dr. Meyer, who also is an associate professor of anesthesiology for the Department of Anesthesiology at the Texas A&M University College of Medicine at the Temple campus. “Many hospitals are seeing volume decreases in admits and surgeries,” she said. “Patients are struggling with high deductibles and more out-of-pocket expenses and

and implemented—provided that they truly cut costs without adding an extra expense or drain on staff resources.”

Thrombate III® (antithrombin III [human])—proven effective for patients with hereditary antithrombin (AT) deficiency during surgery, childbirth, and in the prevention and treatment of thromboembolism1 Thrombate III provides predictable amounts of AT to replace what is normally present in the body AT concentrate purified from human plasma and pasteurized to inactivate viruses, with no confirmed cases of virus transmission In clinical studies, no cases of thrombotic complications during surgical and obstetrical procedures were reported

Easy to administer1

Convenient to store and reconstitute1

One dosing formula Bolus intravenous infusion (not continuous infusion) Pregnancy category B

500 IU vials with sterile water for injection Filter and transfer needles provided Room temperature storage

Important Safety Information Thrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia.

The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk.

No cases of transmission of viral disease or CJD have ever been identified for Thrombate III. Please see brief summary of Thrombate III complete Prescribing Information on adjacent page.

Reference: 1. Thrombate III® (antithrombin III [human]) [prescribing information]. Research Triangle Park, NC: Grifols Inc; 2012. © 2013 Grifols Inc.

All rights reserved.

February 2013

TH05-0113

48 Clinical

Pharmacy Practice News • November 2013

Critical Care

Prehospital Aspiration Ups Pneumonia Risk

O

ne of the deadliest types of hospitalacquired infections in adult trauma patients is set in motion long before patients arrive at the hospital, according to a study reported at the 2013 meeting of the Surgical Infection Society.

The study, involving surgeons and paramedics, showed that trauma patients who aspirate before they get to the hospital have a fourfold increased risk for developing health care–associ-

ated pneumonia (HCAP) and a more than threefold increased risk for ventilator-associated pneumonia (VAP).

In many cases, patients aspirate prior to interventions by paramedics, suggesting that a key event leading to HCAP occurs before patients are treated by paramedics or hospital staff, said lead author Vanessa Fawcett, MD, MPH, a fellow in trauma and surgical critical care at Harborview Medical

THROMBATE

III®

Antithrombin III (Human) BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

FOR INTRAVENOUS USE ONLY DESCRIPTION Antithrombin III (Human), THROMBATE IIIw is a sterile, nonpyrogenic, stable, lyophilized preparation of purified human antithrombin III (ATIII).

THROMBATE III is prepared from pooled units of human plasma from normal donors by modifications and refinements of the cold ethanol method of Cohn. When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0–7.5, a sodium content of 110–210 mEq/L, a chloride content of 110–210 mEq/L, an alanine content of 0.075–0.125 M, and a heparin content of not more than 0.1 IU heparin/IU ATIII. THROMBATE III contains no preservative and must be administered by the intravenous route.

Each vial of THROMBATE III contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation.

The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm.

The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.

An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

CLINICAL PHARMACOLOGY Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on ATIII. ATIII is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin.

The neutralization rate of serine proteases by ATIII proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect in vivo of heparin is mediated by ATIII, heparin is ineffective in the absence or near absence of ATIII. The prevalence of the hereditary deficiency of ATIII is estimated to be one per 500 to 5000 in the general population. The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with ATIII levels of 40%–60% of normal. These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary ATIII deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deficiency have been reported. In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism. Greater than 85% of individuals with hereditary ATIII deficiency have had at least one thrombotic episode by the age of 50 years. In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of ATIII, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals.

In clinical studies of THROMBATE III conducted in 10 asymptomatic subjects with hereditary deficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administered based on immunologic ATIII assays, and 1.4% per unit per kg administered based on functional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of ATIII. These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days.

In clinical studies of THROMBATE III, none of the 13 patients with hereditary ATIII deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures. Eight patients with hereditary ATIII deficiency were treated therapeutically with THROMBATE III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE III reversed heparin resistance in two patients with hereditary ATIII deficiency being treated for thrombosis or thromboembolism.

During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving THROMBATE III became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for ⱖ 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B. INDICATIONS AND USAGE THROMBATE III is indicated for the treatment of patients with hereditary antithrombin III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

Center, in Seattle.

“Health care- and ventilator-associated pneumonias, as the names imply, indicate conditions that are iatrogenic.

However, given that many patients are aspirating around the time of injury, complications associated with such aspiration may need to be relabeled,” she said.

These pneumonias may be part of “the spectrum of traumatic injury,

Subjects with ATIII deficiency should be informed about the risk of thrombosis in connection with pregnancy and surgery and about the inheritance of the disease.

The diagnosis of hereditary antithrombin III (ATIII) deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency.

ATIII in plasma may be measured by amidolytic assays using synthetic chromogenic substrates, by clotting assays, or by immunoassays. The latter does not detect all hereditary ATIII deficiencies.

The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.)

Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation.

CONTRAINDICATIONS None known.

WARNINGS Because THROMBATE III is made from human plasma, it may carry a risk of transmitting infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for THROMBATE III. Inform patients that THROMBATE III is made from human plasma and may contain infectious agents that can cause disease. While the risk that THROMBATE III can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics Inc. [1-800-520-2807].

The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. PRECAUTIONS General 1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.

2. Administer only by the intravenous route.

3. THROMBATE III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions.

4. Product administration and handling of the needles must be done with caution.

Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.

Place needles in sharps container after single use. Discard all equipment including any reconstituted THROMBATE III product in accordance with biohazard procedures.

The diagnosis of hereditary ATIII deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency.

Laboratory Tests It is recommended that ATIII plasma levels be monitored during the treatment period.

Functional levels of ATIII in plasma may be measured by amidolytic assays using chromogenic substrates or by clotting assays.

Drug Interactions The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to THROMBATE III. It is not known whether THROMBATE III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatric Use Safety and effectiveness in the pediatric population have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.)

Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation.

ADVERSE REACTIONS In clinical studies involving THROMBATE III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were dizziness (8), chest discomfort (3), nausea (3), dysgeusia (3), chills (2), pain (cramps) (2), dyspnoea (1), chest pain (1), vision blurred (1), intestinal dilatation (1), urticaria (1), pyrexia (1), and wound secretion and hematoma (1). If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate.

CAUTION & only U.S. federal law prohibits dispensing without prescription.

Grifols Therapeutics Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1871

attributable to patient disease rather than health care interventions.”

The findings come from an ongoing research project in Seattle. Paramedics in the city work closely with local hospitals and undergo rigorous training in emergency airway techniques. In an effort to further improve the quality of trauma care, surgeons and paramedics put together a study to examine rates of prehospital aspiration and intubation in the field, and any association with hospital-acquired pneumonias.

The researchers asked medics to document when adult trauma patients aspirated in the field, and whether they noted blood, emesis or other fluids in the patient’s oropharynx or airway at three points: prior to intubation, during intubation or confirmed via the endotracheal tube.

Paramedics’ reports were compared with patients’ pneumonia and mortalNEW PRODUCT

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Clinical 49

Pharmacy Practice News • November 2013

Critical Care

FDA Approves Injectafer for Iron Deficiency Anemia

Please see the Injectafer® ad on page 23 and 24 for a brief summary of Full Prescribing Information.

—Christina Frangou

TH CE REN NFE CO AL NU AN

I

de rsi ive 14 s R 20 an 9, le –2 Or A 26 w s, L ch e an rg ar n N le x.o M lto Or par Hi ew ho N ww. w

njectafer® (American Regent) is the first non-dextran IV iron for the treatment of adult patients with iron deficiency anemia (IDA) of various etiologies. Injectafer® is indicated for the treatment of IDA in adult patients who have intolerance to oral iron or have had an unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease (NDD-CKD).

Up to 750 mg of Injectafer® may be administered in a single dose, for a total cumulative dose of up to 1500 mg over two administrations.

the study. HCAP is followed closely by these organizations as a potential measure of quality of care. But the study shows clearly that HCAP is greatly affected by prehospital events. These events should be accounted for when measuring outcomes in different centers, Dr. Sawyer said.

The authors are currently conducting a follow-up study of outcomes, in which paramedics will decontaminate patients’ oral cavities prior to intubation.

Re O gi in pe str D ns ati ec on em be r

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may be worth studying in the future,” Dr. Fawcett said.

However, Robert Sawyer, MD, a professor of surgery and the chief of acute care surgery at the University of Virginia, in Charlottesville, considered the finding to have significant implications for clinical care, saying, “I will be more likely to start antibiotics earlier on patients with witnessed aspiration in the field than signs and symptoms of [an HCAP].”

He added that health care regulatory organizations should take note of

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The investigators said current practices to reduce pneumonia, such as ventilator bundles, should be reconsidered in light of the study findings.

“The effectiveness of such measures is recently being called into question in trauma patients, and perhaps intervention is required at an earlier stage,” Dr. Fawcett said.

It is unknown whether prophylactic antibiotics can reduce the incidence of pneumonias in patients who aspirate in the field. “At this point, we would not recommend it, but it

HO

ity outcomes, based on the hospital trauma registry. The diagnosis of pneumonia was made clinically using criteria of the Centers for Disease Control and Prevention or microbiologically with bronchoalveolar lavage. The study differentiated between HCAP, which occurs at least 48 hours after hospitalization, and VAP, which appears at least 48 hours after intubation.

All adult trauma patients intubated in the field and admitted to a Harborview ICU were studied. Of 228 patients who met the study criteria, 89 (39%) aspirated before being brought to the hospital. They were similar in age, sex and comorbidities but had more severe injuries and more severe traumatic brain injuries than patients who did not aspirate.

Patients aspirated most often before intubation. Ninety-five percent of patients who aspirated blood and 77% of those who aspirated emesis did so before intubation was attempted. Nearly half of these patients aspirated again during intubation.

Analysis revealed 15.7% of patients who aspirated went on to develop HCAP compared with 3.6% of patients who did not aspirate ((P=0.02). There was a trend toward increased VAP among patients who aspirated, but the difference was not significant (11.2% vs. 2.9%).

Stop by Booth #2002 at ASHP’s Midyear Clinical Meeting to learn more about HOPA and the benefits of membership.

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52 Clinical

Pharmacy Practice News • November 2013

Educational Review

Management of

Hyperglycemia in Critically Ill Patients ELISABETH DONAHEY, PHARMD, BCPS Clinical Pharmacy Specialist, Neurosciences ICU Loyola University Health System Maywood, Illinois

STACEY FOLSE, PHARMD, MPH, BCPS Clinical Pharmacy Specialist, Medical ICU Emory University Hospital Adjunct Clinical Assistant Professor Mercer University College of Pharmacy and Health Sciences Atlanta, Georgia

Reviewed by:

JUDITH JACOBI, PHARMD, FCCM Critical Care Pharmacy Specialist Indiana University Health Methodist Hospital Indianapolis, Indiana

H

yperglycemia is a common complication of critical illness, regardless of a history of diabetes mellitus. It has an estimated prevalence of approximately 40% in hospitalized patients.1 Initially,

hyperglycemia was presumed to be an adaptive stress response that was beneficial to survival.2-4 However, over the past 2 decades, understanding of this disease process has improved, with several studies showing that hyperglycemia is associated with increased mortality and morbidity.5-7

Hyperglycemia occurs in patients with known or undiagnosed diabetes, or during acute illness (ie, stress hyperglycemia). Stress hyperglycemia is a common problem in critical illness. Although prevalence is difficult to establish due to limited data, stress hyperglycemia confers a high risk for adverse clinical outcomes.8,9 In an observational study, ICU patients with newly diagnosed hyperglycemia had significantly higher mortality (31%) compared with patients with known diabetes (10%) or normoglycemia (11.3%).10 Stress hyperglycemia usually is defined as an increase in blood glucose above 200 mg/dL in the presence of acute illness. Resolution typically occurs after appropriate treatment of the underlying illness. However, if hyperglycemia is left untreated, it can lead to acute kidney injury, sepsis, critical illness polyneuropathy, respiratory failure, and decreased wound healing.11-15 Prudent understanding of blood glucose goals and effective

glycemic control is essential for appropriate management and optimization of patient outcomes.

