The March 2012 Digital Edition of Pharmacy Practice News

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The Pharmacist’s News Source

pharmacypracticenews.com

Volume 39 • Number 3 • March 2012

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Part 2 of a three-part series

Planning and Process Improvement Boost Health-System Savings New Orleans—A little imagination bolstered by careful planning and persistence can yield significant—and sometimes staggering—cost savings for health systems, as we reported in the first two installments of this three-part series. The following examples illustrate still more ways for hospitals to maximize savings and in some cases bring in additional funds.

The initiatives were presented at the American Society of Health-System Pharmacists’ 2011 Midyear Clinical Meeting.

Prior Authorization for IV Drugs Most payers require prior authorization for medications used in infusion clinics, which

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see SAVINGS BOOST, page 6

Hospitals Feeling The Pain of Severe Sedative Shortage

I

n late January, the call went out at the University of Rochester Medical Center (URMC), in upstate New York. Clinicians were advised to dramatically cut back on their use of two mainstay IV sedatives, diazepam and lorazepam, supplies of which were becoming increasingly tight.

Curtis Haas, PharmD, director of pharmacy at URMC, sent an email to staff clinicians, stating that “we currently have very low supplies of both IV diazepam and IV lorazepam and have directed providers ... to use IV midazolam. However, we’re not counting on receiving any more shipments of any IV products until at least next week and maybe not until mid-February and do expect this shortage to be long-term.”

Dr. Haas said he knew the switch to midazolam, although helpful, would only be a temporary solution; he anticipated there would be a domino effect causing midazolam to become scarce. He thus urged his colleagues to use

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see SHORTAGE, page 16

in this issue Up Front

Capsules The good and bad news about cancer-related mortality.

5

Operations & Mgmt

Care Transitions What hospitals are doing to bolster continuity of care.

11

Clinical

Hem/Onc Pharmacy New drug promising for metastatic colorectal cancer.

26

Infectious Disease Hand and glove hygiene deemed keys to safe drug compounding.

38

Policy

Practice Pearl Tips for navigating— and getting paid for— medication therapy management.

52

Gloom and Doom Swirls Around Sepsis Research Houston—In the 1990s, two high-profile drugs for sepsis crashed and burned after promising early mortality data fizzled in later studies and the manufacturers had to halt the clinical trials. The mood among sepsis researchers was understandably gloomy, and it now appears that the storm clouds are back—not only because of the withdrawal of drotrecogin alfa (activated; Xigris, Eli Lilly) from the market in October—but also due to a flurry of more recent, disappointing results from trials of other sepsis medications.

These developments, outlined in presentations during the recent annual meeting of the Society of Critical Care Medicine (SCCM), have fueled the feeling that there are only gray clouds hovering over sepsis research. In fact, “we must be very anxious because the industry may no longer put its money in our field. They may just move away and go to other disciplines,” said Jean-Louis Vincent, MD, PhD, head of the Department of Intensive Care at Erasme University Hospital, in Brussels, Belgium.

Technology

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Informatics Touchscreen computer kiosks help with medication reconciliation.

56

Educational Review

Safe Handling Of Hazardous Drugs: Reviewing Standards for Worker Protection See insert after page 30.

see GLOOM AND DOOM, page 32

Drug With Novel Mechanism May Improve Prostate Cancer Survival San Francisco—An investigational oral drug that halts androgen signaling may significantly improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC), according to a new study presented at the American Society of Clinical Oncology’s 2012 Genitourinary Cancers Symposium (abstract LBA1).

With its novel mechanism of action, the drug, MDV3100 (Medivation), appears to be ushering in a new era in

the battle against prostate cancer.

“MDV3100 works differently than other agents for [this patient population],” said investigator Howard Scher, MD, chief of the Genitourinary Oncology Service and D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan-Kettering Cancer Center, in New York City.

“This drug targets a unique aspect of the malignant process, blocking a biological mechanism that enables tumors to resist

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see PROSTATE CANCER, page 24

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Important Safety Information Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated when oral administration is temporarily not feasible in adults (16 years and older) with: partial onset seizures; myoclonic seizures in patients with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures.

Levetiracetam should be gradually withdrawn to minimize the potential of increased seizure frequency.

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Levetiracetam in Sodium Chloride Injection causes neuropsychiatric reactions including somnolence and fatigue, muscle coordination difficulties and behavioral abnormalities as well as hematological abnormalities. The most common adverse reactions observed with Levetiracetam were somnolence, weakness, infection and dizziness. Important behavioral adverse reactions include hallucinations, delusions, and non-psychotic mood disorders including suicide ideation, aggression, anger, apathy, conduct disorder, irritability, depression, nervousness, anxiety and emotional lability.

Dosing must be individualized according to seizure type, patient’s renal function status and therapy objective. Based on animal data, Levetiracetam may cause fetal harm and therefore should be used during pregnancy after consideration of the potential benefit-risk ratio. Levetiracetam should be gradually withdrawn to minimize the potential of increased seizure frequency.

Please see following pages for accompanying full Prescribing Information. ©2012 Mylan Institutional

JA034

January 2012

Brief Summary of Risk Information for LEVETIRACETAM IN SODIUM CHLORIDE INJECTION, for intravenous use WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Reactions Partial Onset Seizures: Levetiracetam can cause central nervous system adverse reactions: 1) somnolence and fatigue: levetiracetam 14.8%, placebo 8.4%. In a study without titration, 45% reported somnolence from 4000 mg/ day; considered “serious” by 0.3% levetiracetam, versus 0% of placebo patients; discontinuation: 3% levetiracetam, versus 0.7% of placebo patients; dose reduction: 1.4% levetiracetam versus 0.9% placebo; 0.3 % levetiracetam patients were hospitalized for somnolence. Asthenia: levetiracetam 14.7%, versus 9.1% placebo; treatment discontinuation: 0.8% versus 0.5% placebo; dose reduction: 0.5% versus 0.2% of placebo; 2) coordination difficulties (ataxia, abnormal gait, or incoordination): 3.4% levetiracetam versus 1.6% placebo; discontinuation from ataxia: 0.4% levetiracetam versus 0% placebo; dose reduction: 0.7% levetiracetam versus 0.2% placebo; one patient hospitalized from worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. 3) behavioral abnormalities (psychotic symptoms and other behavioral and mood symptoms): Psychotic symptoms: 5 (0.7%) levetiracetam versus 1 (0.2%) placebo. Two (0.3%) levetiracetam patients hospitalized and treatment discontinued. Both developed in the first treatment week, resolved in 1 to 2 weeks following discontinuation. Two events of hallucinations, occurred after 1-5 months and resolved within 2-7 days while remaining on treatment. One psychotic depression occurring within a month, resolved within 45 days while treatment continued. Other behavioral symptoms (aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.): 13.3% levetiracetam versus 6.2% placebo; approximately half reported within the first 4 weeks; treatment discontinued in 1.7% levetiracetam versus 0.2% placebo; dose reduction in 0.8% levetiracetam versus 0.5% placebo.

Serious behavioral event causing hospitalization in 0.8% levetiracetam versus 0.2% placebo. Attempted suicide after 4-6 months treatment (one completed suicide) in 4 (0.5%) levetiracetam versus 0% placebo. Myoclonic Seizures: Somnolence and behavioral abnormalities: It is expected that the events seen in partial seizure patients would occur in patients with juvenile myoclonic epilepsy (JME). In JME patients JME experiencing myoclonic seizures: somnolence occurred in 11.7% of levetiracetam versus 1.7% of placebo patients (no treatment discontinuations); dose reduction in 1.7% levetiracetam versus 0% of placebo. Non-psychotic behavioral disorders (aggression and irritability): 5% levetiracetam versus 0% placebo. Non-psychotic mood disorders (depressed mood, depression, and mood swings) 6.7% levetiracetam versus 3.3% placebo.

Dose reduction or discontinuation: 5.0% of levetiracetam versus 1.7% placebo.

Primary Generalized Tonic-Clonic Seizures: Behavioral symptoms appeared to be associated with levetiracetam. Gait disorders and somnolence were described in patients with primary generalized seizures, but no difference between placebo and levetiracetam groups and no appreciable discontinuations.

In some patients levetiracetam causes behavioral abnormalities: irritability 6.3% levetiracetam versus 2.4% placebo. In patients with idiopathic generalized epilepsy, non-psychotic behavioral disorders (abnormal behavior, aggression, conduct disorder, and irritability): 11.4% levetiracetam (one discontinued due to aggression) versus 3.6% placebo; non-psychotic mood disorders (anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness): 12.7% levetiracetam versus 8.3 placebo. Suicidal ideation in one levetiracetam patient. Delusional behavior in one patient requiring lowering of the levetiracetam dose. In a long-term open label study of various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior, one characterized by auditory hallucinations and suicidal thoughts (led to drug discontinuation), the other as worsening of pre-existent schizophrenia (did not lead to discontinuation). Withdrawal Seizures: Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency. Hematologic Abnormalities: Minor, but statistically significant, decreases in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Hepatic Abnormalities: No meaningful changes in mean liver function tests

(LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment. Laboratory Tests: Relatively infrequent abnormalities seen in hematologic parameters and liver function tests. ADVERSE REACTIONS: Most common (≥ 5%) versus placebo include: somnolence, asthenia, infection, and dizziness; important behavioral (< 5%) include depression, nervousness, anxiety, and emotional lability. See full prescribing information for adverse reactions in specific types of seizures and incidence when levetiracetam was added to concurrent AED therapy.

Postmarketing Experience: Additional adverse events reported worldwide (alphabetically): abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some), thrombocytopenia and weight loss. Alopecia was reported; recovery was observed in majority of cases where levetiracetam was discontinued. Reports of suicidal behavior (completed suicide, suicide attempt and suicidal ideation) with marketed levetiracetam. See Patient Counseling Information. USE IN SPECIFIC POPULATIONS. Pregnancy Category C: No adequate and well-controlled studies in pregnant women. Animal studies: evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus. North American Antiepileptic Drug Pregnancy Registry: Physicians are advised to recommend that pregnant levetiracetam patients enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry, toll free number 1-888-233-2334 (must be done by the patients themselves), website http://www.aedpregnancyregistry.org. Effect on Labor and Delivery: unknown. Nursing Mothers: Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Safety in Pediatric Use: Safety and effectiveness below age 16 years have not been established. Geriatric Use: No overall differences in safety were observed compared to younger subjects. Numbers of clinical trial subjects were insufficient to assess effectiveness in the elderly. A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twicedaily doses for 10 days showed no pharmacokinetic differences related to age alone. Levetiracetam is substantially excreted by the kidney, with concomitant risk of adverse reactions in patients with impaired renal function. Accordingly, care should be taken in dose selection for the elderly, and it may be useful to monitor renal function. Use in Patients with Impaired Renal Function: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis. OVERDOSAGE: Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans: The highest known dose of oral levetiracetam received in the clinical development program was 6000 mg/day.

Only drowsiness was observed in the few known cases of overdose in clinical trials. Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma observed in overdoses in postmarketing use.

Treatment or Management of Overdose: No specific overdose antidote. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions to maintain airway. General supportive care is indicated including monitoring of vital signs and observation of clinical status.

A Certified Poison Control Center should be contacted for up to date information.

Hemodialysis: Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Patient Counseling: Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician as suicide, suicide attempt and suicidal ideation have been reported in patients treated with levetiracetam. To report SUSPECTED ADVERSE REACTIONS, contact Mylan Institutional LLC at 1-877-4RX INFO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pharmacy Practice News • March 2012

Up Front 5

Capsules

Good and Bad News in Cancer Mortality

surf

I

MARCH 2012

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Fiscal Stars That Glimmer in Health-System Firmament 2. Methotrexate Drug Interactions: Are They Slipping Under Radar?

3. Reducing IV Waste Saves Time and Money 4. Knowing 2012 Rules Changes: Your Key to Fiscal Health 5. Survey: More Work Needed To Boost Role of Technicians Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

‘In a world of healthcare heard change, we are reminded that here we need pit crews, not cowboys,

first

and that collaboration and shared leadership in the definition and delivery of care to patients is our new reality.’

—Sharon Murphy Enright, BSPharm, MBA

See article, page 10

n the past two decades, the overall death rate from cancer decreased by 22.9% in men and 15.3% in women, according to the most recent annual report on cancer incidence from the American Cancer Society (ACS).

More than 1 million cancer deaths were avoided between 1990 and 2008, the report’s authors estimated (CA Cancer J Clin 2012;62:10-29). For 10 years with available data (19982008), death rates continued to decrease for all four major cancer sites—lung, colorectum, breast and prostate, with colorectal cancer accounting for much of the decline in both men and women.

“Among men, 78% of the [overall] decline is due to decreases in the top three cancer sites—lung, prostate and colorectal cancers; while among women, 56% of the decline is due to decreases in death rates for breast and colorectal cancers,” said lead author Rebecca Siegel, MPH, an ACS epidemiologist based in Atlanta.

“Lung cancer death rates have been declining among men since 1990, due to the reduction in tobacco use over the past 50 years,” she added, noting that the mortality decline has been smaller for women in part due to smoking prevalence among women peaking 20 years later than among men.

“Decreases in prostate, female breast and colorectal cancer death rates largely reflect improvements in early detection and/or treatment,” Ms. Siegel said.

In an interview, Howard Sandler, MD, MS, chair of radiation oncology and Ronald H. Bloom Family Chair in Cancer Therapeutics at Cedars-Sinai Medical Center, in Los Angeles, attributed the long decline in cancer death rates to a “combination of factors,” including a declining number of smokers, effective methods of early cancer detection and better treatments.

The incidence of some less common cancers have been increasing, according to a second article from the ACS (CA Cancer J Clin 2012 Jan 4 [Epub ahead of print]).

Authors of that study documented increases in cancers of the pancreas, liver, thyroid and kidney, as well as increases in esophageal adenocarcinoma, melanoma and some kinds of throat cancer associated with human papillomavirus (HPV) infection.

“The reason for the increasing rates is unknown, but the obesity epidemic is probably associated with increases for some of these cancers,” Ms. Siegel said. “Increases in early detection practices are a likely contributor as well.”

Dr. Sandler described several factors that may account for the observed increases in cancer incidence rates, such as gastroesophageal reflux associated with obesity for esophageal adenocarcinoma, and hepatitis C and B virus infections for liver cancer.

Ms. Siegel added that the increase in the incidence of thyroid cancer was the largest, and that the increase in kidney cancer incidence was an unexpected finding. “Although most of the increases were confined to whites, rates of kidney cancer increased among both men and women of every racial/ethnic group, although the increase was not statistically significant among American Indian/Alaska Native men.”

—George Ochoa

EDITORIAL BOARD

ART/PRODUCTION STAFF

Administration

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

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

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

Volume 39 • Number 3 • March 2012 • pharmacypracticenews.com

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

Internal Medicine

EDITORIAL STAFF

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

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

Biotechnology

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

Indu Lew, PharmD, Livingston, NJ

Jeffrey Norenberg, PharmD, Albuquerque, NM

Cardiology

Oncology

James O’Neill, Senior Systems Manager Dan Radebaugh, Director of Production and Technical Operations Martin Barbieri, Production Manager Brandy Wilson, Circulation Coordinator

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

McMAHON PUBLISHING

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

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

Van Velle, President, Partner

Robert Ignoffo, PharmD, San Francisco, CA

James Prudden, Group Editorial Director

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

Robin B. Weisberg, Manager, Editorial Services

Larry Ereshefsky, PharmD, San Antonio, TX

Cindy O’Bryant, PharmD, Aurora, CO

Elizabeth Zhong, Associate Copy Chief

Complementary and Alternative Medicine

Ali McBride, PharmD, MS, BCPS, St. Louis, MO

Cathy Rosenbaum, PharmD, Cincinnati, OH

Sara S. Kim, PharmD, BCOP, New York, NY

Critical Care

Pediatrics

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

C. Michael White, PharmD, Storrs, CT CNS/Psychiatry Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA

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

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

McMahon Publishing mcmahonmed.com Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036.

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David P. Nicolau, PharmD, Hartford, CT

Technology

Robert P. Rapp, PharmD, Lexington, KY

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6 Operations & Management

Pharmacy Practice News • March 2012

Finances

continued from page 1

commonly include very expensive chemotherapy and biological agents. But hospital-based infusion clinics that want to ensure that every infusion has been properly reviewed and approved face a number of challenges. Because it lacked a standardized process of securing authorizations in advance of administering infusions to patients, Intermountain Healthcare, a 22-hospital system based in Salt Lake City, estimated that it was losing approximately $1 million annually.

Its response: A team of pharmacy technicians was hired to work with payers, referring providers, patient account services representatives and patient assistance coordinators to ensure that reimbursement issues were buttoned down prior to drug delivery.

Through the efforts of a team of two full-time equivalent (FTE) pharmacy technicians, the health system has secured prior authorizations for more than $3 million at nine infusion clinics since June 2010, with only one denial due to lack of documented prior authorization. The expense for the two FTE pharmacy technicians over the same period totaled roughly $88,000. Infliximab, immunoglobulins and zoledronic acid represented about 64% of secured prior authorizations.

Tina Aramaki, PharmD, corporate director of pharmacy services with Intermountain Healthcare, said she was very pleased with the major reduction in denied claims. But she stressed that the staff doing this work “must be very motivated and not timid, and they must have management support for the program to succeed.”

Documenting the Value Of Pharmacist Interventions At smaller community hospitals, budgetary constraints often limit the roles of pharmacists to primarily dispensing functions—unless of course those expanded roles can be shown to save money. The pharmacy department at the 229-bed St. Joseph’s Wayne Hospital, a division of St. Joseph’s Healthcare System in Patterson, N.J., employs a staff of only one clinical pharmacist and 7.3 FTE staff pharmacists who perform traditional dispensing functions for two shifts, seven days a week.

“We wanted to get our staff pharmacists routinely involved with clinical initiatives and programs instead of having just the single clinical pharmacist doing clinical work, so we integrated the services,” explained Michael Cairoli, RPh, MHA, pharmacy manager in the Department of Pharmacy Services at St. Joseph’s. To make the transition, staff pharmacists were gradually introduced to clinical initiatives and tri-

aged the issues that needed advanced interventions or intervention by the dedicated clinical pharmacist.

For example, an anticoagulant initiative was introduced first. The pharmacists learned about dose-adjustment interventions for elevated international normalized ratio values, low-molecular-weight heparin dose adjustment based on renal function and educating patients about anticoagulant use.

Then they tackled antimicrobial stewardship and were trained to screen cultures for restricted antibiotics and refer inappropriate use of the drugs to the clinical pharmacist. The staff also started monitoring the time and appropriateness of antimicrobial and thrombosis prophylaxis for the surgical care improvement project core measure, as well as timing of β-blockers to avoid delay of therapy due to unavailability of the agents in the formulary. They also began evaluating the medicationrelated risks for patient falls, as well as evaluated drug therapy and monitored laboratory values for patients with heart failure.