Pathophysiology of Stress Hyperglycemia Stress hyperglycemia is caused by several endogenous and exogenous factors (Figure 1).

Endogenous contributors include counter-regulatory hormones, increased cytokines, increased insulin resistance, and decreased glucose uptake.

Acute illness results in activation of the hypothalamic–pituitary–adrenal (HPA) axis, which leads to release of cortisol.3,11 Cortisol causes elevation in blood glucose through stimulation of gluconeogenesis and reduction in glucose utilization.

Other counter-regulatory hormones, such as glucagon, catecholamines, and growth hormone, also are released. These hormones promote insulin resistance through adipose tissue lipolysis, skeletal muscle proteolysis, and hepatic glucose

production.3,4,11-15 All of these processes impair glucose uptake into peripheral tissues, increase circulation of free fatty acids (FFAs), and stimulate gluconeogenesis and glycogenolysis.11-16 Exogenous factors, such as parenteral and enteral nutrition, vasopressors, dextrose, and corticosteroids, further exacerbate hyperglycemia.

Adverse Effects Associated With Stress Hyperglycemia There are various physiologic complications of hyperglycemia (Figure 1). Osmotic diuresis leads to dehydration, which may impair renal function and worsen hyperglycemia.13 The DCCT (Diabetes Control and Complications Trial) revealed that maintaining normoglycemia slowed the progression of nephropathy in individuals with type 1 diabetes.17 In the landmark 2001 trial conducted

by Van den Berghe et al (Leuven 1), surgical ICU patients randomized to a blood glucose target of

Clinical 53

Pharmacy Practice News • November 2013

Educational Review 80 to 110 mg/dL had a decreased incidence of renal replacement therapy compared with those randomized to conventional glucose control.18 Elevations in blood glucose cause mitochondrial injury and endothelial dysfunction, suppressing immunity and leading to an increased risk for infection.11,13-15 In an observational study, patients undergoing elective surgery who were hyperglycemic (blood glucose >220 mg/dL) on postoperative day 1 had a 3-fold higher rate of infection.19 A recent retrospective analysis showed that orthopedic trauma patients with a mean blood glucose greater than 220 mg/dL had a 7-fold increase in the risk for infection.20 Data also suggest that patients with stress hyperglycemia, especially those in the post-cardiothoracic surgery population, are at an increased risk for wound infection.21,22 Additionally, skin graft failure in burn patients has been associated with uncontrolled hyperglycemia.23 Overall, risk for infection is highly correlated with hyperglycemia and occurs across multiple populations.

Stress hyperglycemia also is associated with increased risk for critical illness polyneuropathy (CIP). The pathogenesis of CIP is not well understood, but cytokine release is a presumed cause.24,25 A prospective ICU-based study by Nanas et al revealed an independent association between CIP and elevated blood glucose.26 Similarly, a retrospective analysis by Bercker et al correlated increased daily peak blood glucose with acute respiratory distress syndrome in patients with CIP.27 Patients with CIP also were found to have prolonged mechanical ventilation time and longer ICU stays. Hyperglycemia appears to play a role in CIP severity as well.24,25,28 A 1991 prospective study found that increases in blood glucose were associated with decreases in electrophysiologic peripheral nerve function in critically ill patients.28 Of the patients studied, 30% had clinical manifestations of CIP, including difficulty in mechanical ventilation weaning.

All of these complications can increase mortality. In a retrospective analysis of nearly 260,000 ICU admissions, mortality correlated with increasing blood glucose, independent of baseline disease severity.29 Even moderate hyperglycemia during an ICU stay has been associated with higher mortality.5 In a recent meta-analysis, a statistically significant reduction in overall mortality was associated with a blood glucose target of less than 150 mg/dL.30 However, this finding was not replicated in other meta-analyses. Risk for mortality also may differ depending on patients’ baseline comorbidities. In a retrospective cohort analysis, patients without diabetes randomized to a blood glucose target of 90 to 140 mg/dL had a higher risk for mortality than those with blood glucose target of 80 to 110 mg/dL.31

Glycemic Control in Critically Ill Patients Hyperglycemia during critical illness initially was presumed to be an adaptive metabolic response to stress and only was treated when blood glucose concentrations were above 220 mg/dL. In 1997, Swedish authors published the results of the DIGAMI (Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction) trial, which ushered in an era of change in the management of stress hyperglycemia.32 Patients with underlying diabetes and acute myocardial infarction, who were

Figure 1. Pathophysiology and complications of stress hyperglycemia.

randomized to a blood glucose target of 126 to 196 mg/dL, demonstrated a 28% reduction in mortality. Consequently, the question of optimal glucose range in critically ill patients has come to the forefront over the past decade.

In early 2000, a blood glucose target of 80 to 110 mg/dL was used in many ICUs based on the results of Leuven 1 Surgical Trial. However, the findings of the 2009 NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation) trial contradicted Leuven 1. In this study, 6,104 mixed ICU patients were randomized to a blood glucose target of either 81 to 108 mg/dL or 144 to 180 mg/dL.33 The lower blood glucose target was associated with increased mortality (27.5% vs 24.9%; odds ratio [OR], 1.14; 95% confidence interval [CI], 0.1021.28; P=0.02), as well as higher incidence of severe hypoglycemia (6.8% vs 0.5; P<0.001) when compared with the more conventional glucose target. The results of this trial called into question previous practices of targeting lower glucose in ICU patients.

Various organizations have published recommendations for blood glucose control for critically ill patients. These guidelines reflect the disparity in the literature. The American Association of Clinical Endocrinologists and American Diabetes Association’s (AACE/ADA) 2009

consensus statement recommended a blood glucose target of 140 to 180 mg/dL and against targeting blood glucose below 110 mg/dL.34 Similarly, the 2011 American College of Physicians guidelines recommend against intensive glucose control (80-110 mg/dL) and instead target blood glucose of 140 to 200 mg/dL.1 In 2012, the ADA’s position statement recommended a similar glycemic target (blood glucose 140-180 mg/dL), with a more stringent goal (110-140 mg/dL) for some critically ill patients.35 The Society of Critical Care Medicine (SCCM) developed slightly different recommendations (blood glucose target of 100-150 mg/dL) with absolute maximum blood glucose of 180 mg/dL.30 Limitations to these recommendations include a lack of high-quality evidence; many recommendations were based, in part, on single-center experiences, trials without power to detect certain outcomes, and studies with poor protocol compliance. Thus, it is important to be familiar with literature related to glycemic targets and outcomes in specific ICU populations.

CARDIAC SURGERY The Leuven 1 study was one of the first to suggest tighter blood glucose for ICU patients.18 The trial included 1,548 surgical ICU patients, of which 63% were admitted for cardiac surgery. Glucose targets of 80 to 110 mg/dL and 180 to 200 mg/

54 Clinical

Pharmacy Practice News • November 2013

Educational Review dL were compared and the former resulted in reduced mortality (relative risk reduction of 42%).

Other advantages of the lower target included earlier extubation, decreased renal replacement therapy, and shorter ICU stays. Patients in the 80 to 110 mg/dL group also had a higher incidence of hypoglycemia (blood glucose <40 mg/dL; 5.1% vs 0.8%; relative risk, 6.65).36 A post hoc analysis of these patients revealed a decrease in new kidney injury, critical illness polyneuropathy, ICU mortality, and hospital mortality.18 Smaller studies have reported decreased mortality in cardiac surgery patients, as well as decreased morbidity, such as fewer sternal wound infections, with tighter blood glucose control (≤150 mg/dL).21,22,37,38 A 2010 study by Leibowitz et al targeted a higher blood glucose range of 110 to 150 mg/dL; the groups had similar incidences of hypoglycemic episodes (2.5% moderate glucose control vs 3% conventional).22 Decreased rates of infection and atrial fibrillation also were demonstrated in the moderate control group. Tighter glycemic control should be considered for cardiac surgery patients, but a glucose target of 80 to 110 mg/dL should be avoided due to high rates of hypoglycemia.

NEUROSURGERY/NEUROLOGY In a planned subanalysis of the Leuven 1 study population, patients with isolated brain injury were investigated for degree of intracranial pressure, incidence of seizures, diabetes insipidus, and long-term rehabilitation. A glucose target of 80 to 110 mg/dL was found to have a statistically significant benefit on intracranial pressure and seizure incidence in 63 patients with isolated brain injury.39 However, a recent meta-analysis demonstrated that glucose control after a neurologic event such as ischemic stroke, aneurysmal subarachnoid hemorrhage, intraparenchymal hemorrhage, or traumatic brain injury does not yield a mortality benefit (OR, 0.97; 95% CI, 0.81-1.16).30 Other trials found similar results related to mortality as well as significantly increased episodes of hypoglycemia with a blood glucose target of 80 to 110 mg/dL.40-42 In this population, hypoglycemic episodes also are associated with increased mortality.42 SURGICAL/MEDICAL In 2006, the authors of Leuven 1 published the results of insulin therapy in medical ICU (MICU) patients (Leuven 2).43 A glucose target of 80 to 110 mg/dL was associated with reduced mortality only in a subset of patients admitted to the MICU for more than 3 days. Patients in the MICU for fewer than 3 days had higher mortality. Morbidity was reduced for new renal injury, length of mechanical ventilation, and hospital and ICU stay for the 80 to 110 mg/dL group, regardless of length of stay. The difference in overall rates of hypoglycemia was statistically significant between groups: 18.7% for those with a blood glucose target of 80 to 110 mg/dL versus 3.1% for those with a target of 180 to 200 mg/dL. Furthermore, 25.1% of patients in the 80 to 110 mg/dL group admitted to the ICU for more than 3 days experienced a hypoglycemic episode compared with 3.9% of those with the higher target.

Subsequent studies have not replicated the mortality and morbidity benefits seen in Leuven 2.33,44-46 A recent meta-analysis that included

Oral nutrition

Enteral nutrition

Figure 2. Hypoglycemia treatment algorithm for critically ill patients.

BG, blood glucose

NICE-SUGAR data found mortality to vary by ICU, with surgical ICU (SICU) patients appearing to benefit from tighter blood glucose control.36 Other meta-analyses have shown an inconsistent association in SICU patients.47-50 Overall, a blood glucose target of 80 to 110 mg/dL should be avoided in MICU and SICU patients. Additional studies are needed to determine the optimal blood glucose target for noncardiac surgery patients.

SEVERE SEPSIS

AND

SEPTIC SHOCK

SCCM’s Surviving Sepsis Campaign (SSC) provides specific recommendations on blood glucose goals for patients with severe sepsis or septic shock.51 Following the results of Leuven 1 and 2, SSC guidelines recommended the use of a blood glucose target of 80 to 110 mg/dL. However, in a randomized controlled trial of septic patients treated with hydrocortisone and to a blood glucose target of 80 to 110 mg/dL or 150 mg/dL or

less, there was no difference in mortality.52 Similarly, in patients with severe sepsis, a target of 80 to 110 mg/dL was not associated with a mortality benefit, but it was associated with more adverse events such as hypoglycemia.53 The 2012 SSC guidelines now recommend a blood glucose of ≤180 mg/dL.