When appropriate, simple algorithms and protocols were implemented for clinical decision making. Step-by-step instructions and standardized forms for patient education were developed.

“This approach ensured that each patient’s targeted drug therapy was reviewed and proper interventions were done,” Mr. Cairoli said. The involvement of staff pharmacists in clinical

functions increased dramatically. From the program’s inception in the second half of 2008 through 2010, the number of new clinical interventions and orders monitored by pharmacists increased from 216 to 10,290, whereas the total number of interventions increased from 6,522 to 17,387 over the same period.

The resulting estimated cost savings jumped from $118,000 in 2008 to $343,000 in 2010. Savings was judged on estimates in the literature that equated specific pharmacy interventions with dollar amounts, Mr. Cairoli explained. He added that all of these gains occurred even with significant staffing challenges. “Remember,” he said, “we’re not even a 24-hour pharmacy.”

Tapping Into the Potential Of Ambulatory Pharmacy At the University of Illinois Hospital & Health Sciences System in Chicago, which includes a 491-bed hospital and an outpatient facility, specialty clinics and six health sciences colleges, too many patients were leaving the hospital without filling their prescriptions, according to Tonia Duke, BHA, CPhT, a pharmacy technician in the ambulatory care pharmacy. That meant an increased risk for medication noncom-

‘The [pharmacy] technician is the most familiar with all of the insurance issues in the outpatient pharmacy, so that’s why we chose [a technician] for this job rather than a clinical pharmacist.’

—Kit Moy, RPh 2.0 1,600,000

1.5

Revenue, $

SAVINGS BOOST

1,000,000

1.0

.5

0

363,000

Baseline

Year 1

Year 2

Figure 1. Economic benefits of providing discharge prescription service at the University of Illinois Hospital & Health Sciences System.

pliance and readmission.

“We came up with a pilot program in which we would fill prescriptions for discharged patients before they went home,” Ms. Duke said. The initiative hit on three fronts: get patients the right medications at the right time; increase the role of pharmacy technicians; and grow prescription business and revenue.

Prior to the program’s evolution, University of Illinois Hospital had no formal hospital discharge prescription service. Patients received counseling about their prescriptions but often filled them at offsite retail pharmacies.

Providing prescriptions at the time of discharge would likely promote patient compliance and assure safe and efficient discharge prescription processing—not to mention engage the hospital’s outpatient prescription services more frequently. Patients always have the option to decline the service.

Prescriptions were processed in the University of Illinois Hospital outpatient pharmacy and sent by pneumatic tube to the inpatient pharmacy satellite or picked up by a discharge prescription technician (DPT). The DPT collected payments or copayments from the patient or a family member; sorted out insurance and prior authorization issues; and delivered the prescriptions to the patient’s clinical pharmacist or nurse, who provided medication counseling. Bedside placards advertised the services in patient rooms. The DPT also described the program to new resident physicians on the targeted general medicine and cardiology services.

“The technician is most familiar with all of the insurance issues in the outpatient pharmacy, so that’s why we chose an outpatient pharmacy technician for this job instead of using a clinical pharmacist, who would then have to

•

see SAVINGS BOOST, page 8

8 Operations & Management

Pharmacy Practice News • March 2012

Finances

SAVINGS BOOST

‘We saw the staff so motivated because

continued from page 6

they were part of the whole process.

spend time away from clinical duties,” said Kit Moy, RPh, assistant director of ambulatory care pharmacy, and clinical assistant professor of pharmacy practice.

Prior to the DPT service, approximately 2% of patients discharged from the hospital had prescriptions filled at the hospital’s outpatient pharmacy.

That increased to 4.5% in the first year after the program began, while the discharge prescription volume jumped from a monthly average of 134 to 400— a 198% increase. Currently, 12% of discharged patients get their medications from the outpatient pharmacy, and the average volume has increased to 800 prescriptions per month—an additional 100% increase. Annual discharge prescription revenue totaled approximately $363,000 prior to the DPT service, increasing to $1 million during

Savings, $ (millions)

1.8

They took ownership to make the changes, and patient satisfaction also improved significantly .’

—Roy Guharoy, PharmD its automobile factories.)

At the University of Massachusetts, a team representing pharmacy, nursing, physicians and administration, aided by consultants, evaluated multiple processes to identify gaps in workflow, and then identified opportunities to improve outcomes. For example, they began using an oncology pharmacist to dispense prescriptions at the bedside, which decreases or eliminates patient wait times at the outpatient pharmacy. The clinic also shifted more care to the outpatient set-

Achieved FY 2011 goal

1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Prior authorization

Switch input to output

Dose rounding

Clinic discharge treatment

Figure 2. Outcomes of cost-savings initiatives at UMass Memorial Health Care.

FY, Fiscal year

the first year of the program and to $1.6 million in the current calendar year (Figure 1).

Lean Process Improvement Yields Fat Rewards Reduced waste, inventory reduction, streamlined prior authorization procedures and medication management processes and, ultimately, big savings resulted from the establishment of a “lean process improvement” program at the oncology infusion center at the 781-bed three-facility University of Massachusetts Memorial Medical Center in Worcester.

Simply put, lean process techniques entail a thorough evaluation of how work gets done in any given setting—from manufacturing to patient care—and then altering those processes to boost efficiency. (The strategy first gained traction when Toyota used lean manufacturing to reduce waste and boost quality in

ting when appropriate; decreased the number of times a patient arrives for chemotherapy without prior authorization; and started rounding dosages to the nearest vial size when clinically appropriate, explained Roy Guharoy, PharmD, FASHP, chief pharmacy officer and professor of medicine at UMass Memorial Health Care.

Several steps in the hospital’s approach to oncology management were targeted, Dr. Guharoy noted. “For instance, we standardized the medication ordering system and considered the potential risks for medication errors in the system and why they happen; then we looked at how to decrease them.” Inventory optimization and prior authorizations also were a focus of the quality improvement effort..

Several of these efforts yielded dividends for the hospital (Figure 2).

Because of improved prior authorization procedures, for example, the hospital

had saved $1.17 million by the end of fiscal year 2011 (compared with the previous year). Medical necessity denials declined by $314,000, and just-in-time inventory management resulted in $400,000 in savings.

Part of the reason why these results were achieved, Dr. Guharoy noted, was the fact each At the University of Massachussets Memorial Medical lean initiative resulted Center, prescriptions dispensed at the bedside by an in improved team- oncology pharmacist have decreased patient wait times work and communica- at the outpatient pharmacy. tion among the various departments that participated in the December 2010. The use of ferumoxyoverhaul; trust and job satisfaction tol for IV administration increased increased as well. “We saw the staff from 0% of infusions in 2008 to 25% so motivated because they were part in 2009, and to 38% in 2010. As a of the whole process,” he said. “They result, the average number of patient took ownership to make the changes, hours required to infuse 1 g of IV iron and patient satisfaction also improved dropped 63%, from 10.4 hours in 2008 to 3.8 hours in 2010. That saved 196 significantly.” hours and 104 hours of chair time in Pumping Up Savings From 2009 and 2010, respectively.

Iron Deficiency Therapy The new drug is significantly more At the ambulatory infusion clinic at the expensive than older ones, so medica325-bed Gundersen Lutheran Hospital in tion costs increased over the two-year La Crosse, Wis., pharmacists evaluated period, but decreased chair time resulted the financial and operational effects of in increased revenue per hour, according increased use of ferumoxytol (Feraheme, to Dr. Meyers. “That reallocation of freed Amag Pharmaceuticals) for iron defi- chair time,” he noted, “created the opporciency anemia in patients with chronic tunity for increased revenue to the clinic kidney disease. Their efforts resulted in of about $314,000.” about 300 hours of freed up chair time —Steve Frandzel for other therapies in the busy clinic, and paid off with potential revenue increase of more than $300,000.

Drs. Aramaki, Duke, Guharoy, and Meyers, and Ms. Moy and Mr. Cairoli Ferumoxytol, which was approved as reported no conflicts of interest. an IV iron treatment in 2009, requires fewer patient visits, fewer hours per treatment and less preparation time than other IV iron treatments, said Follow PPN on Michael Meyers, PharmD, administrative director of pharmaceutical services.

“We decided to look at the total cost of each infusion and compare different drug regimens,” he said. “This allowed us to consider efficiency regarding reimbursement and how we could improve chair turnover, which would allow us to treat more patients per day.”

Dr. Meyers collected data on procedure mix, payer mix, length of clinic visit and medication administration @PharmPracNews costs and treatment revenue for the 10-chair clinic from January 2008 to

10 Operations & Management

Pharmacy Practice News • March 2012

Wicked Change

Thinking Differently “Wicked Change” focuses on leadership development and change management. This month’s column is authored by Sharon Murphy Enright, BSPharm, MBA, President of EnvisionChange LLC, Richmond, Va. Ms. Enright is coordinating content over subsequent issues and welcomes your feedback at wickedchange@gmail.com.

W

Sharon Murphy Enright, BSPharm, MBA

hen we’re surrounded by wicked change and the need to constantly shift direction, it is really difficult to maintain a longer-term focus.

That is true for leaders, and even more so for followers.

Today’s health care environment includes many challenges beyond the obvious business and professional ones.

The uncertainty of the next best step in the right direction faces us every day in many ways, regardless of our leadership level. We no longer have the comfort of simple goal achievement, the certainty of meeting every test with flying colors.

What we have is a constant demand to think through complex situations, circumstances that might be totally unfamiliar, turn-on-a dime strategy changes and the uneasiness of facing a future of not just keeping the routine going, but totally rethinking how and what we do continually, to meet the demands of change. In short, thinking differently.

The complacency that may have been acceptable in the past has no place in today’s health care organization. Too often, leaders and followers still focus on how to get things done, but are those things really worth doing? We look for answers to questions, but we don’t always focus on asking the right questions to uncover new ideas, information and insight. We work to meet goals, but too often we set those goals with the comfort of knowing they are within easy reach.

Wicked problems demand leaders (Big L and little) who can think for themselves, formulate new directions, find new ways of doing things—thinking differently and acting boldly with the target of finding and achieving Big Hairy Audacious Goals (BHAGs), a term coined by James Collins and Jerry Porras in their 1994 book, “Built to Last: Successful Habits of Visionary Companies” (Harperbusiness). Today’s leaders must have vision for the future and the ability to share that vision with other leaders and followers to foster an organizational culture of independent thinking, creativity and agility that nurtures the leader in each person, allowing them to apply a range of skills in the most fluid and complex of situations.

The Book of Proverbs tells us, “Where there is no vision, people perish.” Organizations—groupings of people—are no

Q&A

exception, and with no vision they are driven to the futile goal of maintaining the status quo, trying to keep things the way they have always been.

Leaders dream. They see things differently. They reframe every situation to expose opportunity. They think about what could be and focus on a future that is an improvement. Thinking is the key, and it isn’t always easy. Surely, your first thought is never the best and can always be improved on. Vision doesn’t evolve simply; its development involves concentrating, sticking to exploring the hard question(s), being patient, making associations, drawing linkages and connections, and having “aha” moments—all part of the process of thinking through the detail to find the critical ideas. It means not giving in to the temptation to look for and accept “cookbook,” predigested thinking, analysis and solutions.

Leaders take on the risk associated with the failure to test ideas, and whether those ideas succeed or fail, leaders resist impulses to leap to solutions. In the high-pressure world of wicked change, it seems that how quickly one can determine and announce vision is vital, but thinking is best achieved by slowing down and concentrating on what counts.

Shoot for the Moon Vision is not a just dream, although sometimes it is described as one. Classic visions—that at the time seemed out of the realm of possibility, although desirable—include John F. Kennedy’s challenge in the 1960s to commit the nation to achieving a goal, before the decade was out, of landing a man on the moon and returning him safely to earth. He identified a brilliant future state that engaged the imagination of people in a commitment to achieve what was at the time, unthinkable. Steve Jobs’ vision in the 1980s for Apple to put a computer in the hands of every person was at the time a virtual impossibility. It is now far surpassed, some say, largely by Jobs’ power of believing it possible. As demonstrated in these examples, vision must be something that we can feel; it has to inspire others to sense and respond to a higher purpose and commitment. Shared vision can move an organization in new directions and keep it moving toward new purpose with renewed energy, passion and excitement, serving as the glue that holds the organization together through the most challenging circumstances.

An important element of vision is the ability to create meaning from complexity and chaos. The concept, sometimes referred to as “sensemaking” by experts in cognitive science1, creates hope and nurtures opportunity. Sensemaking

•

see THINKING, page 12

Pacira Pharmaceuticals, Inc. The following advertorial is provided as a service to our valued advertisers.

It is designed to support the adjacent advertisement.

Introducing EXPAREL®: Non-Opioid Postsurgical Pain Control For Up to 72 Hours Q: What is EXPAREL (bupivacaine liposome injectable suspension)?

A: EXPAREL is a local analgesic that uses bupivacaine and is indicated for administration into the surgical site to produce postsurgical analgesia. A single dose given at the close of surgery provides up to 72 hoursa of analgesia with reduced opioid requirementsb and without the need for catheters and pumps.

Q: What does EXPAREL do?

A: In a pivotal soft-tissue trial compared with placebo, in which all patients with inadequate pain control received opioids for rescue pain relief, EXPAREL demonstrated a 30% reduction in cumulative pain scores and a 45% reduction in opioid consumptionb through 72 hours.c

Q: How does EXPAREL work?

A: EXPAREL uses DepoFoam®, a multivesicular drug delivery technology, to release bupivacaine over time. Other formulations of bupivacaine should not be administered within 96 hours following the administration of EXPAREL.

Q: How is EXPAREL administered?

A: EXPAREL is infiltrated into the surgical site using the same technique surgeons already use to infiltrate local anesthetics for postsurgical analgesia, and can be administered using needles as narrow as 25 gauge. The recommended dose is based on the surgical site and the volume required to cover the area; the maximum dose should not exceed 266 mg (or one 20 mL vial).

Q: How is EXPAREL supplied?

A: EXPAREL is available in 1.3%, 20 mL single-use vials. EXPAREL can be used as supplied or diluted with up to 280 mL of normal saline to accommodate administration into larger surgical sites.

Q: What important safety considerations should I know before using EXPAREL?

A: EXPAREL is contraindicated in obstetrical paracervical block anesthesia and should not be used in patients under 18 years old.

As with other local anesthetic products, patients should be monitored for cardiovascular and neurological status, and vital signs should be performed during and after injection of EXPAREL. Because amide-type local anesthetics such as bupivacaine are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk for developing toxic plasma concentrations.

The most common adverse reactions (incidence ≥10%) following administration of EXPAREL were nausea, constipation and vomiting.

Q: Why is a new non-opioid option for postsurgical pain management valuable?

A: More than 90 million surgical procedures are performed every year in the United States.d Surveys have indicated that postsurgical pain often is undertreated, with as many as 80% of patients reporting pain after surgery.e Current options to prolong postsurgical analgesia rely heavily on medication delivery devices. Although effective, these devices can be prone to catheter-related issues and often deliver opioids, which are associated with a range of unwanted and potentially costly side effects.f As the only single-dose local analgesic capable of providing pain control for up to 72 hoursa with a reduced reliance on opioids,b EXPAREL has the potential to play an important role in the management of postsurgical pain.

Please see brief summary of Prescribing Information on adjacent insert.

For more information, visit www.EXPAREL.com or contact: Pacira Pharmaceuticals, Inc. 5 Sylvan Way Parsippany, NJ 07054 Phone: (855) RX-EXPAREL (855-793-9727) email: medinfo@pacira.com a

Pivotal studies have demonstrated the safety and efficacy of EXPAREL in patients undergoing bunionectomy or hemorrhoidectomy procedures; additional studies are under way to further demonstrate the safety and efficacy in other procedures. b

The clinical benefit of the attendant decrease in opioid consumption was not demonstrated.

c

Gorfine SR, et al. Dis Colon Rectum. 2011;54:1552-1558.

d

Cullen KA, et al. Natl Health Stat Report. 2009(11):1-25.

e

Apfelbaum JL, et al. Anesth Analg. 2003;97:534-540.

f

Adamson RT, et al. Hosp Pharm. 2011;46(6 Suppl 1):1-8.

EXP-AP-0037-201201

Pharmacy Practice News • March 2012

Operations & Management 11

Care Transitions

What Hospitals Are Doing To Build Better Continuity of Care New Orleans—Hospitals often struggle when it comes to preparing patients for the transition home. Whether it’s a lack of a program to help ensure that patients fill their first post-discharge prescription, or having no strategy for helping patients cope with the high cost of those medications, such oversights can lead to poor drug compliance, high rehospitalization rates and other negative outcomes.

Fortunately, these transition challenges—and several others—can be overcome with a bit of extra planning and resource allocation, according to several facilities that described their efforts at the 2011 American Society of Health-System Pharmacists Midyear Clinical Meeting.

At Geisinger, Rounding With Physicians a Key Part Of the Plan Pharmacists at Geisinger Health System, Danville, Pa., established a system in which clinical pharmacists participate in team rounds. “Our organization puts a lot of emphasis on the transition process because we know how important it is for our patients to go home with a solid plan,” said Angela Slampak-Cindric, PharmD, a clinical pharmacist at Geisinger.

Each morning before clinical rounds, the head nurse, inpatient physician, social worker or care manager and clinical pharmacist convene to review the status of every patient on the floor.

The physician leads the meeting and updates target discharge dates for each patient. That information, noted Dr. Slampak-Cindric, is key to facilitating successful pre-discharge activities such as patient education about their medications and arranging post-discharge care.

“Knowing when a patient will go

home turned out to be very important,” said Dr. Slampak-Cindric, “because it provides a baseline from which nurses and pharmacists can prepare patients prior to their departure.”

If, for example, the pharmacist identifies a patient who will require IV antibiotics after discharge, the pharmacist will contact a home infusion center and request that the appropriate medications be prepared and that home visits be scheduled. The pharmacist also can coordinate orders to switch from IV to oral dosing. For patients who require anticoagulants, the pharmacist will alert the anticoagulation clinic of the need for follow-up appointments; patients new to anticoagulant therapy receive pre-discharge bedside education. The same level of follow-up occurs for patients starting antiplatelet agents and for those prescribed five or more post-discharge drugs. All patient education activities are reported to the group. The program, which began in June 2009 on one inpatient unit, has since expanded to include eight units.

Initial trepidation about how the new arrangement would affect individual workflow was soon put to rest. “We’ve found that it has increased collaborative practice and opened up lines of communication considerably, because everyone is working together to optimize the transition,” said Dr. SlampakCindric. “It’s also our hope that by sending patients home well prepared, educated and with all their medications in place that readmission rates

will decrease.” Since the program’s initiation, the readmission rate among affected patients has trended down, but the numbers have not yet reached statistical significance.

In Cuyahoga Falls, a Pharmacy Concierge Service Debuts Regardless of how well prepared patients are before they leave the hospital, they must still fill their homegoing prescriptions. That simple task becomes an objectionable chore when reaching the comfort of home trumps all else. Caregivers may decide to pick up the medicines later, leading to the possibility that they might not be picked up for days, if at all. To plug the gap, pharmacists at Summa Western Reserve Hospital, in Cuyahoga Falls, Ohio, initiated a pharmacy concierge service in which prescriptions are filled and delivered to patients’ rooms before they leave the hospital.

“After physically leaving the hospital, it is often challenging to go to a community pharmacy to fill newly written prescriptions. There often are long wait times, unavailable products and transportation barriers,” said Tom Bauer, RPh, the hospital’s director of pharmacy. “Any initiative that relieves patients of this inconvenience was identified as a high priority.”

Once all the discharge prescriptions have been written, a pharmacy technician explains the service to the patient.

For those who opt in, the prescriptions are filled at the onsite pharmacy

‘It’s … our hope that by sending patients home well prepared, educated and with all their medications in place that readmission rates will decrease.’

—Angela Slampak-Cindric, PharmD

and delivered to the patient’s room, and a clinical pharmacist counsels the patient about his or her drug regimen.

Copayments also are collected in the room. Patients transferring to nursing homes or extended care facilities are not eligible for the service.

The service was offered to 773 patients between January 2011 and October 2011. The 663 patients (86%) who participated filled 1,504 prescriptions. The main reasons patients gave for declining the service was not having money on hand and the desire to go to their own retail pharmacy.

“Patients tell us they like the convenience, residents like it because they know prescriptions are getting filled and nurses say they appreciate the availability of a pharmacist’s expertise,” Mr. Bauer said. He also has observed that the program potentially reduces the risk for medication errors because inpatient clinicians are familiar with the patient and patient profiles are easily accessible. In one case, a prescription was written for prednisone, 40 mg three times daily, but it should have said once a day. A hospital pharmacist discovered the error and phoned the resident to straighten things out. “That mistake may not have been caught at a community pharmacy because the patient records aren’t accessible,” he said.

Cleveland Clinic Uses Web To Break Through Drug-Cost Barriers Cost is another barrier that frequently comes between patients and their medications. At the Cleveland Clinic, the Pharmacy Department created a Web site that enables patients being discharged to obtain some medications at no charge or at a discount. The drugs

•

see CONTINUITY, page 12

12 Operations & Management

Pharmacy Practice News • March 2012

Care Transitions

CONTINUITY continued from page 11

can be picked up at the on-site pharmacy or from any participating pharmacy.

Since 2004, the Cleveland Clinic’s main campus has not kept drug samples on site, explained Sabrina Spikes, MSW, LSW, administrative program coordinator for Pharmaceutical Patient Assistance Programs. “We wanted to bring something back to our providers and patients that we had taken away, and we wanted to make it something that was accessible throughout our entire health system,” she said. “Drug cost is typically one of the [primary post-discharge challenges] for our patients. If we make it easier for them to get needed medications, that is one more barrier to care that our patients don’t have to deal with.”

About 100 drugs are dispensed either through the free trial or with copay assistance. Among the agents most frequently attained under the program are asthma drugs and antidepressants. “We started with only six drugs and we continue to grow,” said Ms. Spikes, adding that manufacturers interested in joining the program call her frequently.

For many of the drugs covered by the plan, patients receive a 30-day supply.

Others are supplied for 14 days, and for some only a few doses are provided.

Copay assistance cards can sometimes augment free trials. The program also may apply to patients who respond well to a given drug but then need financial relief from high copay costs, explained Ms. Spikes. “For indigent patients, the trial period gives us time to apply to industry assistance programs, which helps to bridge that coverage gap,” she said. In all cases, drug manufacturers finance the drug costs.

Thousands of patients have expressed their satisfaction with the program, according to Ms. Spikes, as have physicians and the clinic’s administration, who recognize it as a means to improve medication compliance and patient satisfaction. Participation in the program has grown steadily: Patients redeemed nearly 4,000 vouchers in 2008, 10,000 in 2009, and more than 18,000 in 2011. Eventually, Ms. Spikes hopes to track the affect of the program on readmission rates.

Normalizing INR Rates Protects Patients—and the Bottom Line For patients at high risk for venous thromboembolism (VTE), suboptimal anticoagulant therapy (AT) leading up to discharge can result in catastrophic outcomes. Yet many of these patients

don’t receive the attention they need, according to Caleb Oh, PharmD candidate at St. Mary-Corwin Hospital’s Coumadin Clinic in Pueblo, Colo.

Due to that lack of focus on VTE prevention, an inordinate number of patients at the clinic were being sent home with subtherapeutic international normalized ratio (INR) levels and without a bridging agent, Mr. Oh said.

“When patients are admitted with various disease states that require anticoagulation, the ideal procedure is to let them stay until their INR reaches therapeutic level and stabilizes—usually at 2 or greater,” he noted. “That’s not always feasible in the hospital because patients are often discharged as soon as they are stable. The problem for us was that sometimes the bridging process—using heparin, enoxaparin or fondaparinux until INR reached therapeutic levels— wasn’t being completed.”

The pharmacy staff developed an evidence-based practice model (EBPM) for prevention of VTE and proceeded to determine if actual therapy complied with the new model—specifically, was AT provided when indicated?

Were target INR goals reached? Was unfractionated heparin, enoxaparin or fondaparinux added as a bridging agent when INR was subtherapeutic?

They found that at the time of discharge, therapeutic INR was reached in only 51% of patients (n=200); 21% had subtherapeutic INR and were discharged with a bridging agent; 28% of patients had subtherapeutic INR but did not get a bridging agent.

“In some cases, patients whose INRs were in the therapeutic range still received a bridging agent although they may not have needed it, and in some cases when patients absolutely needed it, they didn’t get that bridging agent,” Mr. Oh said.

To address the shortcomings, the team developed a mechanism to monitor physicians’ prescribing tendencies for bridging agents, then informed them how well their patients were doing with respect to AT. They also provided education about the availability of the EBPM. In the second, ongoing phase of the work, the investigators are tracking the intervention to determine its affect on outcomes.

“We’re continuing to gather information to see if actual changes are being made by the providers,” Mr. Oh said.

“We hope this will create awareness and assist physicians in adhering to the EBPM and improve patient care and safety.”

—Steve Frandzel

Wicked Change

THINKING continued from page 10

requires the ability to think about what is most critical and essential to future success and to articulate that vision as a roadmap. The leader’s task is pulling others out of the routine of daily work and reframing the mundane in the context of a future state that is an improvement.

As a profession, we face not only a radically changing health care system but also the realization that health professionals— physicians, nurses and pharmacists—are not the stand-alone knowledge agents we were trained and taught to believe we would always be. Rather, in a world of health care change we are reminded that we need pit crews, not cowboys, to borrow a phrase from Atule Gawande2, and that collaboration and shared leadership in the definition and delivery of care to patients is our new reality.

Fast Reflexes Required Regulation and health care financing are changing before our eyes, and the speed and complexity of the change is mind numbing. That can be viewed with trepidation, or leaders with vision can recognize it as an opportunity. In fact, vision can spread like wildfire in an organization that is facing radical change. It can keep the troops moving forward— thoughtfully—in the face of difficult chal-

lenges, and even inspire leaders at every level to reach new heights of accomplishment. Vision creates the springboard for effective delegation and enough guidance to allow people to take initiative that is relevant to the organization’s aspirations and strategies.

Too many leaders believe they must be struck with the inspirational lightning bolt to define a vision to “bestow” on the organization. In reality, vision comes from collective input; a single-source, forced vision or one that is top–down driven by senior leadership alone and imposed by pronouncement is unlikely to succeed. At best, a top–down vision results in compliance, not commitment.

Sharing the development and evolution of a vision, engaging people in comprehending the issues, challenges and driving forces, secures commitment and ownership in moving the organization forward to new horizons.

But leaders are the catalysts for emerging vision, creating and communicating the need for change, creating the sense of urgency to overcome inertia, identifying or creating areas of affinity to support the needed change. And we have never needed that leadership more.

Dealing Effectively with Change Many leaders and their organizations struggle with vision. There is no real script for achievement, but it is defi-

nitely more of a process than a formula.

There are some fundamentals, but they are more guidance than prescriptive: • Conduct an environmental scan to understand stakeholder needs.

• Conduct a SWOT analysis (Strengths, Weaknesses, Opportunities, Threats) • Understand the conditions of employee morale and satisfaction.

• Determine the key questions to pose to stakeholders in order to conduct an environmental and issues assessment; standardize and test the questions for use in a target audience of stakeholders.

Once the environmental scan is completed, a group should be convened to address findings and to develop a draft vision, asking key questions such as: • What kind of organization do we want to become?

• What would we like our reputation to be?

• What mix of services and products should be available?

• How should/will our customer/ patient base change?

• How will people work together?

• What values are in place and/or needed?

Other steps might include conducting organization-wide vision and values dialogues; identifying values priorities; training leaders in dialogue facilitation; scheduling and leading team discussions; establishing behavioral expectations; and

gaining consensus on a code of behavior that forms the culture’s baseline.

Each leader and each team needs to define expectations to align with the vision. How will values be put in play?

How will responsibilities be distributed? How will communication occur and meetings be conducted? How will problems and conflict be resolved?

Although the path to creating a vision has been well defined by a host of experts, the reality is, this is no simple undertaking. It is time consuming, it is demanding—on top of an already demanding set of leadership responsibilities—and it is mentally challenging. It demands that the leader concentrate, THINK, engage, advocate and execute on creative ideas, process innovation and outcome achievement, bringing others along in the thought process. It is more art than science, more improvisational jazz than merely conducting an orchestra.

References 1. Weick KE, Sutcliffe KM. Managing the Unexpected—Assuring High Performance in an Age of Complexity. San Francisco, CA: Jossey Bass; 2001 2. Gawande A. Cowboys and pit crews. The New Yorker. May 26, 2011. Available at: www.newyorker.com/online/blogs/newsdesk/2011/05/ atul-gawande-harvard-medical-school-commencement-address.html

Next column: Exploring the visioning journey in action at Emory Healthcare.

14

Molecules from A to Z

B A L A N C E Between perception and reality.

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Contact your Baxter pharmacy representative at 888-229-0001.

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Medication Delivery

111618A 11/11

14 Operations & Management

Pharmacy Practice News • March 2012

Supply Chain

USP Proposes Standard to Protect Drug Supply T

hreats to pharmaceutical supply chain integrity abound, from counterfeit and adulterated medicines to illegal diversion of drugs. A new U.S. Pharmacopeia (USP) standard, the proposed USP General Chapter <1083> Good Distribution Practices—Supply Chain Integrity, offers recommendations on how to minimize supply chain risks.

Although not mandatory, the new standard is intended to be a central

guidance document outlining core elements of an effective strategy. According to Michael N. Eakins, PhD, principal consultant, Eakins & Associates, East Windsor, NJ, and vice-chair, Packaging, Storage, and Distribution Expert Committee, USP, the new standard differs from other available guidance documents. “While there are numerous articles and guidelines available to help to promote the integrity of indi-

vidual steps in the pharmaceutical supply chain,” he said, the new standard “is intended to provide best practices to protect the integrity of the whole supply chain in a single document.”

Desmond Hunt, PhD, senior scientific liaison, USP, Rockville, Md., added that the USP standard “will provide one, central place that all parties can refer to regarding best practices—and as new issues arise, and technology

advances, USP will update the standard to reflect current realities.”

The standard covers four main areas: importation; counterfeit drugs and medical devices; best practices to combat counterfeit drugs and medical devices; and diversion and theft.

Details include the connection of counterfeit drugs to drug shortages—counterfeiters are “opportunistic” in supplying drugs during shortages—and innovative solutions such as product track-and-trace technology.

USP expects the standard will be useful to all organizations and individuals in the global supply chain, from manufacturers and distributors to hospital and other pharmacies. Particularly important, in the view of Dr. Eakins, are “recommendations on good importation practices, technologies to establish drug pedigrees, approaches to combat illegal Internet pharmacies, and advice on how to reduce the risk of theft.”

Dr. Hunt stressed that the new standard takes multiple approaches to protecting the drug supply chain. In fact, “it is difficult to pull out any one recommendation, which speaks to the real bottom line: every link in the supply chain is important. It only takes one misstep to lead to a substandard product, or a product diversion.”

Public Comment Period Detailed Available at www.usp.org/USPNF/ notices/generalChapter1083.html, the draft general chapter will be published as a formal proposal open for public comment in the March-April Pharmacopeial Forum. The chapter and comments will be discussed at a Supply Chain Integrity Workshop to be convened by USP May 22-23, 2012, in Rockville, Md. “Input from the workshop and from written public comments will assist in determining whether the chapter has got the correct balance between the areas covered and the depth of guidance provided for each area,” wrote Dr. Eakins.

Dr. Hunt expects many comments and changes. “There may be topics we did not think about that should be included in the chapter, or there may be items that people don’t find helpful or relevant.” He added, “USP’s goal is to provide something meaningful, which is why we really are asking for extensive input, and providing multiple forums for people to provide this to us.”

—George Ochoa Dr. Eakins reported no relevant financial disclosures.

Pharmacy Practice News • March 2012

Q & A 15

American Regent

Tranexamic Acid Injection Q&A Q: What is tranexamic acid injection?

A: Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid.

Q: What is the indication for tranexamic acid injection?

A: Tranexamic acid injection is indicated in patients with hemophilia for short-term use (2 to 8 days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.

Q: What contraindications are associated with tranexamic acid injection?

A: Tranexamic acid injection is contraindicated: 1. In patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity.

2. In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients.

3. In patients with active intravascular clotting.

4. In patients with hypersensitivity to tranexamic acid or any of the ingredients.

Q: What are some adverse reactions associated with tranexamic acid injection administration?

A: In worldwide postmarketing reports thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment also have been reported.

Gastrointestinal disturbances (nausea, vomiting and diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid.

Q: How do you dose and administer tranexamic acid injection?

A: Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of tranexamic

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solutions, and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to tranexamic acid injection.

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16 Operations & Management

Pharmacy Practice News • March 2012

Supply Chain

SHORTAGE continued from page 1

oral benzodiazepines whenever possible “even in our intubated patients if the gut works,” and to choose propofol for hemodynamically stable intubated patients with gastrointestinal function. For hemodynamically unstable patients, he recommended “trying to use a fentanyl infusion along with intermittent or even ATC [around-theclock] oral [benzodiazepines],” and to use IV midazolam “as our preferred

intermittent-dose benzodiazepine for anxiety and agitation if an oral route is not an option.”

Dr. Haas ended the email with an optimistic plea: “We ask that you pass this along to the appropriate providers and encourage judicious use of the IV products. Hopefully, if we all conserve as much as we can we’ll be able to squeeze by until our next shipment.”

Unfortunately, as soon as one shortage of sedatives or anesthesic agents is dealt with, another one seems to crop up, Dr. Haas told Pharmacy Practice News. “Just

last week [late February], a shortage of preservative-free morphine for neuroaxial anesthesia hit us hard. Whether it’s Astramorph or Duramorph and other equivalents, they’re simply unavailable.

We hear there may be some new shipments coming in early March, but there’s no guarantees; we have maybe enough drug to last another seven to 10 days.”

In the meantime, Dr. Haas noted, his colleagues in anesthesiology are looking at possible alternatives, such as fentanyl. “It’s not preferred, but at least it’s an option,” he said. Preservative-

free hydromorphone or bipuvicaine are other options for neuroaxial anesthesia, “but bipuvicaine has been in short supply as well. So this is very much still a moving target.”

Nationwide Problem URMC is far from alone in feeling the pinch on key sedatives and anesthetics.

Hospitals across the country are facing similar shortfalls in the supply of these and other important drugs. One major facility in the Midwest listed no fewer than eight “new or high-priority” short-

ISMP: Flawed CMS Storage Standards May Be Worsening Drug Shortages

S

ome parenteral medications in critically short supply may be needlessly discarded because of inconsistencies in the interpretive guidelines for pharmacy management and administration issued by the Centers for Medicare and Medicaid Services, according to the Institute for Safe Medication Practices.

The CMS guidelines aim to provide a standard for measuring health care organization performance. The problem for pharmacies, ISMP noted, is even while the guidelines advise relying on standards and recommendations from professional organizations, CMS continues to use FDA-approved manufacturer drug labeling as the basis for determining how long injectable drugs may be used after being removed from vials and manipulated. The labeling information on expiration dates, however, may be inadequate, missing or even outdated based on new reliable evidence, ISMP reported in the Jan. 26 edition of its Medication Safety Alert! newsletter.

For pharmacies torn between relying strictly on the CMS interpretive guidelines for deciding whether to throw away a scarce medication or following fresh evidence supporting extended dating, the decision often may be colored by the fear of citation by a surveyor from the Joint Commission or state health department.

In January, the ISMP fielded a survey to find out how pharmacists are dealing with the challenge. Although the final results are not yet completed, Michael R. Cohen, RPh, MS, ScD, FASHP, ISMP’s president, said an early look showed that “without a doubt people are throwing things out as a result of not allowing the extended dating.”

Dr. Cohen said ISMP had “spoken to CMS on this issue and they are definitely willing to look into seeing what they might be able to do to address it.”

Patrick Conway, MD, chief medical officer for CMS and director of the Office of Clinical Standards and Quality, responded by stating that “CMS is actively working with our colleagues in the FDA and CDC to identify options available to practitioners to address

Pharmacy Practice News • March 2012

Operations & Management 17

Supply Chain ages during the second week of January.

On the list: etomidate, heparin, ketorolac, morphine, ropivacaine and alfentanil.

Those drugs join a roster of nearly two dozen other agents, from diazepam and midazolam to lorazepam and rocuronium, in the “ongoing” category. A wide range of cancer drugs also have been in short supply (Pharmacy Practice News, January 2012, page 1.)

Reasons for the drug shortages are unclear, but involve production issues, indefinite plant shutdowns and drug makers exiting the market. When they

are able, hospitals and clinics adapt by using substitute drugs or stretching their stocks to the limit. When no alternative is possible, many facilities are turning to the so-called “gray market” for pharmaceuticals, a poorly regulated network of suppliers who charge several times the usual rate for the medications.