Management of Stress Hyperglycemia Stress hyperglycemia in critically ill patients can be challenging to manage. Treatment consists of targeting a blood glucose range that avoids the adverse effects of hyperglycemia while preventing hypoglycemia.9,54 Limiting fluctuations in blood glucose and maintaining a specified goal is essential to success and minimization of adverse patient outcomes.9 In a large retrospective cohort of septic patients, glucose variability was independently associated with hospital mortality.55 Text continues on page 56

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56 Clinical

Pharmacy Practice News • November 2013

Educational Review Text continued from page 54

Similar studies have shown a greater predictive ability of glycemic variability on patient outcomes compared with targeting a specific glucose range.56,57 These studies imply that a more important management goal may be to decrease glucose variability. Recently, MacKenzie et al revealed that central tendency (mean or median serum glucose), glycemic variability, and minimum glucose value all were associated with patient outcomes.58 Further

research is needed to determine glycemic variability goals; nevertheless, specifying blood glucose targets and minimizing glycemic variability are important components of hyperglycemia management.

Treatment of hyperglycemia in critically ill patients in the ICU should occur when blood glucose concentrations are persistently elevated (Figure 2, page 54). Two blood glucose measurements higher than 180 mg/dL should trigger the initiation of insulin.30,33,34 Insulin can be

administered either subcutaneously or via continuous infusion. Patientspecific factors should be taken into consideration when selecting a formulation. Insulin infusions are the most physiologic method for achieving glycemic goals, with a very short half-life (5-9 minutes) that allows for easy titration as clinical status changes. Ideal candidates for insulin infusions include patients who are hemodynamically unstable, undergoing targeted temperature management, edematous, receiving

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vasopressors or high-dose corticosteroids, or have type 1 diabetes or unpredictable nutrition.11,34 Subcutaneous insulin administration during critical illness can be complicated by the aforementioned factors. It may be considered first-line therapy in specific situations, such as in patients with low insulin requirements or in clinically stable patients.34 In critically ill patients, initial treatment of stress hyperglycemia typically is accomplished with IV insulin therapy. An insulin infusion ideally is administered via a protocol. The ideal protocol should quickly reach and maintain target blood glucose, account for the current blood glucose and rate of change in blood glucose values, balance stability and responsiveness, result in minimal rates of hypoglycemia, and clearly communicate titration instructions and frequency of blood glucose monitoring based on blood glucose stability to nurses.59-61 The Yale Insulin Drip Protocol encompasses all of these elements. The initial blood glucose value is used to determine whether a bolus is needed and the initial infusion rate, both of which are based on a formula.

Subsequent adjustments to the infusion incorporate both the current blood glucose and rate of change.62 Additionally, this protocol is associated with a low incidence of both severe and moderate hypoglycemia.63 Similarly, in the North Carolina Protocol developed by Braithwaite et al, columns are selected to maintain blood glucose within target range. Patients begin in column 2 and switch columns on the basis of response, which accounts for rate of change.64 The column method was further modified by the University of Washington. This protocol uses 4 columns based on insulin sensitivity, with column 1 for insulin-sensitive patients and column 4 for insulinresistant patients, whereas the infusion rate for the protocol developed

by Bode et al is based on the degree of insulin resistance calculated with an insulin sensitivity factor.65,66 Initially, blood glucose monitoring should occur hourly until blood glucose reaches the target range and remains within range for 2 to 3 hours; then blood glucose monitoring can occur every 2 hours. Ultimately, there is no preferred insulin infusion protocol. Protocol selection should be a multidisciplinary decision that takes into account institution-specific factors that may affect implementation, adherence, and patient safety and outcomes.

Sensitivity to insulin can change rapidly with improvement in illness,

Clinical 57

Pharmacy Practice News â&#x20AC;˘ November 2013

Educational Review resulting in reduced insulin requirements. In some instances, patients may not require insulin once acute illness has resolved. For other patients, insulin maintenance therapy may be required. In this situation, when blood glucose is consistently within target, transition from IV to subcutaneous therapy may be considered. Patientspecific factors should be taken into account before such a transition.

These include ensuring that patients are receiving consistent nutrition, are hemodynamically stable, are off vasopressors, are receiving a stable dose of corticosteroids, have minimal peripheral edema, and that any infection they might have is resolving.11,30 Transition should be delayed if there is disruption in nutrition.11,30 Overall, patients with type 1 or 2 diabetes or who need more than 1 unit per hour of IV insulin will likely require transition to subcutaneous insulin. Once a patient is transitioned to subcutaneous insulin, blood glucose monitoring should occur 4 to 6 times daily (at least before meals and at bedtime).

A basal-bolus strategy is preferred for conversion from IV to subcutaneous insulin.11,30,33 The basal-bolus strategy should be considered for patients with resolving acute illness who are receiving oral nutrition. This strategy consists of administration of basal insulin in the form of longacting (glargine) or intermediateacting (isophane) with bolus insulin in the form of rapid-acting (aspart) or short-acting (regular) with meals.

Eighty percent of the total insulin infusion dose from the previous 24 hours is divided equally between basal and bolus insulin. 33,59 Conversely, for patients receiving enteral nutrition, basal insulin with corrective doses of short-acting insulin is recommended. In a prospective study, ICU and ward patients were randomized to receive 40%, 60%, or 80% of their total insulin infusion dose as insulin glargine. A conversion of 80% was associated with the highest percentage of blood glucose values within target range.67 Similarly, in a retrospective study of neurosurgical ICU patients, a 60% to 70% conversion to NPH insulin resulted in a higher percentage of glucose values within the desired range compared with â&#x2030;¤50% conversion.68 Based on these data, a conversion of approximately 60% to 80% may be appropriate for most patients.

Overlapping subcutaneous insulin with IV insulin therapy is important to ensure adequate time for absorption and prevent rebound hyperglycemia. For short- and rapid-acting insulin, therapy should be initiated 1 to 2 hours before discontinuation

of IV insulin, whereas a 2- to 4-hour overlap should be allotted for intermediate- and long-acting insulin.

Hypoglycemia is a potential complication of insulin therapy. It is defined as either moderate (blood glucose <70 mg/dL) or severe (blood glucose <40 mg/dL) and is associated with adverse outcomes.33 Subtle signs of hypoglycemia such as headache, fatigue, and confusion may be confounded in critical illness by the underlying disease or use of medications such as sedatives. Seizures,

cardiac arrhythmias, neurocognitive impairment, and coma typically manifest with severe or prolonged hypoglycemia.30,69,70 Hypoglycemia, irrespective of severity, is associated with increased mortality. In a post hoc analysis conducted by the NICE-SUGAR investigators, both moderate and severe hypoglycemia were associated with increased mortality.71 Interestingly, in a study with a more conservative definition of hypoglycemia (blood glucose <81 mg/dL), higher

mortality also was observed.70 Some patients may be predisposed to hypoglycemia. In a retrospective study, several factors were associated with an increased risk for severe hypoglycemia (blood glucose <45 mg/dL): continuous renal replacement therapy with bicarbonate-based replacement fluid, discontinuation of nutrition without adjustment in insulin, and a history of diabetes, sepsis, or vasopressor therapy.72 Mechanical ventilation and severity of illness also have been

58 Clinical

Pharmacy Practice News • November 2013

Educational Review identified as potential risk factors.73 Prevention is crucial to abating the consequences of hypoglycemia.

Interruptions in nutrition should be anticipated and insulin should be held preemptively or dextrose infusion should be administered. In patients with renal or hepatic dysfunction, careful insulin monitoring and titration should be performed. During corticosteroid tapers, empiric insulin dose reductions should be considered. Early recognition and treatment of moderate hypoglycemia averts

progression to severe hypoglycemia.

Conclusions Stress hyperglycemia commonly occurs in the ICU and is associated with adverse patient outcomes such as increased mortality and morbidity. Consequently, diligent monitoring and management are essential parts of care. This consists of identification of glycemic targets including blood glucose goal, reduction of glycemic variability, and prevention of hypoglycemia. Understanding of

these targets and stress hyperglycemia continues to evolve. In particular, blood glucose goals have shifted from one extreme to the other over the past 2 decades. Based on the results of recent studies, conventional glucose control (blood glucose <180 mg/dL) is preferred as opposed to intensive control (blood glucose ≤110 mg/dL), which is likely more harmful than beneficial. Data suggest that stricter blood glucose control (≤150 mg/dL) may be warranted for cardiac surgery and possibly surgical

ICU patients, but further studies are needed before definitive recommendations can be made.

Hyperglycemia in the ICU is best managed with insulin therapy. Insulin infusions are preferred because they can be easily adjusted based on changes in patients’ clinical status and converted to subcutaneous insulin, if needed, when acute illness has resolved. Development of institutionspecific insulin protocols is essential for safe management. These should emerge from a multidisciplinary committee that determines blood glucose targets, evaluates the capability of the protocol to achieve the targets, and analyzes the protocol for areas of quality improvement.

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Qaseem A, Humphrey LL, Chou R, et al. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

2. Van den Berghe G. Should glucocorticoidinduced hyperglycemia be treated in patients with septic shock? JAMA. 2010;303(4):365-366.

3. Robinson LE, van Soeren MH. Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control.

AACN Clin Issues. 2004;15(1):45-62.

4. Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest. 2004;114(9):1187-1195.

5. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc.

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10. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87(3):978-982.

11. Dombrowski NC, Karounos DG. Pathophysiology and management strategies for hyperglycemia for patients with acute illness during and following a hospital stay. Metabolism.

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34. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care.

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35. American Diabetes Association: Standards of medical care in diabetes—2012. Diabetes Care. 2012;35(suppl 1):s11-s63.

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2009;180(8):821-827.

37. Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg.

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38. Schmeltz LR, DeSantis AJ, Thiyagarajan V, et al. Reduction of surgical mortality and morbidity in diabetic patients undergoing cardiac surgery with a combined intravenous and subcutaneous insulin glucose management strategy. Diabetes Care. 2007;30(40:823-828.

39. Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system

of intensive care patients. Neurology.

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40. Bilotta F, Caramia R, Cernak I, et al. Intensive insulin therapy after severe traumatic brain injury: a randomized clinical trial. Neurocrit Care. 2008;9(2):159-166.

41. Bilotta F, Caramia R, Paoloni FP, et al.

Safety and efficacy of intensive insulin therapy in critical neurosurgical patients.

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42. Thiele RH, Pouratian N, Zuo Z, et al. Strict glucose control does not affect mortality after aneurysmal subarachnoid hemorrhage.

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18. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367.

19. Pomposelli JJ, Baxter JK 3rd, Babineau TJ, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. JPEN J Parenter Enteral Nutr. 1998;22(2):77-81.

20. Karunakar MA, Staples KS. Does stressinduced hyperglycemia increase the risk of perioperative infectious complications in orthopaedic trauma patients? J Orthop Trauma. 2010;24(12):752-756.

21. Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg.

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Effects of moderate intensity glycemic control after cardiac surgery. Ann Thorac Surg. 2010;90(6):1825-1832.

23. Gore DC, Chinkes D, Heggers J, et al.

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Find us at the Intersection of Patient Safety and Pharmacy Efficiency

27. Bercker S, Weber-Carstens S, Deja M, et al. Critical illness polyneuropathy and myopathy in patients with acute respiratory distress syndrome. Crit Care Med. 2005;33(4):711-715.

28. Witt NJ, Zochodne DW, Bolton CF, et al. Peripheral nerve function in sepsis and multiple organ failure. Chest.

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30. Jacobi J, Bircher N, Krinsley J, et al.