Keith Candiotti, MD, chief of perioperative medicine at the University of Miami Leonard M. Miller School of Medicine, said his facility recently had been forced to pay as much as 20 times the regular rate for some anesthetic agents. “We’re

having trouble finding fentanyl, sufentanil and even midazolam, as well as diazepam and lorazepam,” Dr. Candiotti said. “So far, if you are willing to pay a premium you can find drug right now, but the supply is clearly reduced.”

Beyond Anesthesia Although anesthesiologists may have workarounds, other clinicians who depend more heavily on benzodiazepines have been even harder hit by the shortages. Gastroenterologists, who rely on the drugs in combination with

opioids for endoscopic procedures, are among them, according to Lawrence Cohen, MD, of Mount Sinai School of Medicine in New York City. “We, like many other groups throughout the country, have been affected by the shortage of certain sedatives and opioid drugs. Currently, there are shortages of fentanyl, midazolam and meperidine—the last one created by the unavailability of fentanyl, which has led to increased use and hoarding of meperidine,” Dr. Cohen said.

The fallout from the sedative short-

•

see SHORTAGE, page 18

the challenge of drug shortages within existing laws and regulations. We continue to welcome suggestions by ISMP and other experts as well seek methods to alleviate the shortage while also ensuring that unsafe medications do not reach patients.”

Fear Over Surveys Can Be Stifling Pharmacists are extremely cautious about admitting to extending the dating of some drugs in short supply, even if supported by newer literature. “You can’t be quoted in print and have a surveyor come back and haunt you,” said one pharmacy director.

However, a safe harbor for determining appropriate injectable medication use and storage may be strict adherence to United States Pharmacopeia (USP) Chapter 797 guidelines. Dr. Cohen said that “if the scientific literature supports extended dating and you’re still sticking within the USP Chapter 797 guidelines for dating, it makes sense to me not to necessarily worry about whether you’re going to get cited or not.”

Alan Knudsen, MS, director of pharmacy services at Shands HealthCare at the University of Florida, Gainesville, said that “what our team has worked hard to do at Shands is to protect our patients by complying with USP guidelines, while at the same time meeting their medication needs. So I’ll spend a lot of money acquiring morphine and fentanyl, for example, from an alternative supplier, and still comply with USP 797 guidelines. We’ll work with our physicians to determine alternative care that creates equivalent patient outcomes. Usually, that means that Shands Hospital pays a lot more money for medications with no additional reimbursement.”

Thomas Burnakis, PharmD, clinical pharmacy director at Baptist Medical Center in Jacksonville, Fla., said that “as a pharmacist I understand the compassionate need for the use of these medications, and I personally feel that the regulatory guidelines are too narrow.”

He added, “I feel pharmacists are trying to do their best to follow guidelines at the potential risk of not having vital medications available for their patients. However, as the clinical pharmacy director for Baptist Medical Center, it is clear that our organization must, and does, and will adhere to all guidelines regarding medication use.”

—Bruce Buckley

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18 Operations & Management

Pharmacy Practice News • March 2012

Drug Shortages

SHORTAGE continued from page 17

age could range from limiting the number of endoscopic procedures to a shift in sedation methods, Dr. Cohen continued. “For example, there has reportedly been a shift in sedation technique from midazolam and fentanyl, administered by the proceduralist, to utilization of propofol.”

In early February, the American College of Gastroenterology (ACG) sent a letter to FDA commissioner Margaret Hamburg, MD, to express its “deep concern” regarding the shortage of sedatives. “[ACG] members across the United States are experiencing tremendous difficulty in accessing certain sedative and narcotic agents that are used routinely during endoscopic procedures such as colonoscopy,” the letter stated. “We urge FDA to use its full authority under current law to help resolve these shortages as supplies continue to dwindle.”

The letter, which cited shortages of fentanyl, meperidine and midazolam, noted that the cost of endoscopy might rise if gastroenterologists turned to propofol and required the presence of an anesthesiologist to perform monitored anesthesia care.

An FDA spokesperson said Dr. Hamburg would “carefully review the letter and respond directly to the American College of Gastroenterology in a timely manner.”

On Jan. 18, an FDA interim final rule took effect, broadening the circumstances under which the sole manufacturer of certain critical drugs must report to the FDA about stopping production. No longer will a company that interrupts, but does not permanently cease, the manufacture of a critical drug be exempt from the requirement to give the FDA a six-month advance notice. According to a press release from the U.S. Department of Health and Human Services, the intent of the presidential executive order that led to the interim final rule was “to take action to help reduce and prevent drug shortages, protect consumers, and prevent stockpiling and exorbitant pricing of drugs in shortage.”

The FDA interim final rule does not establish monetary penalties for failure to provide the required advance notice.

Senate bill 296 and House bill 2245 provide for monetary penalties; both bills await committee action.

Joseph M. Hill, director of federal legislative affairs for the American Society of Health-System Pharmacists, said the new rule was likely to have more of an effect on manufacturers than pharmacies. However, he said there is a “downstream hope” that with more information, the FDA may be able to work behind the scenes to help

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Pharmacy Practice News • March 2012

Operations & Management 19

Supply Chain stop shortages. Mr. Hill said 2011 was a record-setting year for drug shortages, with 267 reported.

At the time this article went to press, the FDA had at least 115 drugs on its list of current shortages, with the latest addition being IV zinc sulfate caused by “manufacturing delays.”

Drug shortages create more than logistic headaches for hospitals and clinics—they also pose ethical dilemmas. In a recent editorial in the American Journal of Health-System Pharmacy, Michael Manolakis, PharmD, PhD,

‘Despite assurances of pedigree, a purchase from a secondary market represents a disruption in the integrity of the drug supply chain, and it places a patient at risk.’

assistant dean at the Wingate University School of Pharmacy, in Wingate, N.C., wrote of three such ethical problems that drug shortages raise: rationing, hoarding and gray market buy-

—Michael Manolakis, PharmD

ing. “Despite assurances of pedigree, a purchase from a secondary market represents a disruption in the integrity of the drug supply chain, and it places a patient at risk,” Dr. Manolakis wrote.

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“Until every hospital refuses to pay the marked-up prices for short-supply products, the problem will persist.”

—Adam Marcus

20 Clinical

Pharmacy Practice News • March 2012

Pain Medicine

Rise in Narcotics Scripts to Elderly Linked to Falls, Fractures Chicago—Following the recall of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib (Vioxx, Merck) in 2004 because of concerns over potential cardiovascular adverse events, narcotic analgesics became an even more important means of treating and controlling chronic pain. Now, a study presented at the 2011 annual meeting of the American College of Rheumatology shows that prescriptions for narcotic analge-

‘We need to rethink our management of chronic pain in the elderly. We can’t just say “no” to NSAIDs and use narcotics instead.’ sics and falls and fractures in elderly patients with osteoarthritis both rose substantially once rofecoxib was taken off the market (abstract 911). Lead

—Eric Matteson, MD author Lydia Rolita, MD, from New York University School of Medicine, in New York City, suggested that the increase in falls and fractures is associ-

Presents

Bridging the gap between the hospital and post-discharge care

Volume 1 • Number 1 • Winter 2012 A Supplement to Pharmacy Practice News

In This Issue

Embracing Rather Than Fighting Specialty Pharmacy

Ask the Expert

4

I

nfusion centers and other community practice sites that manage patients post-discharge share a common lament: Why do so many of those patients often struggle with the basics of care after they leave the (usually) safe confines of the hospital?

One glaring contributing factor is a lack of collaboration between hospitals and the community sites of care, according to Dennis Street, RPh, lead pharmacist at Mercy Home Infusion, which is affiliated with Mercy Hospital in St. Louis. “It’s a big enough transition to get patients out of the hospital, much less getting them out of the hospital and starting them on

Tips for partnering with managed care organizations, plus cost-saving strategies.

Q&A

5

Stephanie Holliday, PharmD, discusses REMS, self-administered oral chemotherapy and other hot topics in specialty pharmacy.

Opinion

6

N. Lois Adams, BPharm, on reining in the high cost of drug therapy.

Operations & Mgmt

9

Aetna Specialty Pharmacy, other providers offer drug adherence strategies.

Educational Review

18

Antimicrobial Efficacy

Policy

24

Patient assistance programs, plus a projection that specialty pharmacy drug spending will soar by 26.5% in 2012.

Building a Better Care Transition: What Works Now

•

see CARE TRANSITION, page 8

University of Illinois clinical staff pharmacist Nehrin Khamo, PharmD, educates a patient on self-injection techniques.

Tips for Surviving The TPN Shortage

A

T

lthough many health-system pharmacists bristle at limited distribution networks and other restrictions placed on some specialty medications, more and more of them are deciding to embrace specialty pharmacy rather than fight it, and thus join the ranks of smaller and larger specialty operations providing that segment of care.

To offer insights into this new source of competition, Specialty Pharmacy Continuum profiled three hospitals that are bolstering their presence in the market: The University of Illinois Hospital and Health Sciences System, Chicago; Fairview Pharmacy Services, Minneapolis; and Duke University Hospital, Durham, N.C. The health systems cite revenue loss as one reason for their recent efforts: they simply can’t afford to continue seeing patients siphoned off to specialty pharmacy providers. But finances aren’t the only motivation; another key driver is the need to provide for patients’ total health needs across transitions of care, as the era of accountable care organizations and payments based on quality standards gets under way.

For Kyle Skiermont, PharmD, director of specialty infusion operations at Fairview Pharmacy Services, improving patient care is the No. 1 reason health systems enter or expand into the specialty pharmacy area. His operation, a part of Fairview Health Services, a large regional network of hospitals, already is well established as a

•

see EMBRACE, page 11

FDA Approvals Kalydeco approved for cystic fibrosis patients with CFR gene mutation.

See page 26.

hings have been heating up on the IV nutrition shortage front. Last fall, Baxter hosted the first-ever nutrition shortage safety summit, and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), which put together a task force to address the supply shortages, has been issuing frequent updates and guidances to help its members prioritize, substitute and manage the limited supplies they have.

But such regulatory and policy efforts only go so far in mitigating the effects of the shortage on patient care. Here are several practical strategies that home infusion centers are using right now to weather the storm.

•

see TPN SHORTAGE, page 10

The Book Page

A new quarterly publication from the editors and publisher of Pharmacy Practice News.

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

Our goal: to help foster high-quality, cost-effective treatment across the entire patientcare continuum.

To subscribe, visit pharmacypractice news.com

MedInfoNow Subscription

See page 27.

Bridging the gap between the hospital and post-discharge care

ated with the rise in narcotic use.

“These findings strongly indicate that recommendations for the treatment of chronic pain need to be re-evaluated,” Dr. Rolita said. However, she added, a cause–effect relationship between narcotic analgesics and falls or fractures cannot be deduced from this research.

The investigators reviewed medical records for 10,000 patients over the age of 65 years who were diagnosed with osteoarthritis between 2001 and 2009.

They used codes from the International Classification of Diseases, Ninth Revision to identify the number of falls and fractures that occurred in this time frame. Additionally, analgesic use was divided into three categories: narcotic analgesics with or without other analgesics; COX-2 inhibitors alone or with other analgesics; and non-COX-2 inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs), other analgesics or no analgesics.

The researchers found that the percentage of study patients who received opioid prescriptions increased from 8% in 2002 to 20% in 2004 and doubled to 40% in 2009. Use of COX-2 inhibitors was low in this population, peaking at 8% in 2004 and then declining. Almost all of these patients were prescribed non-COX-2-blocking NSAIDs and/or other analgesics in 2002, but this number declined to about 70% by 2009.

Patients older than age 70 years who had more comorbidities experienced a greater number of falls and fractures regardless of the type of pain medication they took. The incidence of falls and fractures increased from less than 1% in all patients in 2001 to 4% in 2009.

Use of narcotic analgesics was associated with a 3.7 times greater risk for falls and fractures than use of COX-2 inhibitors (P<0.001), and a 4.4 times greater risk than non-COX-2 NSAIDs (P<0.001) from 2005 to 2009.

The investigators stated that the incidence of falls and fractures “appears to be associated with the increased use of narcotic analgesics.”

Pharmacy Practice News • March 2012

Clinical 21

Pain Medicine

Got Gout Pain? Milk Powder May Help N ew study results show a link between the consumption of skim milk powder enriched with nutrients and reduced uric acid levels, less pain and fewer flare in gout patients.

Researchers at the University of Auckland, New Zealand, randomized 120 gout patients to consume daily eight-ounce flavored shakes with lactose powder, skim milk powder or enriched skim milk powder (containing glycomacropeptide and G600 milk fat extract, both shown to reduce inflammation in gout patients) for three months. Patients, who were followed up monthly, were considered to have gout and thus to be eligible for study inclusion if they reported at least two gout flares over the past four months.

Patients in the enriched skim milk powder group were shown to have fewer self-reported gout flares, improved urine levels of uric acid and greater reductions in pain than those in the other two study groups. Researchers also reported a trend toward fewer tender joints in the enriched milk powder group. No evidence of weight gain or increased blood fat levels were seen by the researchers, led by Nicola Dalbeth, MD, associate professor in the Department of Medicine at the University of Auckland.

Low consumption of dairy products previously has been shown to be

“Using narcotic analgesics—not abusing them—is associated with more falls and fractures in the elderly,” said Eric Matteson, MD, chair of the Division of Rheumatology at Mayo Clinic in Rochester, Minn., who was not involved in the study. “We need to rethink our management of chronic pain in the elderly. We can’t just say ‘no’ to NSAIDs and use narcotics instead.”

In his practice, Dr. Matteson advises his patients to try nonpharmacologic pain management approaches, including exercise to improve strength, endurance and weight loss. “Weight loss is associated with a reduction in pain associated with arthritis,” he said.

In situations where patients anticipate having pain, such as after exercise, he encourages them to take one or two acetaminophen tablets. “Patients could also try one or two Tylenol [acetaminophen] tablets with one ibuprofen, or perhaps two over-the-counter–strength ibuprofen, or an over-the-counter naproxen tablet.” However, he encourages patients not to rely on NSAIDs on a regular basis.

—Alice Goodman

a risk factor for the development of gout and for increases in gout flares (Curr Rheumatol Rep 2011;13:132-137).

The researchers in the current trial describe it as the first “reported randomized controlled dietary intervention in gout management.”

The study was reported online Jan. 23 in Annals of Rheumatic Diseases.

—Donald M. Pizzi

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22

Hem/Onc Pharmacy

Pharmacy Practice News • March 2012

In Focus

Finding a Biomarker for Avastin: An Elusive Target For a decade, investigators have searched in vain for a predictive bevacizumab marker

T

his past fall, when the FDA withdrew bevacizumab’s approval for metastatic breast cancer, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, urged the company’s manufacturer, Genentech, to identify a biomarker that predicts response to the drug. The advice was well taken: Genentech had already submitted a proposed Phase III trial to the FDA to test the suitability of vascular endothelial growth factor (VEGF)-A as a biomarker.

Genentech’s effort, however, is only one of many. For roughly 10 years, researchers have been chasing down a biomarker for bevacizumab (Avastin) that has, so far, remained out of reach.

“We began to put a lot of the negative [biomarker] data into the public domain in the past five years, but the effort has been under way for many, many years,” said Philippe Bishop, MD, Genentech’s vice president and head of clinical development for Avastin. “We just haven’t been able to identify, along the way, biomarkers that could be predictive.”

A Long, Frustrating Search Researchers have explored tumorbased markers, serum- and plasma-based markers such as cytokines and growthfactor expression, DNA-based markers, toxicity-based markers and radiographic predictors. They have looked not only at breast cancer patients, but also at those with colon, kidney, lung and brain cancers. The net has been cast widely, but it has come up empty thus far.

And throughout, expectations have been raised only to be quashed later.

The trend has been that subanalyses of studies yield biomarkers that look promising and then confirmatory studies are negative or yield mixed results.

In 2008, researchers led by Bryan Schneider, MD, associate professor of medical and molecular genetics and an oncologist at the Indiana University Melvin and Bren Simon Cancer Center in Indianapolis, reported a biomarker subanalysis of the E2100 trial in the Journal of Clinical Oncology (2008;26:46724678). They identified two genotypes that were associated with improved survival with the use of bevacizumab and two that predicted hypertension, the drug’s most common toxicity. “There have been several other groups that have looked at similar genetic variations since then,” said Dr. Schneider. “Some groups have found findings similar to ours and some have not.”

“There was hope that triple-negative patients might derive the most benefit as there has been some data that supports

Although there are hundreds of bevacizumab studies, there are few large prospective trials with a suitably powered biomarker component. that suggestion; however, there has been other data that does not,” said Maura Dickler, MD, associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City. At the 2010 San Antonio Breast Cancer Symposium (SABCS), Gunter von Minckwitz, MD, PhD, managing director of the German Breast Group in Neu-Isenburg, reported that a subset analysis of the GeparQuinto trial that tested neoadjuvant bevacizumab plus chemotherapy in early breast cancer showed that the drug increased pathologic complete response in women with triple-negative breast cancer.

However, a benefit in the triple-negative group was not confirmed by results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-40 trial of neoadjuvant bevacizumab.

Rakesh Jain, PhD, the A. Werk Cook Professor of Radiation Oncology for Tumor Biology at Massachusetts General Hospital, in Boston, has conducted studies that have suggested that vascular imaging can be used as a biomarker in recurrent glioblastoma. The findings need to be validated in Phase III trials however, and whether this could translate to breast cancer remains to be seen.

“At the end of the day, although there has been interest in a myriad of biomarkers including VEGF genotypic polymorphisms, VEGF-A and VEGFR-2 in tumor tissue, circulating VEGF levels and the development of bevacizumab-induced hypertension, none of these biomarkers have met the level of evidence to incorporate them into clinical care at the present time,” said Dr. Dickler. “Although there has been some inkling of hope, it has been a tough nut to crack.”

On a basic level, it is still somewhat unclear why bevacizumab works on some cancers and not on others because seemingly, all tumors need to be fed by blood vessels. “The VEGF pathway may not be equally important across solid tumors, and I think that is likely the best explanation,” said Dr. Dickler. Varying mechanisms of resistance or other driving mutations or pathways may be more important in one type of tumor than in another.

“I think Avastin is a tricky drug in terms of finding the perfect biomarker and that may be a function of a few things, one of which is that there is an interesting interaction between the host and the tumor,” said Dr. Schneider. The drug is designed

to block tumor vasculature, but vasculature may be regulated by the host, by the tumor, or by both. “I think most other groups, at least prior to 2008, had really focused on variability within the tumors,” Dr. Schneider said. “I think that may be part of the difficulty.”

Dr. Schneider said another problem in the biomarker search is that some correlative studies are lumping different anti-angiogenic drugs together. “I think many people have looked at a variety of the different anti-angiogenic drugs as a group, combining the data with small tyrosine kinase inhibitors like sunitinib [Sutent, Pfizer], sorafenib [Nexavar, Bayer Healthcare] or pazopanib [Votrient, GlaxoSmithKline], and I think you simply can’t do that,” he said. “I think biomarkers are going to be different for these other drugs because they simply hit more targets.”

Well-powered studies have been another stumbling block. Although there are hundreds of bevacizumab studies, there are few large prospective trials with a suitably powered biomarker component.

Subanalyses are plentiful. In a recent JCO editorial, Dr. Schneider and George Sledge Jr., MD, also from the Melvin and Bren Simon Cancer Center, point out that all the attempts to identify the optimal subgroups for bevacizumab therapy thus far have been conducted retrospectively on prospectively collected clinical trial samples and many of them did not include a control arm (doi: 10.1200/ JCO.2011.34.9266).

Subgroup analyses are tricky for a number of reasons. Investigators need to take steps to ensure that the subgroups being tested mirror the parent study and take into account why samples are missing, so that selection bias can be avoided, the editorial argues. It also is difficult to get sufficient statistical power to determine differences in subgroup analyses. It may be that a biomarker has remained elusive because of “pitfalls in the testing system,” rather than the fact that researchers are testing the wrong markers.

“These biomarker studies are being done in really small trials and that makes the power of finding something really difficult,” Dr. Schneider said. “The danger is [that] if you say ‘Well, nothing

Bevacizumab is a monoclonal antibody that blocks angiogenesis by intercepting VEGF-A in the bloodstream.

was positive here,’ one may interpret that as simply ‘There is just no association,’ when in reality, it had nothing to do with the biological association, but rather the fact that the trial wasn’t set up right to answer that question from a statistical standpoint.”

In their editorial, Drs. Schneider and Sledge argue that retrospective analyses of “old prospective clinical trials will be destined to only cloud the picture,” regardless of how promising the biomarker in question may be. Prospective trials are what are needed.

Current Directions E5103, an ongoing prospective trial with which Dr. Schneider is involved, is looking at this question. This 5,000-patient trial is testing the addition of bevacizumab to a backbone of doxorubicin and cyclophosphamide, followed by taxanebased chemotherapy in the adjuvant setting of breast cancer.

“We have done a genome-wide association study, so we are looking at over 1 million SNPs [single nucleotide polymorphisms] within each of the first 2,200 patients. So, we hope that not only can we validate or refute what we found in the E2100 trial, but if there are other pathways or mechanisms, we can identify them with this approach,” said Dr. Schneider, referring to the hypertension and efficacy biomarkers previously identified.

The trial that Genentech recently submitted to the FDA is another prospective Phase III trial built around

Hem/Onc Pharmacy 23

Pharmacy Practice News • March 2012

In Focus biomarkers. “We have designed the study around it. We are specifically asking a question around the value of plasma VEGF-A,” said Dr. Bishop, who added they would also be looking for other markers. He said that subanalyses of two trials, AVADO and AVEREL, provided evidence that VEGF-A is a good candidate for a predictive marker for bevacizumab benefit. The most recent subanalyses of these two studies were presented at the 2011 SABCS. The double-blind, randomized Phase III AVADO trial evaluated bevacizumab

in combination with docetaxel as first-line therapy for HER2-negative, locally recurrent metastatic breast cancer. VEGF-A and VEGF-R2 were identified as potentially promising candidates for predicting progression-free survival (PFS) with bevacizumab, and VEGF-A levels at baseline did not correlate with known prognostic factors, thus indicating it could be predictive. In a cohort of patients who had received 15 mg/kg bevacizumab and had VEGF-A levels in the top quartile, the hazard ratio for PFS was 0.39 (95% confidence interval, 0.19–0.77) and the

difference in median PFS was more pronounced than in the other groups.

The randomized Phase III AVEREL trial evaluated bevacizumab in combination with trastuzumab plus docetaxel in the first-line therapy of patients with HER2-positive, locally recurrent metastatic breast cancer. Patients were randomized to docetaxel plus trastuzumab alone or in combination with bevacizumab. The median PFS was improved in patients receiving bevacizumab (16.8) compared with those receiving docetaxel plus trastuzumab alone (13.9; P=0.0162).

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An exploratory analysis of plasma VEGF-A suggested a potentially predictive effect with a greater benefit with high VEGF-A levels (plasma VEGF-A equal to or less than median: hazard ratio [HR], 0.83; plasma VEGF-A greater than median: HR, 0.70).

“VEGF-A happens to be a biomarker that is prognostic in breast cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer and renal cancer. In a lot of tumor types that we have tested, we have seen consistently across all of the tumor types that VEGF-A was indeed prognostic,” said Dr. Bishop. He said it wasn’t until recently, however, when a new-generation assay became available that was able to identify a certain isoform of VEGF-A, that researchers began to see inklings that the marker could be predictive. If approved, the Phase III trial will try to confirm that patients who express higher levels of VEGF-A derive the greatest benefit from bevacizumab and those with lower levels derive a lesser benefit.

While the biomarker search continues, clinicians around the country are deciding whether or not to continue using the drug. Decisions are based on what doctors feel comfortable with, given the FDA decision and whether they can get reimbursement.

“We tend to use a paclitaxel-bevacizumab combination whenever a rapid response is needed; that means patients with metastatic breast cancer who are symptomatic or those who have extensive visceral disease where there is little margin for error,” said Gabriel N. Hortobagyi, MD, chair of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

“In a large institution like mine, we are a bit sheltered from reimbursement issues, so I cannot tell you who is reimbursing and who is not, except that I know Medicare is reimbursing routinely, and I have not received calls from pharmacy or administration indicating that we are not getting reimbursed.”

Dr. Dickler said she provides bevacizumab to selected patients in combination with chemotherapy. “I give it to patients who have aggressive and/or symptomatic disease for whom I opt for taxane-based chemotherapy in the firstline setting. Generally, these patients have either progressive disease on endocrine therapy or are not appropriate candidates for endocrine therapy,” said Dr. Dickler.

John Finnie, MD, staff hematologist and medical oncologist at the David C. Pratt Cancer Center at St. John’s Mercy Medical Center in St. Louis, said he follows the guidelines of the National Comprehensive Cancer Network when deciding which patients with metastatic breast cancer get bevacizumab. “I

•

see BIOMARKERS, page 24

24

Hem/Onc Pharmacy

Pharmacy Practice News • March 2012

In Focus

PROSTATE CANCER continued from page 1

other therapies and grow.”

MDV3100 prevents androgens from binding to androgen receptors in the tumor, limits the ability of the androgen receptor to get to the nucleus of the tumor and inhibits binding of the androgen receptor to DNA. This inhibits tumor growth and results in prostate cancer cell death.

During the study, called AFFIRM, 1,199 men with metastatic CRPC were randomized to receive either MDV3100 or placebo. All the patients had cancers that progressed despite previous hormone therapy and docetaxel chemotherapy. After a planned interim analysis, researchers found that median OS was 18.4 months for patients treated with MDV3100 and 13.6 months for those receiving placebo. Treatment with MDV3100 prolonged life by 4.8 months and reduced the risk for death by 37% compared with placebo (hazard ratio [HR], 0.631; P<0.0001). As a result, the trial was halted early, and patients in the placebo arm were offered the drug.

MDV3100 met all secondary end points in the trial, including radiographic progression-free survival (8.3

‘This drug will usher in a new role of

group. Side effects of interest that were grade 3 or greater are listed in the Table.

therapy for prostate cancer; there will

‘A Promising Option’

be a reworking of current treatment

“MDV3100 outperformed our expectations in the AFFIRM trial by meeting the primary and secondary end points with strong statistical significance and demonstrating a favorable safety profile,”

regimens.’

—Ali McBride, PharmD, MS, BCPS

Table. Grade 3 or Higher Side Effects in AFFIRM Trial Side Effect

MDV3100, %

Placebo, %

Fatigue

6.3

7.3

Cardiac disorders

0.9

2

Myocardial infarction

0.3

0.5

Seizure

0.6

0

Liver function test abnormalities

0.4

0.8

NIH Expert’s Take

vs. 2.9 months; HR, 0.404; P<0.0001), soft tissue response rate (28.9% vs. 3.8%; P<0.0001) and time to prostate-specific antigen (PSA) progression (8.3 vs.

3 months; HR, 0.248; P<0.0001). PSA declines of 50% or greater were more common in the MDV3100 group than in the placebo group (54% vs. 1.5%; P<0.0001), as were PSA declines of 90% or greater (24.8% vs. 0.9%; P<0.0001).

MDV3100 was well tolerated during the trial. Common adverse events (AEs) included fatigue, diarrhea and hot flash.

Serious AEs, AEs causing patients to stop treatment and fatal AEs were lower in the MDV3100 group than in the placebo

said Dr. Scher. “These results together with its convenient once-daily oral dosing regimen should make MDV3100 a promising option for men with prostate cancer who have received prior hormone therapy and chemotherapy.”

Co-investigator Johann de Bono, MD, MSc, PhD, FRCP, honorary consultant in medical oncology and professor of experimental cancer medicine at Royal Marsden Hospital and Institute of Cancer Research, in London, said, “The almost five-month overall survival benefit MDV3100 showed over placebo in this trial is noteworthy, as is the fact that men with post-chemotherapy pros-

tate cancer taking MDV3100 lived for a median of a year and a half.”

The next challenge is finding the best way to maximize how to use MDV3100, which may be in sequence or in combination with other treatments. In the meantime, the agent has been fast-tracked at the FDA, and many experts in the area are hoping it will be approved for commercial use within the next six to nine months. “It is going to change the way we treat patients,” predicted medical oncologist Nicholas Vogelzang, MD, head of the section of genitourinary cancer at the Nevada Cancer Institute in Las Vegas. “Hopefully, this drug will be available in the United States this year.”

MDV3100 is being studied in the Phase III PREVAIL and Phase II TERRAIN trials in men with prostate cancer who have failed hormone therapy but have not yet received chemotherapy, as well as in a Phase II study in men with prostate cancer who have not yet

BIOMARKERS

vices said Medicare is still paying for it, but each Medicare contractor has the discretion of whether or not to pay. Representatives of United Healthcare, Harvard Pilgrim Health Care and Aetna said they are still covering the drug for metastatic breast cancer. Blue Shield of California is continuing to cover the drug for patients who were already using it in October, but coverage for new patients is now being determined on a case-by-case basis.

Dr. Schneider said he is not prescribing bevacizumab for his patients with metastatic breast cancer based on the FDA’s recommendation, but he said he is hopeful that a biomarker can be identified. “I strongly believe there is a subgroup of patients who probably gain substantial benefit, and this is simply based on anecdotal observations from my clinic. I truly believe the FDA and regulatory boards would be enthused about using this drug

‘It is an important advance. I am excited to see it coming [and] I think it will be … prescribed early in the course of the disease.’

—William D. Figg, PharmD, MBA

continued from page 23

think it is an appropriate drug for most patients,” he said. He added that he has not had any problem getting reimbursed but that he has spoken to colleagues who were not using it because they were not being reimbursed.

Coverage varies. A spokesperson for the Centers for Medicare & Medicaid Ser-

received hormone therapy.

“This drug will usher in a new role of therapy for prostate cancer,” Ali McBride, PharmD, MS, BCPS, specialty practice pharmacist at The Ohio State University Medi­cal Center, in Columbus, told Pharmacy Practice News. “There will be a reworking of current treatment regimens. One of the at-large questions will be whether MDV3100 will move ahead of abiraterone [Zytiga, Janssen] for treatment and will there be issues with reimbursement, costs for therapy and compliance because this is another new oral drug therapy. In addition, the safety profile may be more favorable for the use of MDV3100 versus other drug therapies for prostate cancer, which may help determine its place in therapy.”

William D. Figg, PharmD, MBA, senior scientist and head of the clinical pharmacology program and molecular pharmacology section at the National Cancer Institute, in Bethesda, Md., said that he considers this new agent to be very promising. He agreed with Dr. McBride that MDV3100 might indicate movement toward a new treatment paradigm for men with metastatic prostate cancer. “It is an important advance. I am excited to see it coming,” Dr. Figg said. “I think it will be something that will be prescribed early in the course of the disease.” However, he added that it is yet to be determined whether this agent would be best given pre-chemotherapy or post-chemotherapy.

—John Schieszer Dr. De Bono reported a financial relationship with Astellas, Johnson & Johnson and Medivation.

Dr. Scher reported a financial relationship with Medivation. Drs. Figg and McBride have no relevant disclosures.

if they can simply find the group who gains good benefit similar to what we have seen with trastuzumab.”

For now, the search continues.

—Kate O’Rourke Drs. Dickler, Hortobagyi and Schneider have served as consultants for Genentech.

Drs. Finnie, Sledge and Jain have no relevant disclosures.

Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®.

Our Specialists can help you navigate the process.

To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources

© 2011 Genentech USA, Inc. All rights reserved. ACS0000716800 Printed in USA.

26

Hem/Onc Pharmacy

Pharmacy Practice News • March 2012

In Focus

Multi-kinase Inhibitor on Horizon for Colorectal Cancer Regorafenib touted as ‘a potential new standard of care’ for refractory disease San Francisco—A first-in-class drug that jumped straight from a Phase I to a Phase III trial is expected to be approved in patients with refractory metastatic colorectal cancer (mCRC).

The Phase III data, presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (abstract 385), has shown that treating this patient population with regorafenib (Bayer) increased median overall survival by 1.4 months.

“I would suggest the [benefits] are clinically meaningful for many, but not for all patients,” said Herbert Hurwitz, MD, an associate professor of medicine at Duke Cancer Institute, Durham, North Carolina, who was not involved with the study. “The toxicity profile is acceptable, but does require dose adjustment and monitoring of the patient.

This is likely to be a candidate for regulatory approval in 2012.”

Regorafenib is the first small-molecule, multi-kinase inhibitor with proof of efficacy in colorectal cancer. Documenting that efficacy in patients with resistant disease is a major advance, according to principal investigator Axel Grothey, MD, a professor of oncology at Mayo Clinic, Rochester, Minn.

“The vast majority of colorectal cancer patients with metastatic disease are in a palliative situation,” having failed a wide range of standard therapies, he said. “They may still have a good performance status, but no [effective] salvage therapy exists.” Thus, regorafenib could offer these patients a much-needed therapeutic option once the FDA approves the drug, Dr. Grothey said.

Pathways to Approval Research demonstrating that compensatory pathways are activated by bevacizumab sparked the idea of using multitargeted agents after disease progression.

Regorafenib is a promising candidate because it inhibits multiple cell-signaling kinases: angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-b, FGR), and oncogenic (KIT, PDGFR, RET).

After regorafenib was shown to be effective in a Phase I expansion trial of mCRC, an international research team launched the Phase III CORRECT trial.

Patients were eligible if they had mCRC disease progression during or within three months after the last administration of approved standard therapy, including fluoropyramidine, oxaliplatin, irinotecan, bevacizumab (Avastin, Genentech) and, if KRAS wild-type, cetuximab (Erbitux, BMS/Imclone) or panitumumab (Vectibix, Amgen).

The double-blind multicenter trial

Table 1. Comparison of select treatment-emergent adverse events, all grades.

Regorafenib, %

Placebo, %

Hand-foot skin reactions

46.6

7.5

Fatigue

47.4

28.1

Hypertension

27.8

5.9

Diarrhea

33.8

8.3

Rash/ desquamation

26.0

4.0

Anorexia

30.4

15.4

Mucositis

27.2

3.6

Thrombocytopenia

12.6

2.0

Fever

10.4

2.8

Nausea

14.4

11.1

Bleeding

11.4

5.5

Voice changes

29.4

5.5

Weight loss

13.8

2.4

Delaying Tumor Progression Key

‘One assumes that labeling will be based on the inclusion criteria of the Phase III trial …. But more to the point for patient care and access, how will this be interpreted by prescribing oncologists and by the carriers of the patient’s prescription drug coverage?

We’re all interested to see how this plays out.’

—Marlo Blazer, PharmD, BCOP recruited 760 patients within the first ten months. Patients were randomized in a 2:1 fashion to regorafenib (160 mg orally once daily) plus best supportive care (BSC) or placebo plus BSC. Placebo and regorafenib were given for three weeks on, one week off, until

disease progression.

The median overall survival, the primary end point of the trial, was 6.4 months in patients receiving regorafenib and

Table 2. Comparison of select Grade 3/4 treatment-emergent adverse events.

Hand-foot skin reactions

5.0 months in patients receiving placebo (hazard ratio, 0.77; P=0.0052) “We see a 23% reduction of death events on the trial, which I perceive as clinically meaningful,” said Dr. Grothey, who called regorafenib “a potential new standard of care.” The results come from a prespecified interim analysis after 74% of events were reported. The median professionfree survival (PFS) was also improved in the regorafenib arm (1.9 months vs. 1.7 months, hazard ratio 0.49, P<0.000001)

Regorafenib, %

Placebo, %

16.6

.4

Fatigue

9.6

5.1

Hypertension

7.2

.8

Diarrhea

7.2

.8

Rash/desquamation

5.8

0

Anorexia

3.2

2.8

Mucositis

3.0

0

Thrombocytopenia

2.8

0.4

The efficacy of regorafenib was driven by improvements in stable disease (44.8% vs. 15.3%) and progressive disease (49.5% vs. 80.0%), rather than complete responses, of which there were none, or partial response rate, which revealed only a minor improvement for regorafenib (1.0 vs. 0.4) (all P<0.000001). “The strength of this drug is clearly more in delaying tumor progression than in inducing tumor responses,” Dr. Grothey said.

Adverse events were managed with dose delays and reductions. There were few grade 4 events (Tables 1, 2). Patients discontinued therapy slightly more often in the active arm because of treatmentrelated adverse events (8.2% vs. 1.2%).

According to Dr. Hurwitz, the median overall survival improvement of 1.4 months “may be a reasonable representation of the likely benefit for the average patient,” and the Kaplan-Meier PFS curves suggest there is a subset of patients who may derive more benefit.

Oncology Pharmacists’ Take Marlo Blazer, PharmD, BCOP, specialty practice pharmacist, outpatient oncology, Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, The Ohio State University, Columbus, said she “is optimistic” about regorafenib’s approval, given the drug’s activity when compared with placebo. That’s especially the case, Dr. Blazer noted, given the fact that such efficacy was not demonstrated in single-agent trials assessing bevacizumab and sunitinib in this clinical setting. However, “that optimism is cautiously applied,” she stressed, “due to the increased risk of grade 3 rash (including hand-foot syndrome), fatigue, diarrhea and hypertension” documented in the CORRECT trial.