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31. Lanspa MJ, Hirshberg EL, Phillips GD, et al. Moderate glucose control is associated with increased mortality compared with tight glucose control in critically ill patients without diabetes. Chest.

2013;143(5):1226-1234.

32. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.

BMJ. 1997;314(7093):1512-1515.

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60 Clinical

Pharmacy Practice News • November 2013

Educational Review Text continued from page 59

43. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;35(5)4:449-461.

44. Arabi YM, Dabbagh OC, Tamim HM, et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients.

Crit Care Med. 2008;36(12):3190-3197.

45. De La Rosa Gdel C, Donado JH, Restrepo AH, et al. Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care. 2008;12(5):R120.

46. Preiser JC, Devos P, Ruiz-Santana S, et al.

A prospective randomised multi-centre controlled trial on tight glucose control by

intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009;35(10):1738-1748.

47. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.

JAMA. 2008;300(8):933-944; Erratum in: 2009;301(9):936.

48. Marik PE, Preiser JC. Toward understanding tight glycemic control in the ICU: a systematic review and metaanalysis. Chest.

2010;137(3):544-551.

49. Friedrich JO, Chant C, Adhikari NK. Does intensive insulin therapy really reduce mortality in critically ill surgical patients?

A reanalysis of meta-analytic data. Crit Care. 2010;14(5):324.

50. Kansagara D, Fu R, Freeman M, Wolf F, et al. Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med. 2011;154(4):268-282.

51. Dellinger RP, Levy MM, Rhodes A, et al.

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

52. COIITSS Study Investigators. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010;303(4):341-348.

53. Brunkhorst FM, Engel C, Bloos F, et al.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139.

54. Inzucchi SE. Clinical practice. Management of hyperglycemia in the hospital setting. N Engl J Med. 2006;355(18):1903-1911.

55. Ali NA, O’Brien JM, Jr., Dungan K, et al. Glucose variability and mortality in patients with sepsis. Crit Care Med. 2008;36(8):2316-2321.

56. Egi M, Bellomo R, Stachowski E, et al. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology.

2006;105(2):244-252.

57. Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36(11):3008-3013.

58. Mackenzie IM, Whitehouse T, Nightingale PG. The metrics of glycaemic control in critical care. Intensive Care Med. 2011;37(3):435443; Erratum in: 2013;39(4):799.

59. Bode BW, Braithwaite SS, Steed RD, et al. Intravenous insulin infusion therapy: indications, methods, and transition to subcutaneous insulin therapy. Endocr Pract. 2004;10(suppl 2):71-80.

60. Krikorian A, Ismail-Beigi F, Moghissi ES. Comparisons of different insulin infusion protocols: a review of recent literature. Curr Opin Clin Nutr Metab Care.

2010;13(2):198-204.

61. Anger KE, Szumita PM. Barriers to glucose control in the intensive care unit.

Pharmacotherapy. 2006;26(2):214-228.

62. Goldberg PA, Siegel MD, Sherwin RS, et al.

Implementation of safe and effective insulin infusion protocol in a medical intensive care unit. Diabetes Care. 2004;27(2):461-467.

63. Marvin MR, Inzucchi SE, Besterman BJ. Computerization of the yale insulin infusion protocol and potential insights into causes of hypoglycemia with intravenous insulin.

Diabetes Technol Ther. 2013;15(3):246-252.

64. Braithwaite SS, Edkins R, MacGregor KL, et al. Performance of dose-defining insulin infusion protocol among trauma service intensive care unit admissions. Diabetes Technol Ther. 2006;8(4):476-488.

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65. Trence Dl, Kelly JL, Hirsch IB. The rationale and management of hyperglycemia in in-patients with cardiovascular disease: time to change. J Clin Endocrinol Metab.

2003;88(6):2430-2437.

66. Wilson M, Weinreb J, Soo Hoo GW. Intensive insulin therapy in critical care: a review of 12 protocols. Diabetes Care.

2007;30(4):1005-1011.

67. Schmeltz LR, DeSantis AJ, Schmidt K, et al.

Conversion of intravenous insulin infusions to subcutaneously administered insulin glargine in patients with hyperglycemia.

Endocr Pract. 2006;12(6):641-650.

68. Weant KA, Ladha A. Conversion from continuous insulin infusions to subcutaneous insulin in critically ill patients. Ann Pharmacother. 2009;43(4):629-634.

69. Kavanagh BP, McCowen KC. Clinical practice. Glycemic control in the ICU. N Engl J Med. 2010;363(26):2540-2546; Erratum in: 2011;364(12):1182.

70. Egi M, Bellomo R, Stachowski E, et al.

Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc. 2010;85(3):217-224.

71. The NICE-SUGAR Study Investigators.

Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012;367(12):1108-1118.

72. Vriesendorp TM, van Santen S, DeVries JH, et al. Predisposing factors for hypoglycemia in the intensive care unit. Crit Care Med. 2006;34(1):96-101.

73. Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med. 2007;35(1)):2262-2267.

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Letters

Debate on Canagliflozin’s Role for Type 2 Diabetes Janssen Comments On Diabetes Article

T

hanks for your article, “Look for Patterns To Optimize Insulin Therapy,” in the September issue of Pharmacy Practice News [page 23]. I work with Janssen Pharmaceuticals and wanted to provide some additional perspective and background information on Invokana (canagliflozin), the company’s sodium glucose co-transporter 2 (SGLT2) inhibitor, which the FDA approved earlier this year for adults with type 2 diabetes. The article included commentary from Dr. Eric Ip suggesting [that canagliflozin] produces only modest reductions in A1c.

In fact, results across the global Phase III clinical program showed that both doses of [canagliflozin], when used as monotherapy or as combination therapy with other glucose-lowering medications, significantly improved glycemic control. For example, when used as monotherapy, [canagliflozin] 100 and 300 mg reduced A1c by 0.91% and 1.16%, respectively, compared with placebo.

Furthermore, comparative studies have shown the [canagliflozin] 300-mg dosage provided greater improvements in blood glucose control compared with the commonly prescribed therapies glimepiride or sitagliptin. As briefly noted in the article, in addition to improved glycemic control, both doses of [canagliflozin] also produced significant reductions in the prespecified secondary end points of body weight and systolic blood pressure. For additional information on [canagliflozin’s] clinical results, please see http://www. multivu.com/players/English/60562janssen-invokana/ links/60562K02CAN13156A-INVOKANA-MediaFact-Sheet.pdf and Invokana safety information.

—Christian Pflaumer Chandler Chicco Agency, on behalf of Janssen Pharmaceuticals, Inc.

Expert Responds Canagliflozin is a SGLT2 inhibitor, a novel class of medications used to treat type 2 diabetes mellitus and improve glycemic control.1 Canagliflozin lowers blood glucose levels by blocking the reabsorption of glucose in the kidneys.1 Although it has been shown to lower A1c levels,1 this reduction is relatively modest compared with that seen with other antihyperglycemic agents. According to the 2012 position statement regarding the management of hyperglycemia in patients with type 2 diabetes from the American Diabetes Association and the European Association for the Study of Diabetes, the therapeutic agents that

have a “high” glucose-lowering effect include metformin, sulfonylureas, thiazolidinediones, GLP [glucagon-like peptide]-1 agonists and insulin.2 Metformin is considered the first-line oral medication for the treatment of type 2 diabetes2 and has proven to lower A1c levels by approximately 1.5% to 2%.3-8 The sulfonylureas include the agents glipizide, glyburide and glimepiride.

Glipizide and glyburide decrease A1c by

approximately 1.5% to 1.9%,9-11 whereas glimepiride was shown to lower A1c levels by approximately 1.1%.12 The thiazolidinedione pioglitazone was shown to lower A1c by 0.53% to 1.6%,13-21 with a majority of patients showing a decrease greater than 1%.13-18 The GLP-1 agonist liraglutide was shown to decrease A1c by 0.30% to 1.56%, with a majority of patients achieving greater than 1%.22-27 Finally, multiple studies have shown

an A1c reduction of 1% to 2% for basal insulin in individuals with type 2 diabetes.10,27-32 Thus, metformin, sulfonylureas, thiazolidinediones, GLP-1 agonists and insulin are considered to have “high” A1c-lowering potential because most studies demonstrate an A1c lowering of at least 1%.

In comparison, canagliflozin was shown to decrease A1c levels, but not

•

see CANAGLIFLOZIN, page 64

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62 Last Word

Pharmacy Practice News • November 2013

The Transplant Pharmacist

Pharmacists and Students Improve Donation Rates Barrett Crowther, PharmD, BCPS Clinical Pharmacist Pediatrics & Solid Organ Transplant University Health System San Antonio, Texas

T

here are more than 115,000 individuals in the United States awaiting a potentially lifesaving kidney, liver, pancreas, heart, lung, and/or intestine transplant. This number greatly overshadows the 28,052 solid organ transplants completed in 2012 (http://optn.transplant. hrsa.gov/). Although this imbalance seems dramatic, pharmacists are making a difference in closing this disparity.

Transplant pharmacists are actively involved in efforts by transplant centers to increase and efficiently use the potential organ pool. Many transplant pharmacists assist with living donor programs.

Living donation is most common with kidney transplantation, although living donation is also available with lungs and livers (http://www.transplantliving. org/living-donation/). Transplant pharmacists are involved in education and management of both the donor and the recipient. Additionally, many transplant centers participate in paired kidney exchange programs, in which incompatible blood type donor and recipient pairs are matched with others who are compatible. Transplant pharmacists are involved in evaluating patients, helping to make decisions for matching and post-transplant care. Transplant pharmacists also can be key decision makers in their transplant center’s kidney desensitization program. Desensitization typically involves plasmapheresis and/ or a combination of medications, such as IV immunoglobulin and rituximab, to reduce the amount and strength of circulating antibodies in the potential recipient to make a previously incompatible donor and recipient pair compatible. Alloway et al have further outlined work roles and responsibilities of the transplant pharmacist ((Am J Transplant 2011;11:1576-1583).

Organ Donation Awareness Beyond routine work duties, many transplant pharmacists have helped to educate the community about organ donor awareness, thus allowing these pharmacists to embrace the public health promotion role that is expected of pharmacists in all areas of practice.

Pharmacy students have embraced these organ donation awareness projects/ events as well, working closely with the transplant pharmacy community. These collaborations have allowed pharmacy students to learn more about the field of transplant pharmacy.

For the past four years, the American Society of Transplantation (AST)

Transplant Pharmacy Community of Practice (CoP) has supported an annual Organ Donation Awareness Challenge.

The Challenge highlights partnerships with U.S. schools of pharmacy to increase donor awareness. Past projects have ranged from holding organ donation drives and helping community members sign up on state online registries. One particularly creative example included the development of a special ice cream flavor to celebrate Donate Life Month in April. Past winners of the Challenge have received recognition at the annual American Transplant Congress, with the presentation of an engraved plaque from AST recognizing their school.

The Challenge has been well received by pharmacy students. Jillian Descourouez, PharmD, BCPS, a clinical pharmacist in solid organ transplant at the University of Wisconsin Hospital and Clinics, in Madison, explained, “What amazes me most about the Challenge is the fact that so many students are willing to put in a vast amount of time and energy in developing and implementing such a wide variety of events, with little more incentive than increasing organ donation awareness and a small donation from the American Society of Transplantation for the winning team. While some people may think that pharmacy students have too many things going on with school, work, clubs and their personal lives to dedicate much time to volunteerism, the students who have participated in the Challenge prove this notion wrong.”

Participation in the Challenge has risen steeply in four short years, with only a few schools of pharmacy participating in 2009 to 13 schools participating this past year. The winner of the 20122013 Challenge, University of Arkansas for Medical Sciences (UAMS) College of Pharmacy, recently was recognized at the 2013 American Transplant Congress. UAMS pharmacy students educated nearly 300 high school students at four different high schools on organ donation. One of the education sessions was recorded and broadcast by a local news station with an interview of one of the group’s members. Also, Seth Heldenbrand, PharmD, a clinical specialist of solid organ transplant and an associate professor at UAMS College of Pharmacy, participated in a different live local NBC news interview discussing the common myths regarding organ donation. UAMS students educated approximately 200 adults in person and collected more than 200 organ donation pledge forms, many from high school students. Additionally, UAMS students raised $1,000 for their local organ procurement organization by selling Donate Life Month shirts that they designed.

New groups are participating in the Challenge each year. Karen Hardinger, PharmD, BCPS, a clinical associate professor of pharmacy practice at the University of Missouri-Kansas City (UMKC) School of Pharmacy, said UMKC “participated in the initiative for the first time last year. The students raised donor awareness through health fairs and created a manual that instructs students on how to educate potential donors. The students were able to reach numerous potential donors through their efforts and educated many people. I would encourage all schools to participate in this very beneficial competition.”

transplant pharmacist liaisons for the Challenge also can email Dr. Crowther at Barrett.Crowther@uhs-sa.com.

Dr. Crowther reported no relevant financial conflict of interest.

Series Editor Eric M. Tichy, PharmD, BCPS Clinical Pharmacy Specialist Solid Organ Transplant Director, PGY-2 Residency Transplant Yale-New Haven Hospital Department of Pharmacy New Haven, CT

The Rewards of Educating The Public Pharmacy students and the community benefit from participation in the Challenge. Dr. Descourouez said, “The Challenge helps students realize there is a bigger picture than completing pharmacy school. It helps to keep their education in perspective as they realize the impact they can have on health care across the United States. By responding to the call for organ donation awareness and increasing the number of registered donors, the pharmacy students participating in the Challenge are increasing the odds that someone waiting will receive a lifesaving organ.”

Pharmacist participants of the Challenge have noted a sense of fulfillment with conducting organ donation awareness projects. “Getting involved with our students and community to promote organ donation awareness was one of the most rewarding things I have done in my career as a transplant pharmacist,” said Dr. Heldenbrand.

This upcoming year, the AST Transplant Pharmacy CoP is supporting the fifth annual Organ Donation Awareness Challenge. The ultimate goal for the project is to have all U.S. schools of pharmacy participating in at least one organ donation awareness activity each year. Each school of pharmacy has been assigned a transplant pharmacist point-of-contact/liaison for assistance with projects. To submit projects for the Challenge, applicants must have a collaborator who is a current member of the AST Transplant Pharmacy CoP. Applicants should submit a twopage, typed summary of activities in paragraph form via email to Barrett Crowther at barrett.crowther@uhs-sa. com. The submission deadline for the 2013-2014 academic year is May 19, 2014.

Those interested in more information regarding the annual AST Transplant Pharmacy CoP Organ Donation Challenge and a copy of the Organ Donation Challenge manual, which lists potential

T

he Transplant Pharmacy Community is a major stakeholder in the promotion of organ donation, because without donation there is simply no transplantation.

Realization of this undeniable fact has led the American Society of Transplantation’s (AST) Pharmacist Community of Practice to include promotion of organ donor awareness as a major goal since the inception of this community. There can never be enough community education and engagement to explain the “miracle of transplantation” to the public. As pharmacy professionals experiencing this miracle firsthand, we must all do our best to spread the “good news” of transplantation to our colleagues, friends and families. Pharmacists are the most accessible of all health care professionals, and we can collectively have a powerful impact by virtue of this reach.

Pharmacy professionals and students are embracing the entire challenge of transplantation today, and that must include the voices of our patients and their families when it comes to organ donation. You can promote organ donor awareness in many ways and here is a list to start from: 1. Make sure information about donor awareness is included in lectures at your school of pharmacy.

2. Discuss organ donation personally with your friends, family and colleagues.

3. Use social media (eg, Facebook) to promote organ donation.

4. Mentor a team in the AST’s Pharmacist Community of Practice. (It’s not too early to start planning for 2014!)

5. Reach out to your local Donate Life chapter and volunteer at an event.

As AST president Daniel R. Salomon, MD, has said, the real answer (to reducing the waitlist of almost 120,000 people) remains, “It’s donation, stupid.” As a pharmacy professional, please help advance this goal by making organ donation awareness part of your life.

During the next year, “The Transplant Pharmacist” column will continue to present contemporary issues in transplant pharmacy for examination. Topics will include novel patient education techniques, analysis of the transplant pharmacy business model and new drug use developments.

If you have any ideas for column topics, please email me at Eric.Tichy@ynhh.org.

Rationale, Reversal, and Recovery of Neuromuscular Blockade Part 1: Framing the Issues Case Study Harold is a 74-year-old man undergoing a video-assisted right upper lobectomy for stage I non-small cell lung cancer.

Current Symptoms • Dyspnea • Coughing with hemoptysis • Chest pain Vital Signs • Height: 177.8 cm (70”) • Weight: 65 kg (143 lb) Signi¿cant Medical History • Hypertension • Chronic obstructive pulmonary disease (moderate) Current Medications • Metoprolol succinate ER 50 mg/d • Tiotropium bromide inhalation powder Laboratory Results • 2-cm lesion in right upper lobe revealed on chest computed tomography (CT) scan; malignancy con¿rmed with needle biopsy • No abnormal bronchopulmonary or mediastinal lymph nodes; brain CT, isotopic bone scan, abdominal ultrasonography negative for distant metastases • Forced expiratory volume in the ¿rst second: 43.6% of predicted value (1.44 L) • Carbon monoxide diffusing capacity: 71.7% of predicted values (20.19 mL/min/mmHg) • Cardiac ultrasonography: normal pulmonary artery pressure (22 mm Hg) At induction, Harold receives propofol 1.5 mg/kg and rocuronium 0.6 mg/kg. During the procedure, movement of the diaphragm interferes with surgery.

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Supported by an educational grant from Merck.

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Each activity will present a clinical scenario that you face in your daily practice. After reading the introduction to the case, consider the challenge questions, and then visit www.CMEZone.com/nmb1 to ¿nd out how your answers stack up against those of our multidisciplinary faculty panel.

Access the activities on your desktop, laptop, or tablet to explore the issues surrounding safe, effective, neuromuscular blockade and reversal via a unique multimedia learning experience and earn 1.0 AMA PRA Category 1 Credit.™ Participate in the coming months as well to complete the whole series and earn a total of 3.0 AMA PRA Category 1 Credits.™ This activity’s distinguished faculty Jon Gould, MD Glenn S. Murphy, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Clinical Professor, Anesthesiology University of Chicago Pritzker School of Medicine Director Cardiac Anesthesia and Clinical Research NorthShore University HealthSystem Evanston, Illinois

Challenge Questions 1. What would you do next?

2. What potential postoperative risks does this patient face?

Access this activity at www.cmezone.com/nmb1

64 Last Word

Pharmacy Practice News • November 2013

Letters

CANAGLIFLOZIN continued from page 61

to the same consistent magnitude as metformin, sulfonylureas, pioglitazone, liraglutide and basal insulin. When used as monotherapy or as add-on therapy, canagliflozin was shown to reduce A1c by 0.60% to 1.03%.1,33-36 However, all but one study demonstrated an A1c reduction below 1%.1,33-36 Thus, because the A1c-lowering effect generally is between 0.5% and 1.0%, canagliflozin may be grouped into the “generally

lower” A1c-reducing antihyperglycemic medications, along with meglitinides, DPP-4 inhibitors, α-glucosidase inhibitors, colesevelam and bromocriptine.2,33-36 Because canagliflozin is relatively new on the market, further data are needed to evaluate its long-term safety and to determine its place in type 2 diabetes management.

References 1. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise.

with a focus on dual therapy. Clin Ther.

2003;25(12):2991-3026.

Diabetes Obes Metab. 2013;15(4):372-382.

2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care.

2012;35(6):1364-1379.

3. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulindependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541-549.

4. Setter SM, Iltz JL, Thams J, Campbell RK. Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review

5. Grant PJ. The effects of high- and mediumdose metformin therapy on cardiovascular risk factors in patients with type II diabetes.

Diabetes Care. 1996;19(1):64-66.

6. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebocontrolled, dose-response trial. Am J Med. 1997;103(6):491-497.

7.

Fujioka K, Brazg RL, Raz I, et al. Efficacy, dose-response relationship and safety of once-daily extended release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies.

Diabetes Obes Metab. 2005;7(1):28-39.

8. Hermann LS, Kalen J, Katzman P, et al. Longterm glycaemic improvement after addition of metformin to insulin in insulin-treated obese type 2 diabetes patients. Diabetes Obes Metab.

2001;3(6):428-434.

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Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information as well as unique searching features and printing capabilities.

Each installment contains brief summaries of the most important articles from the current month’s issue, and breaking news ahead of print.

9. Simonson DC, Kourides IA, Feinflos M, Shamoon H, Fischette CT. Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled trials. The Glipizide Gastrointestinal Therapeutic System Study Group.

Diabetes Care. 1997;20(4):597-606.

10. Abraira C, Henderson WG, Colwell JA, et al.

Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM).

Diabetes Care. 1998;21(4):574-579.

11. Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin T, Kourides IA. Comparative efficacy of a once-daily controlled-release formulation of glipizide and immediate-release glipizide in patients with NIDDM. Diabetes Care. 1994;17(12):1460-1464.

12. Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, doubleblind assessment of metabolic parameters and cardiovascular risk factors. Clin Ther.

2003;25(2):472-484.

13. Wainstein J, Katz L, Engel SS, et al. Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes. Diabetes Obes Metab.

2012;14(5):409-418.

14. Charbonnel BH, Matthews DR, Schernthaner G, Hanefeld M, Brunetti P, QUARTET Study Group. A long-term comparison of pioglitazone and gliclazide in patients with type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial. Diabet Med. 2005;22(4):399-405.

15. Rajagopalan R, Perez A, Ye Z, Khan M, Murray FT. Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus. Drugs Aging. 2004;21(4):259-271.

16. Scherbaum WA, Goke B; German Pioglitazone Study Group. Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study. Horm Metab Res. 2002;34(10):589-595.

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17. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improved glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care.

2000;23(11):1605-1611.

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Letters 18. Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9(2):175-185.

19. Temboonkiat S, Satyapan N, Benjasuratwong Y, et al. Clinical efficacy of pioglitazone: generic vs. original product. J Med Assoc Thai.

2012;95(suppl 5):s58-s62.

20. Perez A, Zhao Z, Jacks R, Spanheimer R. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr Med Res Opin. 2009;25(12):2915-2923.

21. Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes.

Diabetologia. 2005;48(6):1093-1104.

22. Garber A, Henry RR, Ratner R, et al. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(4):348-356.

23. Garcia-Hernandez P, Arechavaleta-Granell Mdel R, Yamamoto J, Falahati A, GonzalezGalvez G, Grupo de Investgadores de LEAD-3 en Mexico. [Liraglutide and glimepiride on glycaemic control in type 2 diabetes in the Mexican cohort (LEAD 3)]. Rev Med Inst Mex Sequro Soc. 2010;48(5):543-548.

24. Garber A, Henry R, Ratner R, et al.

Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, doubleblind, parallel-treatment trial. Lancet.

2009;373(9662):473-481.

25. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD).

Diabetes Care. 2009;32(7):1224-1230.

26. Russel-Jones D, Vaag A, Schmitz O, et al.

Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-2055.