Dr. Blazer also raised the question of how will “refractory” disease be worded in regorafenib labeling. “One assumes it will be based on the inclusion criteria of

•

see MULTI-KINASE, page 29

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28

Hem/Onc Pharmacy

Pharmacy Practice News • March 2012

In Focus

New Drug for CLL Promises To Be a Game Changer San Diego—A first-in-class new drug PCI-32765 (Pharmacyclics, Inc.), which inhibits the Bruton’s tyrosine kinase (BTK), has experts excited about its potential role in the treatment of chronic lymphocytic leukemia (CLL).

BTK is a central mediator of B-cell receptor signaling, which is essential for normal B-cell development. PCI32765, which is given orally, irreversibly inhibits BTK, induces apoptosis

and inhibits cellular migration and adhesion in malignant B cells.

In a study presented at the American Society of Hematology 2011 annual meeting, treatment with PCI-32765 was well tolerated and associated with high objective response rates (ORR) and six-month progression-free survival (PFS) in patients with relapsed or refractory CLL. The Phase Ib/II study included 61

patients with relapsed or refractory disease who received either 420 or 840 mg of oral PCI-32765 per day. Patients in the 420 mg per day cohort had a median of three (range 2-10) prior treatment regimens, and those in the 840 mg per day cohort had a median of five (range 1-12) prior regimens.

Nearly three-fourths of the patients had at least one molecular feature that increased their cancer risk, including

del(17p), del(11q), and IgVH unmutated.

After 10.2 months median follow-up, the ORR was 70% in the 420 mg per day group. The ORR was 44% in the 840 mg per day group, after 6.5 months of median follow-up. Additionally, 19% of the patients in the 420 mg per day group and 35% of patients in the 840 mg per group, respectively, had a 50% or more reduction in node volume, with residual lymphocytosis.

Five (8%) patients had progressive disease. The six-month PFS in the 420 mg per day group was 92%, and in the 840 mg per day group, it was 90%.

‘[PCI-32765] shows a lot of promise; it’s an exciting drug.’

—Julianna Roddy, PharmD

Building leadership, clinical excellence, and professional expertise in hematology/oncology pharmacy Join HOPA today. www.hoparx.org

The most frequently reported adverse events (AEs) were grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis. Serious AEs occurred in 38% of patients, and of these, 10% were considered to be potentially related to PCI-32765. Grade 3 or greater AEs, including neutropenia, anemia, thrombocytopenia and infections, occurred in 21% of patients.

So far, three patients have discontinued the study due to disease progression.

Refractory Patients Did Well Susan O’Brien, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, in Houston, who led the study, told Pharmacy Practice News that the new drug “is very exciting” for several reasons.

“The patient population in this trial is very refractory, with a median of three to five prior regimens,” Dr. O’Brien said. “Some had very bad cytopenias, which would disqualify them in many protocols from even being in a trial. We have a response rate of about 70%, and that rate continues to evolve over time so it may even get better.

“The other important aspect is that,

Hem/Onc Pharmacy 29

Pharmacy Practice News • March 2012

In Focus

MULTI-KINASE continued from page 26

the Phase III trial, which mandated that patients had been exposed to irinotecan, oxaliplatin, a fluoropyrimidine, bevacizumab, and, for K-Ras wild-type patients, an EGFR-inhibitor,” she said. “But more to the point for patient care and access, how will this be interpreted by prescribing oncologists and by [insurers]? We’re all interested to see how this plays out.”

Supportive care issues may play into the equation, Dr. Blazer noted. “While

we’d like to think we’re all adept at keeping patients on therapy until progression, what about patients who become intolerant to the drug regimen—for example, due to cumulative neurotoxicity with oxaliplatin?” Based on the FDA labeling, she added, “will we have to ‘prove progression’ on standard therapies, or will moving on due to cumulative toxicities be allowed in the eyes of payers?”

Dina Patel, PharmD, BCOP, clinical pharmacy specialist-GI medical oncology, The University of Texas MD Cancer Center, in Houston, said regorafenib

with a median follow-up of nine to 12 months, only three people have come off [the] study for progressive disease,” she added. “So, not only are people responding, the responses are not cosmetic in the sense that they last six weeks; these are quite durable responses.”

In addition to high efficacy, the drug has little toxicity. “The most common side effect with this drug is mild diarrhea; it’s often self-limited and very responsive if necessary, and it’s not always necessary to give Imodium or Lomotil,” Dr. O’Brien said.

“That’s really the main side effect.

Some patients have absolutely no side effects whatsoever.”

A huge plus is the lack of myelosuppression associated with PCI-32765.

Myelosuppression is the biggest complication from the treatments currently used to treat CLL, “so to have a very active agent that’s also non-myelosuppressive is very exciting,” she stressed.

Moreover, patients who entered the study with cytopenia had “dramatic improvement,” she added. “Not only is it non-myelosuppressive, cytopenia improves on therapy, so for a variety of reasons, efficacy, durability of response, lack of toxicity, PCI-32765 is one of the most exciting drugs out there for CLL.” If or when the drug is approved, its first indication will probably be for refractory or relapsed disease, said Julianna Roddy, PharmD, specialty practice pharmacist in hematology at The Ohio State University Medical Center Department of Pharmacy, Columbus.

Eventually, there may be potential use as first-line therapy, and also would be useful in subsets of patients selected according to their cytogenetics, as well as elderly patients, Dr. Roddy told Pharmacy Practice News.

“I also see it being used in combination with monoclonal antibodies, such as ofatumumab,” she said. “We are conducting a study with this combination here with various cohorts. This drug shows a lot of promise; it’s an exciting drug.”

could be a game-changer in the treatment of patients with refractory colorectal cancer. But she agreed that reimbursement issues “definitely need to be worked out.

It’s going to be an expensive agent, and so my guess is that we’re going to have to document very clearly in the patient record the fact that a patient has indeed failed all previous therapies that were cited in the Phase III inclusion criteria. In our institution, that may well become the pharmacists’ responsibility—we already are tasked with documenting clinical need for other cancer drugs, in order to

ensure adequate reimbursement.”

—Kate O’Rourke, with additional reporting by David Bronstein Dr. Grothey disclosed a consultant or advisory role at Bayer. Dr. Hurwitz disclosed a consultant or advisory role for BristolMyers Squibb and Genentech/Roche, honoraria from Roche, and research funding from Acceleron Pharma, Amgen, BMS, Cephalon, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, Threshold, and Tracon. Drs. Blazer and Patel had no relevant conflicts of interest to disclose.

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F

or more than 4 decades, there has been concern for health care workers

exposed to cytotoxic and other hazardous drugs (HDs).1 Despite this concern, continuing research in this area, promoted by the National Institute for Occupational Safety and Health (NIOSH), demonstrates ongoing exposure. In April 2011, NIOSH, the Occupational Safety and Health Administration (OSHA), and the Joint Commission highlighted the need for safe practices in the handling of HDs in a joint letter to hospitals in the United States.2 Additional and ongoing efforts are needed to reduce the health risks

associated with this exposure.

Hazardous drugs, including antineoplastic agents, antiviral agents, biological modifiers, hormones, and other agents, provide therapeutic benefit to patients, but studies have shown that healthy workers exposed to these drugs may experience adverse effects.3-5 Potential health

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

risks for workers who compound and administer these agents include adverse reproductive outcomes and cancer.6 This review focuses on new activities, including those of NIOSH and the United States Pharmacopeia (USP), whose 2008 revision

P H A R M AC Y P R AC T I C E N E WS â&#x20AC;˘ M A R C H 2 0 1 2

1

of USP Chapter <797> mandates compliance with environmental, engineering, and training standards for worker and product protection.

Routes of Occupational Exposure Many studies have documented both surface and worker contamination from HDs.7-14 Standard work practices for handling injectable drugs in vials and syringes generate powder and liquid aerosols. These drug residues may contaminate the air and surfaces in the work area.7-9,15,16 Many HD vials are delivered from the manufacturer with drug residue on the outside of the vials, creating yet another opportunity for contamination.17 Certain HDs have been shown to vaporize at room temperature, resulting in drug contamination of the air.18-20 Workers may breathe contaminated air or touch contaminated surfaces and absorb HDs. Drug uptake also may occur through the ingestion of contaminated food or drink that is inappropriately located in or near drug-handling areas. Additionally, the transfer of contaminated residues from hands to mouth may result in the ingestion of HDs. Needlesticks with HD–contaminated needles or cuts from glass fragments of vials or ampules also may result in exposure by injection.

Guidelines for Safe Handling Of Hazardous Drugs Since 1980, numerous organizations have issued guidelines for the safe handling of HDs. OSHA issued guidelines in 1986,21 updated them in 1995,22 and made them available online in 1999.23 The American Society of Health-System Pharmacists (ASHP) published guidelines on the safe handling of cytotoxic agents as Technical Assistance Bulletins in 1985 and 1990, and new guidelines on HDs in 2006.24-26 In an effort to influence nursing practice and protect its members from exposure, the Oncology Nursing Society (ONS) published “Chemotherapy and Biotherapy Guidelines and Recommendations for Practice” and developed an extensive educational program.27-29

Continuing Exposure Opportunities for HD exposure and adverse health effects have occurred among health care workers for more than 2 decades. Studies of surface and worker contamination conducted in the late 1990s and the early years of the following decade continued to document exposure.7-9,11,15,16 Some possible reasons for the

2

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

problem include new workers’ lack of awareness of the issue, a lack of vigilance in work practices, poor adherence to the use of personal protective equipment (PPE),30-33 and potential sources of contamination that have yet to be discovered.34 In 2000, NIOSH convened a working group of interested individuals to examine the issue of occupational exposure of health care workers to HDs. The Hazardous Drug Safe Handling Working Group was composed of representatives from government (OSHA, NIOSH, and FDA), industry, pharmaceutical manufacturers, academia, membership organizations (eg, American Nurses Association, ASHP, and ONS), and union leaders whose members handle HDs. The Working Group assessed existing information and formulated a plan to increase affected workers’ awareness of the risks and to reduce those risks.

In 2004, as a result of the efforts of the Working Group, NIOSH issued “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”35 This NIOSH Alert is similar to the OSHA documents in that it is a guidance document without enforcement authority. However, OSHA may enforce the recommendations in the NIOSH Alert and the OSHA Technical Manuals under the general duty clause of the Occupational Safety and Health (OSH) Act, which sets safety and health standards for US workers. Employers subject to the OSH Act have a general duty to provide work and a workplace free from recognized, serious hazards.36 Additionally, NIOSH actively continues to increase awareness of this issue by maintaining 2 Safety and Health Topic pages online: “Hazardous Drug Exposures in Health Care”37 and “Occupational Exposure to Antineoplastic Agents.”38 These pages provide links to extensive background information, the latest studies, updates on related activities, and NIOSH publications.

In 2007, the USP released Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” which became effective in 2008.39 This revision of the 2004 standard includes a section specific to the compounding of HDs and is coordinated with much of the 2004 NIOSH Alert. More importantly, USP Chapter <797> is an enforceable standard and establishes many of the NIOSH recommendations as requirements. The standards set by USP Chapter <797> are applicable in all settings in which sterile doses of HDs are compounded, not just hospitals and clinics.

To assess the impact of the 2004 NIOSH Alert on

Table 1. Comparison of NIOSH 2004 and ASHP 1990 Definitions NIOSH

ASHP

Carcinogenicity

Carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer

Teratogenicity or developmental toxicity

Teratogenicity in animal studies or in treated patients

Reproductive toxicity

Fertility impairment in animal studies or in treated patients

Organ toxicity at low doses

Evidence of serious organ or other toxicity at low doses in animal models or treated patients

Genotoxicity

Genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems)

Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria ASHP, American Society of Health-System Pharmacists; NIOSH, National Institute for Occupational Safety and Health Originally published in reference 26 © 2006, American Society of Health-System Pharmacists, Inc. All rights reserved.

Reprinted with permission.

HDs, NIOSH designed a large, multifacility study to provide a comprehensive evaluation of the workplace and the potential sources of exposure. Published in 2010, the study included surface sampling in pharmacy and nursing areas, self-report exposure diaries, and urine and blood sampling of various health care workers.40 Consistent with the results of previous studies, the NIOSH study detected contaminated surfaces in all study sites.

The findings of the study included a correlation between the size and spatial design of the compounding area and the amount of surface contamination. Preliminary reports support the USP Chapter <797> design standard that requires an appropriate buffer area around the primary engineering control (PEC).39 One study site with a smaller, less delineated compounding area had higher surface contamination. Surprisingly, the percentage of surfaces contaminated with hazardous drug residue in this study is almost identical to that found in a similar study published in 1999.34 In both studies, 75% of surfaces sampled in the pharmacies were found to have residue of at least one of the marker HDs. This shows that the efforts of NIOSH and USP have made little difference to safe handling.

Similar results of another study were presented at the Safe Handling of Hazardous Drugs in the Clinical Environment Symposium in Massachusetts in October 2009 and at the ASHP Midyear Clinical Meeting in Las Vegas in December 2009, by members of the Massachusetts General Hospital (MGH) Hazardous Drug Safety Task Force.41,42 At these meetings, speakers presented the findings of an extensive, longitudinal study designed to assess contamination from receipt of the HD (loading dock) to transport of waste. The MGH Task Force identified a “chain of custody” for HDs and found surface contamination in most of the study areas along this chain, including on elevator buttons.

These reports are not surprising, but they are alarming. Additional concern was generated by a substudy within the NIOSH research. In this companion study, also published in 2010, investigators at the University of Maryland evaluated chromosomal effects of the HDs studied to determine specific effects in the health care workers involved in the study.43 Therapy-related malignancies (myelodysplastic syndrome and acute myeloid leukemia) are known to be associated with signature lesions in chromosomes 5, 7, and 11 based on

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fluorescence in situ hybridization. In the Maryland study, the DNA of exposed workers showed a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01). These results provide additional evidence for valid concerns regarding occupational exposure to HDs.

Barriers Although many studies document continuing HD contamination and worker exposure, few have attempted to identify why the efforts to improve worker safety have not been successful. A recent study of nurses sought to explain this issue. The purpose of the study was to examine relationships among factors affecting nurses’ use of HD safe-handling precautions and to identify factors that promote or hinder the use of precautions. In a cross-sectional, correlational design, 165 nurses from oncology centers across the United States who reported handling chemotherapy completed a mailed survey. Instruments measured the use of HD precautions and various factors thought to influence the use of precautions. Despite the fact that nurses were knowledgeable about chemotherapy exposure, total precaution use during administration and disposal of these drugs was low. The following factors were predictive of higher use of precautions: fewer patients per day per nurse, fewer barriers (eg, availability and convenience of PPE), and a better workplace safety climate (eg, training provided, supervisors encourage precaution use, and expectations that policies are followed). These findings have important implications because factors in the workplace environment seem to be the most important concepts affecting safe-handling practices.44

Defining HDs A number of drug types that are potent and toxic to patients have the potential to cause adverse effects in persons occupationally exposed to them. Although the cytotoxic potential of the alkylating agents is of primary concern, there are multiple mechanisms by which drugs cause hazardous effects. In 1990, ASHP attempted to categorize these drugs in its “Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”25 for the first time using the term hazardous drug in reference to drugs that involve risks from occupational exposure. The terminology was selected to be inclusive of the types of drugs with safety

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concerns and to be compatible with the then newly developed OSHA Hazard Communication Standard (HCS).45,46 The HCS is intended to ensure that employers and workers who are at risk for exposure to hazardous chemicals in the workplace are informed of the specific hazardous chemicals, their associated health and safety hazards, and the appropriate protective measures to be taken.

The HCS defines a hazardous chemical as any chemical that poses a physical or health hazard. It further defines a health hazard as any chemical for which statistically significant evidence from at least one study conducted in accordance with established scientific principles is available to indicate that it may cause acute or chronic health effects in exposed workers. The HCS further notes that the term health hazard includes chemicals that are carcinogens, toxic or highly toxic agents, reproductive toxins, irritants, corrosives, sensitizers, and agents that produce target organ effects.

ASHP has used similar criteria to define HDs.25,26 Data on the side effects of a drug are collected during both the drug’s premarket investigational phase and clinical use. These data reasonably may be used to infer health hazards in workers occupationally exposed to the drug. As such, ASHP proposed the following criteria to define HDs25: • genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems); • carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer; • teratogenicity or fertility impairment in animal studies or in treated patients; and • evidence of serious organ or other toxicity at low doses in animal models or treated patients.

ASHP’s criteria for HDs were revised by NIOSH for the 2004 Hazardous Drug Alert. The NIOSH 2004 and ASHP 1990 definitions of HDs are compared in Table 1.

USP Chapter <797> has adopted the following definition of HDs, which supports both the HCS and the NIOSH Alert definitions: Drugs are classified as hazardous if studies in animals or humans indicate that exposures to them have a potential to cause cancer, developmental or reproductive toxicity, or harm to organs.39 NIOSH has adopted a mechanism both to review its hazardous drug criteria and to judge newly FDA-approved drugs against these criteria on a regular basis. The review process for the addition of the new listings is described in the Federal Register.47 In

Table 2. Comparison of the NIOSH, ASHP, and USP Chapter <797> Recommendations for the Hazardous Drug Compounding Environment NIOSH

ASHP

USP Chapter <797>

Storage environment

Store hazardous drugs separately from other drugs in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Segregate hazardous drug inventory and store in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Hazardous drugs shall be stored separately from other inventory, preferably within a containment area such as a negative-pressure room.

Compounding

Prepare hazardous drugs in an area that is devoted to that purpose alone and is restricted to authorized personnel.

Hazardous drugs should be compounded in a controlled area where access is limited to authorized personnel trained in handling requirements.

Hazardous drugs shall be prepared in a PEC, which shall be placed in an ISO class 7 area that is physically separated from other preparation areas.

Ventilation

Where feasible, exhaust 100% of the filtered air to the outside.

Because of the hazardous nature of these preparations, a contained environment where air pressure is negative relative to that of the surrounding areas or that is protected by an air lock or anteroom is preferred.

Storage: area should have exhaust ventilation of at least 12 air changes per hour.

Compounding: optimally at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas.

ASHP, American Society of Health-System Pharmacists; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 26, 35, and 39.

2007, a group of experts met to review the drugs that had been approved by the FDA since 2004 to evaluate which ones should be considered hazardous. Additionally, drugs that the FDA approved between 2007 and 2010 were recently evaluated for their hazard characteristics. Following a rigorous review process,22 drugs from many different therapeutic categories met at least one criterion for hazard in the analysis and have been added to the NIOSH list of HDs. The updated list was published in 2010, and is available, along with a discussion of hazard criteria and instructions for generating a similar list of drugs for a given facility, on the NIOSH Web site.48 This list supersedes the 2004 list in Appendix A.