27. Kaku K, Rasmussen MF, Clauson P, Seino Y. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2010;12(4):341-347.

28. Heise T, Tack CJ, Cuddihy R, et al. A newgeneration ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naïve people with type 2 diabetes: a randomized, controlled trial. Diabetes Care.

2011;34(3):669-674.

29. Ligthelm RJ, Gylvin T, DeLuzio T, Raskin P. A comparison of twice-daily biphasic insulin aspart 70/30 and once-daily insulin glargine in persons with type 2 diabetes mellitus inadequately controlled on basal insulin and oral therapy: a randomized, open-label study.

Endocr Pract. 2011;17(1):41-50.

30. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets-the TITRATE study. Diabetes Obes Metab. 2009;11(6):623-631.

31. Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a compari-

son of biphasic and basal insulin analogs.

Diabetes Care. 2005;28(2):260-265.

mellitus: a randomized trial. Hosp Prac (1995).

2013;41(2):72-84.

32. Janka HU, Plewe G, Riccle MC, Kliebe-Frisch C, Schweitzer MA, YKi-Jarvinen H. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care.

2005;28(2):254-259.

35. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232-1238.

33. Devineni D, Morrow L, Hompesch M, et al.

Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14(6):539-545.

36. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomized, doubleblind, phase 3 non-inferiority trial. Lancet.

2013;382(9896):941-950.

34. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes

Amber A. Mann, PharmD/MPH Candidate, 2015 Touro University California College of Pharmacy Vallejo, California

Eric J. Ip, PharmD, BCPS, CSCS, CDE Associate Professor and Chair, Pharmacy Practice Department Touro University California College of Pharmacy Vallejo, California Diabetes Specialist/Clinical Pharmacist Kaiser Permanente Mountain View Clinics Mountain View, California

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66 Technology

Pharmacy Practice News • November 2013

Automation

Smart Pump Launches Require the Whole Team Chicago—The launch of a new smart pump system should be a multidisciplinary effort, according to Erick Borkowski, PharmD, who has spearheaded such efforts as the manager of the Pharmacy Department at Northwestern Lake Forest Hospital (NLFH), in Illinois.

In a presentation at the Hematology/ Oncology Pharmacy Association’s (HOPA) fall conference, Dr. Borkowski described how NLFH, in the process of launching its second smart pump system, learned how to plan more effectively based on the implementation of its first system more than four years ago.

“It is critically necessary to engage everyone in the planning for the implementation,” he stressed, “so that everyone who works with the pumps plays a part in the implementation and maintenance process. I don’t think that was done the first time out. … Pharmacy alone did most of the planning, and we think that’s one of the reasons why nursing’s compliance with the pumps consistently averaged just over 50% and never exceeded 55% no matter what we tried.”

In contrast, NLFH’s new smart pump system went live April 30, and it has been much more successful. “Compliance has been averaging 92% for the past three months,” Dr. Borkowski said.

The implementation was made significantly easier, he added, because NLFH’s parent, Northwestern Memorial Hospital (NMH), in Chicago, had been using the same pump system for over five years. “There were a lot of things they had gone through that we were learning from.”

For example, NLFH was able to leverage the library build that had been completed at NMH when they implemented their smart pumps, Dr. Borkowski noted.

“Moving to a consolidated library within the pumps was a lot easier than it would have been without that earlier work.”

Additionally, work that NLFH had done to standardize IV concentrations during their electronic medical record (EMR) conversion aided in the implementation of the new smart pumps.

But NLFH did have to create a pediatrics database for the library from scratch because it was not part of NMH’s library. “Building a new pediatric library allowed us to scrutinize our current library as well as ensure that all orderable medications were available in the pump,” Dr. Borkowski said.

“That was one of the biggest lessons we learned and one of the biggest improvements we made,” he said.

Before the changes, “medications that were to be delivered by infusion would be in our EMR, but they might not have had analogous entries in the drug library for the pumps. So we made

‘Whenever possible, we try to implement ... strategies for addressing drug library issues to make it difficult for nursing to program the entry incorrectly.’

—Wyndie Tse, PharmD sure that if it could be ordered in the EMR, the corresponding medication also would be in the pump. That helped enhance compliance tremendously.”

A great deal of the team’s time was focused on deciding what the dose range limits should be. “We wanted to make sure the limits were within reason from the nurse’s point of view,” Dr. Borkowski said. “We wanted to know what the nurses wanted to be able to see and do in the system.”

In planning for the implementation, NMH’s pharmacy programmers developed processes that struck a fine balance between rules to ensure that an infused medication would be “safe” for the patient and rules that were not “overly restrictive,” for example, creating alarms when nurses tried to infuse a drug as a special procedure under circumstances that made that exception appropriate.

“We tried to set alert limits in the software that would make alarms meaningful but with enough of a buffer that nuisance alarms weren’t being set off.”

NMH and NLFH update the pumps quarterly, with pharmacy and nursing sharing information to try to ensure that all pumps are updated effectively.

The Pharmacy Department also shares reports with nurses frequently to stay on top of issues and continually searches for new ways “to make it easy to use the pumps.”

In another presentation, Wyndie Tse, PharmD, a medication safety pharmacist at City of Hope National Medical Center, in Duarte, Calif., described ways for pharmacy to take a “proactive role” in smart infusion pump optimization.

By “managing infusion pump data and evaluating smart pump alerts to identify potential drug library improvements, creating tools for nursing education and coordinating library updates with

nursing,” she said, pharmacists can help enhance pump use.

At City of Hope, the pharmacy now has the primary responsibility for analyzing smart pump utilization data to identify issues that need improvement.

One problem area identified through the continuous quality improvement (CQI) review was that a significant number of nurses were overriding the duration limit for mycophenolate mofetil.

Many nurses were confused by information on the patient label, which listed a diluent volume and a final volume. The nurses were entering the wrong volume when programming the pump. “It was a case of the label saying one thing and the software another,” said Dr. Tse, “so the nurses’ misinterpretation of that caused an alert to fire. The solution was to create prebuilt entries in the drug library software that made it unnecessary for the nurses to program volume.” The result was that the drug “fell off our top 5 override list” and error alerts decreased, she said, adding, “Whenever possible, we try to implement high-leverage strategies for addressing drug library issues to make it difficult for nursing to program the entry incorrectly.”

To begin the drug library updating process, Dr. Tse said she looked at “best practice guidelines for smart pumps— which included a review of our formulary to see what drugs were missing from our library and needed to be added—as well as reviewed CQI data, internal medication event reports involving infusion pumps and nursing staff feedback.”

Additionally, quarterly internal compliance audits implemented starting last spring revealed that although compliance with the library to infuse medications met the 90% goal, compliance using the library to infuse hydrations was around 70%, Dr. Tse said. “By con-

ducting the real-time audits,” she said, “we learned that nursing was not aware that hydrations should infuse using the fluid section of our library, which has rate-protected limits. In this case, education was very important.”

Another best practice recently implemented at City of Hope is that pharmacy now coordinates library updates with nursing, rather than leaving the lead role responsibility to nursing alone.

“Now pharmacy and nursing are equal partners and the advantage is that process improvement changes will get done consistently and in a timely manner.

“One of the lessons we learned is that you cannot set a smart pump and forget about it. We had been updating our library every one to two years before 2012. The recommendation from the [Institute for Safe Medication Practices] Summit on the Use of Smart Pumps is to update a minimum of quarterly. So we were a little bit behind. Now we are updating our library two to three times a year, so we are moving in the right direction.”

City of Hope is a wireless environment, and Dr. Tse stressed that in optimizing smart pumps, hospitals have to keep in mind that “even in a wireless environment, there is still a significant investment of nursing time in performing the library update.” The drug library cannot be updated while the pumps are actively in use, she noted.

“So pumps need to be powered off, turned back on and then the nurses need to select a new patient in order to receive the new library.” Many nurses did not realize they had to select a new patient to finalize the update. “So that was an education tip we emphasized to solve this issue, and it has [worked].”

—Liz Parks

SAMSCA A® (tolvaptan) tablets for oral use Brief Summary of Prescribing Information. Please see Full Prescribing Information for complete product information.

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.

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Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%)

(N = 220) n (%)

Placebo

16 (7)

4 (2)

11 (5)

2 (1)

14 (6)

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SAMSCA® (tolvaptan) JDVWURLQWHVWLQDO EOHHGLQJ ZDV UHSRUWHG LQ RXW RI WROYDSWDQ WUHDWHG SDWLHQWV DQG RXW RI SODFHER WUHDWHG SDWLHQWV 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLFF SDWLHQWV WUHDWHG ZLWK SAMSCA and at a rate greater than placebo LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV with hyponatremia (N = 111) and are not mentioned elsewhere in the label: Blood and Lymphatic System Disorders: Disseminated LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU ¿EULOODWLRQ ,QYHVWLJDWLRQV 3URWKURPELQ WLPH prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis.

Postmarketing Experience: 7KH IROORZLQJ DGYHUVH UHDFWLRQV KDYH EHHQ LGHQWL¿HG GXULQJ SRVW DSSURYDO XVH RI 6$06&$ %HFDXVH WKHVH UHDFWLRQV DUH UHSRUWHG YROXQWDULO\ IURP D SRSXODWLRQ RI DQ XQNQRZQ VL]H LW LV QRW DOZD\V SRVVLEOH WR UHOLDEO\ HVWLPDWH WKHLU IUHTXHQF\ RU HVWDEOLVK D FDXVDO UHODWLRQVKLS WR GUXJ H[SRVXUH Neurologic: 2VPRWLF GHP\HOLQDWLRQ V\QGURPH Investigations: Hypernatremia 5HPRYDO RI H[FHVV IUHH ERG\ ZDWHU LQFUHDVHV VHUXP RVPRODOLW\ DQG VHUXP VRGLXP FRQFHQWUDWLRQV $OO SDWLHQWV WUHDWHG ZLWK WROYDSWDQ HVSHFLDOO\ WKRVH ZKRVH VHUXP VRGLXP OHYHOV EHFRPH QRUPDO VKRXOG FRQWLQXH WR EH PRQLWRUHG WR HQVXUH VHUXP VRGLXP UHPDLQV ZLWKLQ QRUPDO OLPLWV ,I K\SHUQDWUHPLD LV REVHUYHG PDQDJHPHQW PD\ LQFOXGH GRVH GHFUHDVHV RU LQWHUUXSWLRQ RI WROYDSWDQ WUHDWPHQW FRPELQHG ZLWK PRGL¿FDWLRQ RI IUHH ZDWHU LQWDNH RU LQIXVLRQ 'XULQJ FOLQLFDO WULDOV RI K\SRQDWUHPLF SDWLHQWV K\SHUQDWUHPLD ZDV UHSRUWHG DV DQ DGYHUVH HYHQW LQ RI SDWLHQWV UHFHLYLQJ WROYDSWDQ YV RI SDWLHQWV UHFHLYLQJ SODFHER DQDO\VLV RI ODERUDWRU\ YDOXHV GHPRQVWUDWHG DQ LQFLGHQFH RI K\SHUQDWUHPLD RI LQ SDWLHQWV UHFHLYLQJ WROYDSWDQ YV LQ SDWLHQWV UHFH I LYLQJ placebo.

DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHO¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVWW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV should not be co-administered [see Dosage and Administration (2.3) and Contraindications (4.4)].

Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: Reduction in the dose of SAMSCA may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. Rifampin and Other CYP 3A Inducers: 5LIDPSLQ LV DQ LQGXFHU RI &<3 $ DQG 3 JS &R DGPLQLVWUDWLRQ RII ULIDPSLQ DQG 6$06&$ UHGXFHV H[SRVXUH WR WROYDSWDQ E\ 7KHUHIRUH WKH H[SHFWHG FOLQLFDO HIIHFWV RI 6$06&$ LQ WKH SUHVHQFH RI ULIDPSLQ DQG RWKHU LQGXFHUV H J ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH DQG 6W -RKQ¶V :RUW PD\\ QRW EH REVHUYHG DW WKH XVXDO GRVH OHYHOV RI 6$06&$ 7KH GRVH RI 6$06&$ PD\ KDYH WR EH LQFUHDVHG [Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ GLJR[LQ IXURVHPLGH DQG K\GURFKORURWKLD]LGH ZLWK 6$06&$ KDV QR FOLQLFDOO\ UHOHYDQW LPSDFW RQ WKH H[SRVXUH WR WROYDSWDQ Effects of Tolvaptan on Other Drugs: Digoxin: 'LJR[LQ LV D 3 JS VXEVWUDWH &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK GLJR[LQ LQFUHDVHG GLJR[LQ $8& E\ DQG &PD[ E\ Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide: Co-administration RI WROYDSWDQ GRHV QRW DSSHDU WR DOWHU WKH SKDUPDFRNLQHWLFV RI ZDUIDULQ IXURVHPLGH K\GURFKORURWKLD]LGH RU DPLRGDURQH RU LWV DFWLYH PHWDEROLWH GHVHWK\ODPLRGDURQH WR D FOLQLFDOO\ VLJQL¿FDQW GHJUHH Lovastatin: 6$06&$ LV D ZHDN LQKLELWRU RI &<3 $ &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ DQG 6$06&$ LQFUHDVHV WKH H[SRVXUH WR ORYDVWDWLQ DQG LWV DFWLYH PHWDEROLWH ORYDVWDWLQ È&#x2022; K\GUR[\DFLG E\ IDFWRUV RI DQG UHVSHFWLYHO\ 7KLV LV QRW D FOLQLFDOO\ UHOHYDQW FKDQJH Pharmacodynamic Interactions: 7ROYDSWDQ SURGXFHV D JUHDWHU KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDQ GRHV IXURVHPLGH RU K\GURFKORURWKLD]LGH &RQFRPLWDQW DGPLQLVWUDWLRQ RI WROYDSWDQ ZLWK IXURVHPLGH RU K\GURFKORURWKLD]LGH UHVXOWV LQ D KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDW LV VLPLODU WR WKH UDWH DIWHU WROYDSWDQ DGPLQLVWUDWLRQ DORQH $OWKRXJK VSHFL¿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during concomitant drug therapy. As a V2 UHFHSWRU DQWDJRQLVW WROYDSWDQ PD\ LQWHUIHUH ZLWK WKH 92 DJRQLVW DFWLYLW\ RI GHVPRSUHVVLQ G'$93 ,Q D PDOH VXEMHFW ZLWK PLOG 9RQ :LOOHEUDQG Y: GLVHDVH LQWUDYHQRXV LQIXVLRQ RI G'$93 KRXUV DIWHU DGPLQLVWUDWLRQ RI RUDO WROYDSWDQ GLG QRW SURGXFH WKH H[SHFWHG LQFUHDVHV LQ Y: )DFWRU $QWLJHQ RU )DFWRU 9,,, DFWLYLW\ ,W LV QRW UHFRPPHQGHG WR administer SAMSCA with V2 agonist.

USE IN SPECIFIC POPULATIONS: 7KHUH LV QR QHHG WR DGMXVW GRVH EDVHG RQ DJH JHQGHU UDFH RU FDUGLDF IXQFWLRQ [see Clinical Pharmacology (12.3)].

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Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$MSCA >VHH 8VH ,Q 6SHFL¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered g trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

86 / % 5HY © 2013 Otsuka Pharmaceutical Co., Ltd.

For 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

WHEN FLUID RESTRICTION IS NOT ENOUGH, HELP PATIENTS BREAK FREE WITH FREE WATER CLEARANCE

Once Daily

Statistically significantly increased serum sodium vs placebo—in as early as 8 hours compared to baseline Primary endpoint was average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan, 4.0 mEq/L vs placebo, 0.4 mEq/L) and baseline to Day 30 (tolvaptan, 6.2 mEq/L vs placebo, 1.8 mEq/L).

• Too rapid correction of serum sodium can cause serious neurologic sequelae • Avoid fluid restriction during the first 24 hours of therapy

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 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.

Warnings and Precautions: • 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 • SAMSCA can cause serious and potentially fatal liver injury. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired. Limit duration of therapy with SAMSCA to 30 days • 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 • Co-administration with hypertonic saline is not recommended • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors • Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels Commonly Observed Adverse Reactions – (SAMSCA incidence ≥5% more than placebo, respectively): 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%).

Gastrointestinal Bleeding in Patients with Cirrhosis – In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptantreated patients vs 2% for placebo.

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.

SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

©2013 Otsuka America Pharmaceutical, Inc.

For more information please visit SAMSCA.com

August 2013

0713A-8929E

Distributed by

NOVEMBER 2013

REPORT Transforming the Pharmacy into a Strategic Asset Improving Patient Care and the Bottom Line right route, and right freost hospitals and quency.” It is now optimal to health systems are Why Consider a Pharmacy as a create a hospital pharmaworking to prepare for health Strategic Asset? cy that is a strategic asset care reform and capitalize to the hospital system. And on the opportunities it pres• Capitalize on new growth opportunities and that means shifting to the ents. At a minimum, they are increase reimbursements 4 F Framework: “Find meanlooking at clinical and opera• Benchmark to reduce costs and deploy best ingful growth, Fix ineffitional changes to better optipractices ciencies, Fulfill quality care mize the cost and quality of mission, and Follow the care, and the financial per• Recover entitled reimbursements and patient (Figure).” formance of the hospital. leverage federal program dollars When developed, staffed, At Cardinal Health, it’s our • Increase pharmacist retention, recruitment, and managed to its full belief that to be successful, and engagement potential, a hospital pharhospitals need to leverage macy can and should play the Pharmacy as a Strate• Elevate the role of the pharmacist as an a much greater role in furgic Asset. We are designing integral part of the patient care team thering the hospital’s missolutions to help our cli• Optimize clinical outcomes through evidencesion; supporting high-quality ents advance the pharmabased practice and drug therapy patient care; fostering efficy as a strategic driver for ciency; and creating a comthe hospital’s agenda. This • Improve the standard and continuum of petitive advantage. report summarizes some of patient care, reducing readmissions In short, the hospital pharthe successes achieved by

By Mary Baxter, vice president, macy can be a true strahospitals and health sysPerformance and Outcomes, Cardinal Health tegic asset to a hospital or tems when applying this an entire health system. To approach. accomplish these goals, In today’s changing health health systems are increasingly turning to specialized care climate, the old model of a hospital pharmacy is no experts who can help create exponential benefits to the longer sufficient. It is not enough to hold down costs and bottom line and most importantly, improve patient care. deliver the 5 rights: “Right drug, right patient, right dose,

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Figure. Pharmacy as a Strategic Asset: The 4 F Framework.

Find Meaningful Growth Meaningful growth opportunities exist on both sides of the ledger—in increased sales and reduced purchasing costs.

One obvious route to greater revenue for a hospital is through expanding pharmacy services to a retail pharmacy, serving patients at discharge, as well as hospital employees. An onsite pharmacy allows the hospital to capture revenues, while increasing convenience for employees and patients and helping ensure that patients leaving the hospital have their time-ofdischarge prescriptions filled.

The Regional Medical Center at Riverside Health System, the largest of 6 hospitals in the Riverside Health System based in Newport News, Virginia, will open a retail pharmacy managed by Cardinal Health. “Its primary function is to serve patients,” said Michael Doucette, vice president of Operations for the health system. “All patients will be offered the option to

have their discharge prescriptions filled and brought to their room before they leave so they don’t have to drive to a pharmacy on the way home.”

The pharmacy also will offer soft goods and medical supplies needed for post-acute care. Additionally, patients with a high risk for readmission will receive a call from a pharmacist to make sure their medication therapies are going well and to answer any questions.

The pharmacy will fill prescriptions for employees under the health system’s self-insured medical plan. “We’re at risk for the cost of those medications no matter where they are filled,” said Mr. Doucette. “Having the pharmacy in-house means we can reliably direct people toward generic drugs and other lower-cost alternatives, saving money on our health plan outlays.”

Riverside Health System looked to Cardinal Health for support in formulating a strategy for participation in

With consultation from Cardinal Health, IASIS Healthcare secured $32.2 million in incentive payments in 2011-2012, and an estimated

$5.4 million in the first quarter of 2013.

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flat from fiscal years 2009 to 2012. “That is more impressive government-regulated 340B pricing and in complying with the than it sounds,” he said, noting that the major cost compoprogram’s complex regulations. “The Regional Medical Cennents—drug purchases and pharmacists’ salaries and beneter of Riverside Health System qualifies for 340B for outpatient fits—increased during that time: “If you were to trend the lab, medications, but the application and the monitoring are comradiology, or any other department, you would likely see that plicated, and the government is increasingly strict about audittheir costs have escalated. The fact that pharmacy stayed flat ing,” said Mr. Doucette. is a testament to how Cardinal Health helps Another hospital found ready cash by in managing our bottom line.” selling its entire pharmacy inventory to Cardinal Health, which in turn managed it. The “Cardinal Health made Benchmarking Identifies transaction enhanced the hospital’s cash Opportunities it easy for us, and as position by $5.98 million, improved its bond rating, and helped finance the modernizaSavings resulted in part from the role of the 340B program has tion of an older facility.

Cardinal Health in controlling medication changed, they have costs. Each facility chooses 3 to 5 diagRevenue also can come from governnosis-related groups (DRGs) to monitor ment incentives. At IASIS Healthcare, a helped us stay in coneach year. The hospitals receive quarter$2.8 billion health system with 20 acute tinuous compliance.” ly reports on specific metrics: top 10 drugs care hospitals, a computerized physician used, cost per case, physicians using high order entry (CPOE) system was instruvolumes of each drug, and others. The hosmental in meeting Meaningful Use cri—Mike Doucette pitals can benchmark against each other teria. With consultation from Cardinal and against national standards drawn from Health, IASIS Healthcare secured $32.2 all hospitals managed by Cardinal Health. million in incentive payments in 2011That helps identify opportunities to work with physicians, 2012, and an estimated $5.4 million in the first quarter of deploy best practices, and encourage delivery of drugs that 2013. “The ability to communicate the prescription electronprovide the desired patient outcomes while reducing costs. ically to the pharmacist, have it reviewed, have it show up Pharmacists review prescriptions and can substitute lowerin the electronic medical record (EMR), and have the discost generic drugs, as long as efficacy is not compromised. charge medications rectified—all that is part of Meaningful Use,” observed Tedd Adair, vice president of Clinical Operations for IASIS Healthcare.

Take a Look at Your Drug Distribution

Fix Inefficiencies

System

Efficient operations in purchasing, inventor y, staffing, and other key areas can drive down costs and significantly improve operating margins. Cardinal Health has access to industry benchmarks that provide a roadmap to more efficient operations. This offers proven best practices shared across multiple facilities in a health system. Ready-made dashboards track and report progress against key performance metrics.

Mr. Adair reports that his organization’s overall pharmacy costs as measured per adjusted patient-day remained

Perhaps the most fundamental efficiency improvement is in drug distribution. At IASIS Healthcare, Cardinal Health applied the expertise of specially trained buyers and an automation subject matter expert to create a minimum/maximum (Min/ Max) system that helps determine the optimum amount of each medication to place in the automated dispensing cabinets.