Recommendations Recommendations for the safe handling of HDs have been available since the early 1980s. As more research has been conducted and more groups have been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert and OSHA Technical Manuals are broad guidelines; the ONS â&#x20AC;&#x153;Chemotherapy and Biotherapy Guidelinesâ&#x20AC;? focus on administration and patient safety information; ASHP addresses pharmacistsâ&#x20AC;&#x2122; concerns; and USP Chapter <797> deals exclusively with sterile compounding.

All guidelines agree that to reduce exposure to HDs in the occupational setting, a comprehensive

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Table 3. Comparison of NIOSH, ASHP, and USP Chapter <797> Recommendations for Primary Engineering Controls NIOSH

ASHP

USP Chapter <797>

Primary engineering controls

• Aseptic containment ventilation control class II BSC-type B2 is preferred.

• Class III BSC or CACI.

• Class II BSC-type B2 with outside exhaust is preferred.

• Total exhaust is required if the hazardous drug is known to be volatile.

• Class III BSC or CACI.

• BSC or CACI that meets or exceeds the standards for CACI in USP Chapter <797>.

Ventilation

• Do not use a ventilated cabinet that recirculates air inside the cabinet or exhausts air back into the room environment if a drug is volatile.

• Without special design considerations, class II BSCs are not recommended in traditional, positive-pressure clean rooms.

• BSCs and CACIs optimally should be 100% vented to the outside air through HEPA filtration.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; USP, United States Pharmacopeia Based on references 26, 35, and 39.

safety program must be developed that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, administration, spill control, and waste management. Key components of such a program are administrative controls, environmental and engineering controls, work practice controls, and PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate risks from other occupational exposures.49

Administrative Controls Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. All aspects of HD handling must be identified, staff performance expectations clearly defined, methods for validating staff competency determined, and processes for the ongoing monitoring of adherence to policies judiciously established.

USP Chapter <797> emphasizes administrative controls for the safe compounding of HDs by mandating conditions that protect health care workers and other personnel in preparation and storage areas.

Additional requirements include extensive training of

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all personnel who handle HDs in the storage, handling, and disposal of these drugs. USP Chapter <797> reinforces the OSHA and NIOSH recommendations by requiring training before the preparation or handling of hazardous compounded sterile preparations, and by mandating that the effectiveness of training be verified by testing specific HD preparation techniques. Ongoing training must be documented at least annually. The components of the training program are specified to include didactic overview of HDs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new HD that enters the marketplace. Training in work practices also must include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposures.

OSHA and NIOSH include medical surveillance in their safety program recommendations. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances.

In 2007, NIOSH released “Workplace Solution: Medical

Table 4. Comparison of NIOSH, OSHA, ASHP, And USP Chapter <797> Recommendations for PPE

General handling

NIOSH/OSHA

ASHP

USP Chapter <797>

• Use double gloving for all activities involving hazardous drugs.

• Wear double gloves for all activities involving hazardous drugs.

• Guidelines for the safe handling of hazardous drugs recommend the use of gowns for compounding in the BSC, administration, spill control, and waste management to protect the worker from contamination by fugitive drug generated during the handling process.

• Hazardous drugs shall be handled with caution at all times with the use of appropriate chemotherapy gloves during receiving, distributing, stocking, taking inventory, preparing for administration, and disposal.

OSHA: • Protective equipment, including PPE for eyes, face, head, and extremities, protective clothing, respiratory devices, and protective shields and barriers shall be provided, used, and maintained in a sanitary and reliable condition wherever it is necessary by reason of hazards of processes or environment, chemical hazards, radiological hazards, or mechanical irritants encountered in a manner capable of causing injury or impairment in the function of any part of the body through absorption, inhalation, or physical contact.

Receiving and storage

• Wear chemotherapy gloves, protective clothing, and eye protection when opening containers to unpack hazardous drugs.

• Gloves must be worn at all times when drug packaging, cartons, and vials are handled, including during the performance of inventory control procedures and the gathering of hazardous drugs.

Compounding

• Wear PPE (including double gloves and protective gowns) while reconstituting and admixing drugs.

• Make sure that gloves are labeled as chemotherapy gloves.

• Use disposable gowns made of polyethylene-coated polypropylene material (which is nonlinting and nonabsorbent).

• Select disposable gowns of material tested to be protective against the hazardous drugs to be used.

• Coated gowns must not be worn for longer than 3 hours during compounding and must be changed immediately when damaged or contaminated.

• Gowns worn as barrier protection in the compounding of hazardous drugs must never be worn outside the immediate preparation area.

• Wear PPE (including double gloves, goggles, and protective gowns) for all activities associated with drug administration.

• Gowns worn during administration should be changed when the patient care area is left and immediately if contaminated.

Administration

Sterile compounding: • Shoe covers, head and facial hair covers (eg, beard covers in addition to face masks), and face masks; a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck; sterile powder-free gloves.

Hazardous drug compounding: • Appropriate PPE shall be worn during compounding in a BSC or CACI and during the use of CSTDs. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemotherapy-type gloves, and compliance with manufacturers’ recommendations when a CACI is used.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; OSHA, Occupational Safety and Health Administration; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; PPE, personal protective equipment; USP, United States Pharmacopeia Based on references 23, 26, 35, and 39.

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Surveillance for Health Care Workers Exposed to Hazardous Drugs,â&#x20AC;? which provides direction for establishing such a program and the elements that should be included.50 USP Chapter <797> requires that all compounding personnel with reproductive capability confirm in writing that they understand the risks associated with handling HDs. Although USP Chapter <797> mandates this only for personnel responsible for compounding, prudent practice dictates that the requirement should extend to all personnel who handle HDs along the chain of custody.

Environmental and Engineering Controls The recent revision to USP Chapter <797> contains extensive mandates to improve the environment in which sterile doses of HDs are compounded. These directives are designed to increase safety for patients by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positivepressure compounding environments. Table 2 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for the environment in which HDs are compounded.

HDs must be stored separately from other inventory in a manner to prevent contamination and exposure of personnel. Because of the concerns of volatilization at room temperature, storage is preferably within a containment area such as a negative-pressure room with sufficient exhaust ventilation and at least 12 air changes per hour (ACPH) to dilute and remove airborne contaminants.

An International Organization for Standardization (ISO) Class 5 PEC is required for HD compounding to prevent microbial contamination of sterile preparations and to protect workers and the environment by preventing the escape of HD aerosols or residue. Appropriate PECs for compounding sterile HD preparations include Class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs) meeting or exceeding the standards set forth in USP Chapter <797>.

Isolators are recommended as a PEC in both the NIOSH Alert and the ASHP HD guidelines. The USP Chapter <797> revision sets performance standards for isolators used to compound sterile preparations, for compounding aseptic isolators (CAIs), and for isolators used to compound sterile HD preparations (CACIs).

To meet the criteria of USP Chapter <797>, an isolator

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must provide isolation from the room and maintain ISO Class 5 air quality within the cabinet during dynamic operating conditions. CAI and CACI air quality must be documented by particle counts during compounding operations and during transfer of material in and out of the isolator. Recovery time to ISO Class 5 air in the main chamber must be documented after material is transferred into and out of the main chamber. Work practices must be developed to reduce disruption of the air quality in the isolator and to minimize recovery time.

A CACI meeting all of these conditions, as detailed in USP Chapter <797>, is exempt from the requirement that the CACI be placed in an ISO Class 7 buffer area.

For HD compounding, however, the compounding area must maintain negative pressure and have a minimum of 12 ACPH. A Class II BSC has an open front and depends on an air barrier to prevent HD contamination from escaping the cabinet.51 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.52 The design of this type of cabinet is questionable for product protection because the air barrier is composed of air coming from the buffer area around the BSC. As air is pulled into the BSC, poor air quality in the buffer area may compromise the ISO Class 5 compounding environment within the Class II BSC. A Class II BSC or CACI not meeting the conditions listed in USP Chapter <797> must be placed in an area that is physically separated from other compounding areas and have air quality of ISO Class 7. Optimally, this area should be at negative pressure relative to adjacent positive-pressure ISO Class 7 or better ante-areas, thus providing inward airflow to contain airborne drug.

It also is optimal for a PEC used for compounding sterile HD preparations to be 100% vented to the outside air through high-efficiency particulate air (HEPA) filtration.

All environments in which sterile preparations are compounded must be provided with HEPA-filtered air from outside the environment. The PEC may not be the sole source of HEPA-filtered air and it may not provide more than 50% of the ACPH in that environment. The ISO Class 7 buffer area and ante-area must be supplied with HEPA-filtered air providing at least 30 ACPH. The NIOSH, ASHP, and USP Chapter <797> recommendations for hazardous drug PECs are compared in Table 3.

Work Practice Controls Work practices must be designed to minimize the generation of HD contamination and maximize the

containment of inadvertent contamination that occurs during routine handling or in the event of a spill. The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of HDs.53 These techniques, when performed accurately, minimize the escape of drugs from vials and ampules.

earlier devices, but with the added protection that they can be locked into place on the drug vial. CSTD components also provide protection during the administration of IV push and IV infusion doses, which previously had not been available. Numerous studies using markers for HDs have demonstrated the effectiveness of CSTDs in reducing HD contamination in the workplace.7,15,16 At clinical practice sites representing inpatient and outpatient

Many adjunct devices have been developed to reduce the generation of contamination during the compounding process. Vented needles with 0.2-micron hydrophobic filters were designed to reduce the powder and liquid drug residues that escape from vials through standard vented needles. Dispensing pins with small spikes and hydrophobic filters were introduced to make the compounding process more efficient. One study documented the effectiveness of one of these devices, but the investigators used only a visual inspection process because no sensitive drug assays were available at the time of the study.54 Since then, sensitive, drug-specific assays have been developed that provide a means to validate work practice controls at different work sites. The persistent presence of contamination in hospitals and pharmacies generated interest in adjunct devices, generically named by NIOSH in the 2004 Alert as “closed-system drug-transfer devices” (CSTDs). NIOSH defines a CSTD as a device that mechanically prevents the transfer of environmental contaminants into the system and the escape of hazardous concentrations of drug or vapor from the system.35 USP Chapter <797> similarly defines CSTDs as “vial transfer systems that allow no venting or exposure of hazardous substance to the environment.” USP Chapter <797> further states that CSTDs must be used within the ISO Class 5 environment of a BSC or CACI. These devices provide some of the benefits of the

compounding and administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.7,15,16 In facilities that prepare a low volume of HDs, the use of 2 tiers of containment (eg, a CSTD within a BSC or a CACI that is located in a non–negative-pressure room) is acceptable. The NIOSH Alert specifies that CSTDs should be used only within a ventilated cabinet.

Neither USP Chapter <797> nor NIOSH has developed performance standards for any device marketed as a CSTD. Because the configurations of available CSTDs vary from that of the tested device, it is unclear how effective these devices are in reducing environmental contamination resulting from the compounding and administration of HDs. Any device marketed as a CSTD should be clinically tested.

Personal Protective Equipment In addition to environmental and engineering controls, PPE is required to provide a barrier between the health care worker and HDs during episodes of potential contact. This is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no PECs are in place for these activities. All PPE should be selected for effectiveness.

Glove and gown materials should be able to withstand permeation by a variety of HDs.55-57 Several HDs require nonaqueous diluents for patient use and may permeate PPE more readily than others. The American Society

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for Testing and Materials has developed a standard for testing chemotherapy gloves.58 There is no standard for chemotherapy gowns, but recommendations have been made based on several studies.56,57 A comparison of PPE recommendations is presented in Table 4.

During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP Chapter <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and facial hair covers (eg, beard covers in addition to face masks), a non-shedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves.

Appropriate PPE must be worn when the sterile compounding of HDs is performed in a BSC or CACI and when CSTDs are used. PPE includes coated gowns, masks or respirators, eye protection, hair covers, shoe covers, and double gloving with sterile HDâ&#x20AC;&#x201C; tested gloves.

New Technologies Technological advances include robotic devices that can compound sterile doses of HDs. Replacing the human compounder, robots reduce the occupational exposure of health care workers by using techniques to reduce the generation of HD residues during compounding. Robots also provide a degree of accuracy and patient safety not available with manual compounding. CytoCare from Health Robotics, Apoteca Chemo from Loccioni Humancare, and RIVA (Robotic IV Automation) from Intelligent Hospital Systems provide robotic solutions to the compounding of sterile preparations of HDs. The robots require human staff to load and clean them. HD contamination may be generated in the compounding environment and transferred to the final product. Cleaning of the compounding environments requires both disinfection as well as decontamination of HD residues. No particular cleaner has been shown to effectively deactivate all known HDs,12 so routine cleaning and spill control are still challenges to the health care personnel working with robots. The robots help only with the compounding process, leaving the workers administering HDs without protection.

Spill control and waste handling also remain issues for human workers to address.

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Conclusion Despite continuing reports of workplace and worker contamination, progress has been made. NIOSH is working with OSHA and the Joint Commission to promote employer and employee awareness of safety. USP Chapter <797> has elevated many of the NIOSH recommendations to a standard, ensuring compliance with at least the compounding segment of safety program controls.

USP has also commissioned an Expert Panel to further examine compounding with HDs. This panel will make recommendations to and work at the direction of the USP 2010-2015 Compounding Expert Committee. In addition, the Washington State Department of Labor & Industries (L&I) has adopted rules to protect workers who handle chemotherapy and other HDs. L&Iâ&#x20AC;&#x2122;s HDs rule was adopted on Jan. 3, 2012, and is consistent with but does not exceed provisions in the NIOSH 2004 Alert.59 New generations of health care workers need to be educated about the risks of handling HDs and the importance of training in the proper techniques to reduce their exposure. Health care workers must promote continued vigilance about this important safety issue.

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13. Ensslin AS, Huber R, Pethran A, et al. Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies. Int Arch Occup Environ Health. 1997;70(3):205-208.

14. Sessink PJ, Wittenhorst BCJ, Anzion RB, Bos RP. Exposure of pharmacy technicians to antineoplastic agents: reevaluation after additional protective measures. Arch Environ Health.

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16. Harrison BR, Peters BG, Bing MR. Comparison of surface contamination with cyclophosphamide and fluorouracil using a closed-system drug transfer device versus standard preparation techniques. Am J Health Syst Pharm. 2006;63(18):1736-1744.

17. Connor TH, Sessink PJ, Harrison BR, et al. Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: results of three studies. Am J Health Syst Pharm.

2005;62(5):475-484.

18. Connor TH, Shults M, Fraser MP. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37 degrees C using a desiccator technique. Mutat Res. 2000;470(1):85-92.

19. Opiolka S, Schmidt KG, Kiffmeyer TK, Schoppe G. Determination of vapor pressure of cytotoxic drugs and its effects on occupational safety. J Oncol Pharm Pract. 2000;6:15. Abstract.

20. Kiffmeyer TK, Kube C, Opiolka S, et al. Vapour pressures, evaporation behaviour and airborne concentrations of hazardous drugs: implications for occupational safety. Pharm J. 2002;268:331-337.

21. Yodaiken RE, Bennett D. OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Occupational Safety and Health Administration. Am J Hosp Pharm.

1986;43(5):1193-1204.

22. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995:chap 21.

23. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (TED 01-00-015 [TED 1-0.15A] Sec VI Chap 2); 1999. http://www. osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. Accessed February 13, 2012.

24. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals.

Am J Hosp Pharm. 1985;42(1):131-137.

25. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs.

Am J Hosp Pharm. 1990;47(5):1033-1049.

26. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm.

2006;63(12):1172-1191.

27. Brown KA, Esper P, Kelleher LO, O’Neil JEB, Polovich M, White JM, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 2001.

28. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 2nd ed.

Pittsburgh, PA: Oncology Nursing Press; 2005.

29. Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed.

Pittsburgh, PA: Oncology Nursing Press; 2009.

30. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-based oncology nurses. Oncol Nurs Forum.

2003;30(4):575-581.

31. Nieweg R, de Boer M, Dubbleman R, et al. Safe handling of antineoplastic drugs. Results of a survey. Cancer Nurs.

1994;17(6):501-511.

32. Valanis B, McNeil V, Driscoll K. Staff members’ compliance with their facility’s antineoplastic drug handling policy. Oncol Nurs Forum. 1991;18(3):571-576.

33. Valanis B, Vollmer WM, Labuhn K, Glass A, Corelle C. Antineoplastic drug handling protection after OSHA guidelines. Comparison by profession, handling activity, and work site. J Occup Med. 1992;34(2):149-155.

34. Connor TH, Anderson RW, Sessink PJ, Broadfield L, Power LA. Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health Syst Pharm. 1999;56(14):1427-1432.

35. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004-165. http://www.cdc.gov/niosh/docs/2004-165/. Accessed February 13, 2012.

36. Code of Federal Regulations. Title 29—Labor. Subtitle B—Regulations Relating to Labor. Chapter XVII—Occupational Safety and Health Administration, Department of Labor. Part 1910—Occupational Safety and Health Standards. Subpart A—General. Article 1910.2—Definitions. Washington, DC: US Government Printing Office; 2004. Accessed February 13, 2012.

37. National Institute for Occupational Safety and Health. NIOSH safety and health topic: hazardous drug exposures in health care. http://www.cdc.gov/niosh/topics/hazdrug. Accessed February 16, 2011.

38. National Institute for Occupational Safety and Health. NIOSH safety and health topic: occupational exposure to antineoplastic products. http://www.cdc.gov/niosh/topics/antineoplastic/.

Accessed February 13, 2012.

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11

39. US Pharmacopeial Convention. Chapter <797> Pharmaceutical compoundingâ&#x20AC;&#x201D;sterile preparations. In: The United States Pharmacopeia, 35th rev, and The National Formulary, 30th ed. Rockville, MD: US Pharmacopeial Convention; 2011.

40. Connor TH, DeBord DG, Pretty JR, et al. Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers. J Occup Environ Med. 2010;52(10):1019-1027.

41. Demonaco HJ. Report on the Massachusetts General Hospital Hazardous Drug Study. Presented at: Safe Handling of Hazardous Drugs in the Clinical Environment Symposium; October 23, 2009; Bedford, MA. 42. Ahmed S. Massachusetts General Hospital (MGH) study of hazardous drug (HD) work practices: Study design and results. Presented at: American Society of Health-System Pharmacists Midyear Clinical Meeting; December 6-10, 2009; Las Vegas, NV. 43. McDiarmid MA, Oliver MS, Roth TS, Rogers B, Escalante C. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med. 2010;52(10):1028-1034.

44. Polovich M, Clark PC. Nursesâ&#x20AC;&#x2122; use of hazardous drug safe handling precautions (2010). Nursing Dissertations. Paper 21. http://digitalarchive.gsu.edu/nursing_diss/21. Accessed February 14, 2012.

45. Occupational Safety and Health Administration. Hazard Communication 59:6126-6184. http://www.osha.gov/pls/oshaweb/owadisp. show_document?p_table=federal_register&p_id=13349. Accessed February 13, 2012.