This system helps avoid stock-outs and relieves staff members from spending excessive time replenishing drugs. Inventories are then monitored monthly against specific metrics and adjustments are made as necessary.

Over 3.5 years, IASIS Healthcare had an overall cost savings of

$2.14 million on antibiotics

$4.69 million:

$2.14 million on anticoagulants for DVT prophylaxis $415,000 on anemia drugs

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Pharmacist Recruiting and Retention Effective pharmacist recruiting and retention adds significant efficiency and ensures continuity of expertise. That came into play at IASIS Healthcare when 3 hospitals in rural Texas had difficulty recruiting pharmacists.

More broadly, IASIS Healthcare uses remote pharmacy services across its network to increase hours of coverage. “Most hospitals can’t afford to keep a pharmacy open 24/7,” noted Mr. Adair. “In the early morning hours, for example, there is no need to have a pharmacist available, but orders are still being written. Through remote pharmacy services, a doctor writes an order, it’s reviewed by a licensed pharmacist in another location, the order is entered, and the medicine becomes available through the Pyxis® to machine on the floor.”

“It’s a holistic, integrated, multidisciplinary way of managing the patient experience from admission post-discharge. The pharmacists listen to the reports on the patients and make sure they are on the right medication regimens. Their input is very valuable.”

—Tedd In response, Cardinal Health took charge of recruiting pharmacists and directly employed them under a blended staffing model, leveraging clinical pharmacy expertise within the hospitals along with a remote order entry service. Each facility is assigned a full-time remote order entry specialist who works 8 hours per day on a schedule determined by each hospital’s peak-time order volume.

Fulfill Quality Care Mission

Among the key objectives of pharmacy management is the ability to help health systems achieve quality care objectives. The demands on pharmaAdair cists’ time are numerous—they must be able to juggle management training, compliance training, staffing, and multiple other administrative functions.

When the pharmacy is leveraged as a strategic asset, the scope of a pharmacist’s responsibilities further increases, as well as the degree of collaboration and integration.

Pharmacists as Clinical Partners Pharmacists must be available on the hospital floors to consult with physicians and nurses, helping to ensure that patients

Additional Benefits Supporting Centralized Pharmacy Management Compliance and Accreditation

Staff Recruiting and Retention

This includes helping to correct deficiencies for Joint Commission or DNV compliance and maintaining a continuous state of readiness for compliance audits. At IASIS Healthcare, Cardinal Health applies a pharmacy operations dashboard to track, monitor, and display monthly metrics on key performance indicators in the hospital pharmacies.

This helps to illuminate areas for continuous improvement and keep the facilities prepared for annual DNV visits.

Cardinal Health helped create a residency program that accepts 2 pharmacy school graduates each year. “It creates a recruitment pipeline for us, and a number of them end up staying,” said Mr. Doucette. “An organization like ours would have difficulty developing such a program on its own.”

Preventing Diversion The pharmacy managers from Cardinal Health at Riverside Health System installed best-practice controls against drug diversion, according to Mr. Doucette: “Many sophisticated processes need to be in place to keep theft from occurring.

Between the controls covering CPOE, distribution through the Pyxis® machines, trending of drug use by nurse, and other documentation, many opportunities for diversion were reduced.”

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Medication Safety This includes a shift from punishing mistakes (which employees then learn to hide) to fostering a Just Culture in which people trust each other, are rewarded for providing safety information and reporting errors, understand their responsibilities for safe choices, and share accountability. A medication safety expert can help instill a Just Culture in which different types of errors are treated appropriately and a fertile environment for continuous improvement is created.

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the hospital—they are seen as a lot more than a person behind receive the most appropriate medications and therapies. “We a cage with all the medications.” have board-certified pharmacists on the units, deeply involved in the care of the patients—not just validating orders the docComparing Drug Therapies tors have written,” Mr. Doucette said. “Some are employees of our outsourcing partner [Cardinal Health]; most are our Centralized pharmacy management also enables close employees whom our partner has trained. Our physicians have tracking of DRGs. The goal at Riverside Health Systems is that come to rely on them as integral members of the care team.” similar patients with essentially the same conditions receive At IASIS Healthcare, pharmacists are part of a hospital medessentially the same drug therapy. ical management quality program. “It’s a holistic, integrat“Cardinal Health runs the data for us. They have the capability ed, multidisciplinary way of managing the patient experience from admis“We are now able to pull all that together. Everything is coordinated. We sion to post-discharge,” do the right thing for each patient. They transition from one setting to said Mr. Adair. “We have daily patient management another with more assurance that their medications are correct. There is meetings involving all the less likelihood of medication errors. We believe this goes hand in hand players who are part of the care process: imaging, with the goals of health care reform, where the incentive is to keep people laboratory, hospitalists, well, keep them out of high-cost care areas, and prevent readmissions.” and a pharmacy representative. The pharma—Mike Doucette cists listen to the reports on the patients and make sure they are on the right medication regimens. Their input is very valuable.” to break it down to say, ‘For this DRG, here are the drug variPharmacists also take part in ICU rounds: “Pharmacists actuations we see across physicians or across hospitals.’ Some ally respond to codes and bring drug trays with them,” said Mr. variations of course are justified by the patients’ conditions, Adair. “Some of our pharmacists have been trained to administer whereas others are preference items. We also look at length the influenza vaccine. They are pretty well integrated throughout of stay and outcomes—so if we paid more for a drug, was it

What does your pharmacy’s “full potential” look like?

When a hospital pharmacy is leveraged to its full potential, it can become a key driver for achieving the organization’s strategic agenda.

Pharmacists are not confined to the pharmacy itself but spend time on the floors in multidisciplinary collaboration with physicians and nurses, consulting with patients about their medications and providing predischarge counseling.

They also work with physicians and administrators to share ideas that can add value, lower operating costs, improve care quality, and enhance patient satisfaction.

Clinical pharmacists focus on ensuring the most appropriate drug treatments and avoiding adverse events.

Patients have their prescriptions filled and delivered to their rooms before discharge. Pharmacists make followup contacts to inquire about any medication questions and

ensure patients are complying with their regimens to help prevent readmissions.

Purchasing policies take full advantage of discounts, including government programs such as 340B pricing.

Drug inventories turn at a rate appropriate to the size of the hospital or network, operating close to just-in-time while still ensuring availability. On-floor automated dispensing cabinets are stocked optimally. Cost, quality, and other performance metrics are tracked meticulously and are used to compare system facilities to each other, and to peer-group facilities around the nation.

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worth it? Or was it just a costly drug that had the same effect as something less expensive? All that comes from the central database,” Mr. Doucette said.

Follow the Patient Effective pharmacy management can have positive effects on care even after patients are discharged from the hospital. It begins with delivering all prescriptions at discharge and following up to ensure compliance. This program extends to the coordination of care as patients move from the hospital to other care facilities.

Riverside Health’s system-wide pharmacy management, provided by Cardinal Health, enables continuity of care for the system’s Lifelong Health and Aging-Related Services, encompassing senior services, nursing and retirement homes, and rehabilitation centers.

“Patients may come into one of our primary care practices, then receive acute care services, and from there enter a Lifelong Health facility,” said Mr. Doucette. “Having central management on the pharmacy side helps significantly. Traditionally, nursing homes had an entirely different way of managing pharmacy, as did retirement communities, and both were very different from the hospital world.”

Meanwhile, IASIS Healthcare is exploring its own ways to prevent readmissions. “Patients get readmitted for a number of

reasons that include failure to follow discharge instructions or failure to fill their discharge prescriptions,” said Mr. Adair. “We’re looking at ways to bridge that gap. The pharmacists at Cardinal Health are always available to patients, and that includes giving time-of-discharge drug consultation. The pharmacy team is exploring how we can ensure that patients leave with everything they need so that they don’t get readmitted within 30 days.”

Reaching Full Potential Unfortunately, the pharmacy often is perhaps the least optimized asset in a typical hospital. Changes in health care—from the Affordable Care Act, to the Accountable Care Organization model, to the sheer imperative to cut costs and improve performance—all point to greater attention to the pharmacy and the development of its full potential. The tools and methods already exist. Yet, it is not easy to deploy them to their full effect so that the pharmacy becomes a true strategic asset— supporting patient care, quality, safety, and financial performance. In this respect, the services of a management partner can be essential.

“As we have grown from a system of a dozen hospitals to 20 today, we have had a strategic partner along the way,” observed Mr. Adair. “I have worked with Cardinal Health for 10 years, and I have never worried about pharmacy operations. I trust our pharmacy management partner.”

By leveraging the pharmacy’s full potential, it can become a key driver in achieving the hospital’s strategic agenda.

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Is your hospital pharmacy ready to perform as a strategic asset?

A high-performing hospital pharmacy is more than a utility for efficiently and accurately dispensing medication. Instead, it adds value to the organization’s financial performance, competitive position, patient and staff satisfaction, and clinical outcomes. Here are some steps to take toward leveraging your pharmacy as a strategic asset:

Pharmacy leadership ❏

Maintain a strong presence in multidisciplinary committees: Medication Safety, Pharmacy and Therapeutics Committee, and others.

❏

Engage pharmacists as active participants in physician rounds to ensure that optimal medication therapies are in place.

❏

Foster an environment of innovation for achieving strategic directives, and sharing ideas that add value, lower operating costs, improve care quality, and enhance patient satisfaction.

Stakeholder engagement ❏

Encourage collaboration between physicians and hospitalists, nurses, technicians, pharmacists, and case managers to improve patient outcomes and care—including active multidisciplinary participation in key committee and planning teams.

❏

Use a strategic agenda, and develop goals and priorities with guidance and inclusion of key stakeholders throughout the facility.

Clinical pharmacy program management ❏

Align key metrics to monitor results from various initiatives.

❏

Develop a scorecard and report regularly on results to build momentum and sustain improvements.

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Ensure that communication is timely and consistent across the facility and various work teams.

Hospital leadership ❏

Facilitate engagement and support across all stakeholders and set the expectations for multidisciplinary participation in strategic initiatives.

❏

Provide accountability for the delivery of program objectives and goals.

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Drive the adoption of cultural changes that reflect the spirit of collaboration, and communicate to all hospital employees about strategic priorities and advancements.

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About the Author Mary Baxter is vice president of Performance and Outcomes with Cardinal Health.

She can be reached at mary.baxter@cardinalhealth.com. Cardinal Health has more than 45 years of experience in positioning hospital Pharmacies as Strategic Assets. The company uses professional services and commercial software solutions to provide savings, revenue streams, and pharmacy process and quality improvements across the entire continuum of care.

About Cardinal Health

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Cardinal Health, and the author neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

Copyright Š 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Headquartered in Dublin, Ohio, Cardinal Health, Inc. (NYSE: CAH) is a $101 billion health care services company that improves the cost-effectiveness of health care. As the business behind health care, Cardinal Health helps pharmacies, hospitals, ambulatory surgery centers, clinical laboratories, and physician offices focus on patient care while reducing costs, enhancing efficiency, and improving quality. Cardinal Health is an essential link in the health care supply chain, providing pharmaceuticals and medical products and services to more than 100,000 locations each day, and is also the industry-leading direct-to-home medical supplies distributor. The company is also a leading manufacturer of medical and surgical products, including gloves, surgical apparel, and fluid management products. Additionally, the company operates the nationâ&#x20AC;&#x2122;s largest network of radiopharmacies that dispense products to aid in the early diagnosis and treatment of disease. Ranked 19th on the Fortune 500, Cardinal Health employs 34,000 people worldwide. More information about the company may be found at cardinalhealth.com and @CardinalHealth on Twitter.