46. Occupational Safety and Health Administration. Hazard Communication Standard 1910.1200. http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10099.

Accessed February 13, 2012.

47. National Institute for Occupational Safety and Health. Hazardous drug alert. NIOSH Docket No. 105-A. Washington, DC: NIOSH; 2009. http://www.cdc.gov/niosh/docket/archive/docket105A.html.

Accessed February 13, 2012.

48. National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare

12

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

settings 2010. http://www.cdc.gov/niosh/docs/2010-167/.

Accessed February 13, 2012.

49. US Department of Labor. 1998. OSHA 3143. Informational booklet on industrial hygiene. http://www.osha.gov/Publications/ OSHA3143/OSHA3143.htm. Accessed February 13, 2012.

50. National Institute for Occupational Safety and Health. Medical surveillance for healthcare workers exposed to hazardous drugs.

NIOSH Publication No. 2007-117. http://www.cdc.gov/niosh/docs/ wp-solutions/2007-117/. Accessed February 13, 2012.

51. NSF International. NSF/ANSI 49-2007: NSF 49 Class II (Laminar Flow) Biosafety Cabinetry. Ann Arbor, MI: NSF International; 2007.

52. Clark RP, Goff MR. The potassium iodide method for determining protection factors in open-fronted microbiological safety cabinets.

J Appl Bacteriol. 1981;51(3):439-460.

53. Wilson JP, Solimando DA Jr. Aseptic technique as a safety precaution in the preparation of antineoplastic agents.

Hosp Pharm. 1981;16(11):575-576, 579-581.

54. Hoy RH, Stump LM. Effect of an air venting filter device on aerosol production from vials. Am J Health Syst Pharm. 1984;41(2):324-326.

55. Connor TH. Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18 antineoplastic drugs. Am J Health Syst Pharm. 1999;56(23):2450-2453.

56. Harrison BR, Kloos MD. Penetration and splash protection of six disposable gown materials against fifteen antineoplastic drugs.

J Oncol Pharm Pract. 1999;5(2):61-66.

57. Connor TH. An evaluation of the permeability of disposable polypropylene-based protective gowns to a battery of cancer chemotherapy drugs. Appl Occup Environ Hyg. 1993;8:785-789.

58. American Society for Testing and Materials. D 6978-05 standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs. West Conshohocken, PA: American Society for Testing and Materials; 2005.

59. Washington State Department of Labor & Industries. Hazardous drugs. http://www.lni.wa.gov/Safety/Topics/AtoZ/HazardousDrugs/. Accessed February 13, 2012.

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Pharmacy Practice News • March 2012

Infectious Disease

GLOOM AND DOOM continued from page 1

A Lack of PROWESS In the beginning, the prospects for drotrecogin alfa were promising. The drug was approved in 2001 based on results from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial, which demonstrated a 6% improvement in 28-day mortality for patients with severe sepsis who received the drug (30.8% vs. 24.7%; P=0.05). Until it was withdrawn, this drug was the only available pharmaceutical specifically designed to treat sepsis.

PROWESS-SHOCK was launched in 2008 at the request of the European Medicines Agency (EMA). In 2007, the EMA said the positive PROWESS results had not been reproduced in other studies and encouraged Eli Lilly to conduct a randomized placebo-controlled study in patients with severe sepsis and documented organ failure to confirm that the drug’s benefits outweighed the risks, the most serious being bleeding.

PROWESS-SHOCK included 1,696 patients with severe sepsis and septic shock (Table 1). The patient population was “a subset with a strong efficacy signal in PROWESS,” said B. Taylor Thompson, MD, professor of medicine at Massachusetts General Hospital and Harvard Medical School, in Boston, who presented the data at SCCM. The 28-day mortality in patients receiving drotrecogin alfa (n=846) was 26.4% compared with 24.2% in the placebo arm (n=834), which was not a statistically significant difference (P=0.31). Mortality was not improved in the subset of patients with severe protein C deficiency. No increase in serious bleeding events during infusion was identified.

Compared with the patients in the original PROWESS study, patients in PROWESS-SHOCK had fewer primary sites of infection in the lung (44% vs.

54%) and abdomen (3% vs. 20%), whereas more patients in PROWESS-SHOCK experienced organ failure (Table 2) and received mechanical ventilation (82% vs.

75%). But, regardless of differences, said Dr. Thompson, the PROWESS-SHOCK population was one in which the drug would have been expected to work.

Dr. Thompson said subgroup analyses would be published in an upcoming journal article, but there was no glimmer of hope in the forest plots. “We found no benefit in any of the prespecified subgroups,” he said.

Anatomy of a Failed Trial At the SCCM meeting, Dr. Vincent offered a number of possible explanations for the trial’s failure. Perhaps, he said, the original PROWESS was positive by chance and the drug never worked. Perhaps the mortality rate, which has fallen

Table 1. PROWESSSHOCK Patient Inclusion Criteria Meet at least two of the four systemic inflammatory response syndrome criteria

‘I understand [Xigris] is a difficult and expensive compound to produce, and so unless there is some orphan status, it would probably not be a good business [decision to resume production].’

—Judith A. Jacobi, PharmD

Clear evidence of infection Received IV fluid resuscitation of ≥30 mL/kg administered 4 h before or after initiation of vasopressor therapy Continuous requirement of at least one of four vasopressors for at least 4 h

Table 2. Comparison of Organ Failures at Baseline in PROWESS and PROWESS-SHOCK Number of Organ Failures

Prowess, %

Prowess-Shock, %

One

2.5

25

Hypoperfusion (renal, acidosis, hepatic)

Two

13

32

Three

34

26

Drotrecogin initiated within 24 h of shock onset

Four

38

14

Five

13

4

PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.

in recent years due to better care, makes detecting a difference more difficult. Perhaps PROWESS-SHOCK suffered from the drug being available on the market for the best candidates, and the randomized patients were not good candidates for the drug. “I would vote for the third option, but nobody knows,” said Dr. Vincent.

According to Dr. Thompson, the mortality rate in the placebo arm of PROWESS-SHOCK (24%) was lower than projected (32%). This is consistent with other recent randomized trials.

In a study evaluating the small molecule TAK-242, the 24.2% mortality rate identified in the placebo arm was much lower than the 40% that was expected (Crit Care Med 2010;38:1685-1694). The nine-year observational ARISE (Australasian Resuscitation in Sepsis Evaluation) study identified a 21% mortality rate for patients with sepsis.

“If the attributable mortality from sepsis has been reduced, much larger sample sizes will be needed to detect potential beneficial effects of new therapies. That is just simple math,” said Dr. Thompson. “If the lower attributable mortality from sepsis is due to early and more effective care, then the severity and/or consequences of aberrant innate immune activation, and thus the therapeutic target, will be reduced.”

Dr. Thompson presented data from 11 registries showing a benefit in mortality for the use of drotrecogin, including a U.S. registry of 1,576 patients (mortality, 47% vs. 41%) and a French registry of 1,049 patients (68% vs. 47%). Questioning whether a responsive subset of patients could have been included in the registries that were excluded in the PROWESSSHOCK trial, he said, it is possible that registries of usual-care practices include under-resuscitated patients with greater degrees of inflammation and/or organ/ endothelial injury than what was seen in PROWESS-SHOCK. Another possibility

is that observational studies do not adequately control for residual confounding factors. “If there is some subset out there that responds to this drug, you would think that we would have a few of [these patients] in PROWESS-SHOCK.” According to Dr. Thompson, severe sepsis and septic shock phenotypes are unreliable surrogate markers for aberrant or excessive innate immune/coagulation system activation. “We need to better understand innate immune suppression,” he said. “We need enrichment strategies like the cancer community—biomarkers and genetics—to find the responsive subsets. But I think the severe sepsis phenotype is obsolete.”

Outgoing SCCM President’s Take Judith Jacobi, PharmD, a critical care pharmacist at Indiana University Health Methodist Hospital, in Indianapolis, and outgoing president of the SCCM, said the results of PROWESS-SHOCK are “very disappointing.” She added that she will miss the drug the most when treating patients who have sepsisinduced coagulopathy. “The mechanism of action of the activated protein C is geared toward that underlying problem of sepsis coagulopathy,” Dr. Jacobi said.

When Dr. Thompson was queried as to whether patients with sepsis coagulopathy were included in the trial, he

responded “only unless severe thrombocytopenia was also present.”

Dr. Jacobi said, “I suspect that the decision [whether or not] to continue to sell this agent is a business decision

by Lilly. I understand it is a difficult and expensive compound to produce, and so unless there is some orphan status, it would probably not be a good business [decision to resume production]. If they continue to make it available on an emergency basis, I am sure there would be opportunities to use it in selected patients.” According to a spokesperson for Lilly, the company is not pursuing any further avenues for the drug.

Conflicting Results Not all the news presented on drotrecogin at SCCM was bad. Two small studies showed positive results for the drug in bone marrow transplant patients, a group that was excluded from PROWESS because of their increased risk for bleeding (abstracts 369 and 705). In a third study—a retrospective propensity-matched, cohort study—researchers used the Co-operative Antimicrobial Therapy of Septic Shock database to investigate the real-world effectiveness of drotrecogin alfa (abstract 39). The database includes consecutive patients older than age 18 years who were admitted to 29 academic and community

•

see GLOOM AND DOOM, page 34

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34 Clinical

Pharmacy Practice News • March 2012

Infectious Disease

GLOOM AND DOOM continued from page 32

intensive care units between 1997 and 2007. “It is essentially a pseudo-randomization method,” said Emily Rimmer, MD, hematologist from the University of Manitoba, in Winnipeg, Canada, who presented the study.

The final study cohort included 310 patients who received drotrecogin and 630 patients who did not. The researchers identified a 7% absolute reduction in 30-day mortality associated with the use of drotrecogin (34.5% vs. 41.5%; P=0.05).

Subgroup analyses identified a significant reduction in mortality in patients in the lowest APACHE II quartile (9.5% vs.

22%; P=0.04) and consistent but nonsignificant reductions in mortality among all remaining quartiles.

“The results of our study are at odds with the recent PROWESS-SHOCK study, and we believe that our data may help to provide some insight into possible reasons for these discrepant results,” said Dr. Rimmer. “Our study suggests that the mortality rate of patients with septic shock is decreasing over time. This may be related to improvements in the supportive care of these patients, including improvements in the administration of timely antibiotics.”

from the ACCESS trial that evaluated the toll-like receptor (TLR)4 inhibitor eritoran tetrasodium. This Phase III randomized, double-blind trial compared eritoran with placebo in patients with severe sepsis. The international, multicenter trial, which analyzed data from almost 2,000 patients, found that eritoran did not improve the primary end point of all-cause mortality at day 28 or the secondary end point of mortality at one year. “There is no separation in the curves,” said Dr. LaRosa. No benefit

could be identified in any subgroups.

“We are left with endotoxin being thought to be a key mediator of sepsis pathology and a drug that, at least in vitro, appears to block TLR4 signaling quite well, and yet, we have a very stone-cold negative result,” said Dr. LaRosa.

According to Dr. LaRosa, large sepsis trials are challenging for a myriad of reasons including patient heterogeneity, as well as sepsis involving a variety of pathogens and infection sites and widely different practice patterns. “It

is hard to think that a single agent is going to behave the same in all the patients,” said Dr. LaRosa. He pointed out, however, that in the case of eritoran, they might have just picked the wrong agent or perhaps a multi-targeted attack is required. Another possible explanation is that once septic shock has begun, it is too late to intervene with a TLR4 inhibitor.

Future Outlook The wave of negative trials has fueled the gloom surrounding sepsis research.

Other Disappointing Agents The bad news from PROWESSSHOCK is compounded by a flurry of disappointing results from studies assessing other agents. Herwig Gerlach, MD, PhD, director of the Department of Anesthesiology, Critical Care and Pain Management at the Vivantes Klinkikum Neukoelln Hospital in Berlin, discussed a number of negative prospective trials and meta-analyses that evaluated immunoglobulin use in sepsis. For this reason, the 2012 Surviving Sepsis Campaign guidelines suggest that IV immunoglobulin G not be used in adult patients with severe sepsis/septic shock.

The investigational agent talactoferrin (Agennix) is the most recent drug to take a nosedive. Researchers were excited when a randomized Phase II trial involving 190 patients with severe sepsis showed that talactoferrin reduced 28-day all-cause mortality (26.6% vs.

14.6%; P=0.04). On Feb. 2, however, Agennix announced that the promising results did not pan out in the Phase III OASIS (Oral Talactoferrin in Severe Sepsis) trial. Preliminary data from the 930-patient trial showed 28-day mortality was higher in the talactoferrin arm than in the placebo arm.

At the SCCM meeting, Steven LaRosa, MD, director of the Division of Infectious Disease and associate professor of Medicine at Texas A&M Health Science Center College of Medicine, in Temple, presented data

INDICATION: Venofer ® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).

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Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse.

If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer ® immediately.

Monitor patients for signs and symptoms of hypersensitivity during and after Venofer ® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.

• Venofer ® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer ®. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered.

Leading anemia management.™

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

Pharmacy Practice News • March 2012

Clinical 35

Infectious Disease According to Dr. Vincent, little headway is being made because there are fundamental problems with the way sepsis research is being done. Trials have included a potpourri of patients—those with trauma, elective surgery, early sepsis and late sepsis. Should these patients be grouped together?

According to Dr. Vincent, biomarker analysis and genomic research are the future of sepsis clinical trials. A study published in December concluded that similarities in gene expression patterns between different injuries reveal a fun-

damental human response to severe inflammatory stress, with genomic signatures surprisingly far more common than different (J Exp Med 2011;208:2581-2590). “Maybe in the future, we may not target the infection so much, but rather the host immune response,” said Dr. Vincent.

Dr. Thompson pointed out that if Phase II trials with strong signals for efficacy do not predict results in Phase III trials, then all of the efficacy risk is carried over to Phase III trials. Although this is not attractive

to industry, neither is the fact that positive results from a Phase III trial may not predict the success of a second Phase III trial, as in the case of PROWESS-SHOCK. A recent study in Lancet Infectious Disease concluded that a deeper understanding of the process leading to sepsis is needed before investigators can design an effective suite of interventions (2012;12:89).

In the meantime, researchers will continue their efforts. Ongoing clinical trials are evaluating AZD9773 (Astra-

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• Venofer ® is contraindicated in patients with known hypersensitivity to Venofer ®. Do not administer to patients with evidence of iron overload.

• In efficacy studies in non-dialysis dependent-CKD patients (N=139), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were nausea (8.6%), taste disturbance (7.9%), peripheral edema (7.2%), diarrhea (7.2%), dizziness (6.5%), hypertension (6.5%), infusion site pain or burning (5.8%), dyspnea (5.8%), and vomiting (5.0%).

• In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%). In the study of peritoneal dialysis-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer ®, reported by 5% of these patients were infections and infestations (nasopharyngitis, sinusitis, upper respiratory tract, pharyngitis) (16.0%), diarrhea (8.0%), vomiting (8.0%), hypertension (8.0%), peripheral edema (5.3%), and nausea (5.3%). *100 mg vials and ampules worldwide from 1992 to February 2011.

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Please see brief Prescribing Information on adjacent page.

Zeneca), an antibody against tumor necrosis factor, and endotoxin removal by hemoperfusion through a polymyxin B column (Spectral Diagnostics).

—Kate O’Rourke

Dr. Thompson disclosed relationships with AstraZeneca, Hemodec and Lilly. Dr. LaRosa disclosed receiving investigator grants from Eisai. Dr. Vincent disclosed serving on the advisory board of 39 companies and receiving study grants from 34. Drs. Jacobi and Rimmer had no disclosures.

36 Clinical

Pharmacy Practice News • March 2012

Infectious Disease

Team Approach Slashes Central-Line Infections Houston—Can hospitals drive their rates of central-line bloodstream infections to zero? Although it sounds like a pipe dream, multidisciplinary team approaches are making great strides in dramatically reducing rates, new research has found.

At the University of Massachusetts (UMASS) Memorial Medical Center in Worcester, for example, a team of clinicians dedicated to preventing central-

line infections in eight of the hospital’s intensive care units (ICUs) cut the rate by almost 90% over a seven-year period. Similarly, a team effort at the Ohio State University Medical Center in Columbus, decreased infection rates in a 25-bed ICU by roughly 33% in one year.

Researchers presented details of the two approaches at the 2012 annual meeting of the Society of Critical Care Medicine (abstracts 583 and 584).

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Venofer safely and effectively. See full prescribing information for Venofer.

Initial U.S. Approval: 2000 RECENT MAJOR CHANGES Warnings and Precautions 6/2011 INDICATIONS AND USAGE Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).

DOSAGE AND ADMINISTRATION Administer Venofer intravenously either by slow injection or by infusion.

CKD patients on hemodialysis: 100 mg undiluted slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl, over a period of at least 15 minutes.

CKD patients not on dialysis: 200 mg undiluted slow IV injection over 2 to 5 minutes.

• CKD patients receiving peritoneal dialysis: infuse 300 mg over 1.5 hours given on two occasions 14 days apart followed by a single infusion 14 days later of 400 mg given over 2.5 hours. Dilute each Venofer dose in a maximum volume of 250 mL of 0.9% NaCl. DOSAGE FORMS AND STRENGTHS • 10 mL single use vial / 200 mg elemental iron (20 mg/mL) • 5 mL single use vial / 100 mg elemental iron (20 mg/mL) • 2.5 mL single use vial / 50 mg elemental iron (20 mg/mL) CONTRAINDICATIONS • Known hypersensitivity to Venofer WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.

• Hypotension:Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer.

• Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload.

ADVERSE REACTIONS • The most common adverse reactions (≥ 2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness,hypotension,pruritus,pain in extremity,arthralgia,back pain,muscle cramp,injection site reactions,chest pain,and peripheral edema.

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION 2 DOSAGE AND ADMINISTRATION Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs.

2.1 Adult Patients with CKD on dialysis Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session.Venofer should be administered early during the dialysis session.

2.2 Adult Patients CKD not on dialysis Administer Venofer 200 mg undiluted as a slow IV injection undiluted over 2 to 5 minutes on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on day 1 and day 14.

2.3 Adult Patients with CKD receiving peritoneal dialysis Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion.

5.2 Hypotension Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension following administration of Venofer may be related to the rate of administration and/or total dose administered.

5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation).

Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing.

6 ADVERSE REACTIONS Venofer injection may cause serious hypersensitivity reactions and hypotension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

6.1 Adverse Reactions in Clinical Studies The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse events reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

Table 1. Treatment-Emergent Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator Adverse Reactions (Preferred Term) Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting

HDD-CKD Venofer (N=231) %

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

PDD-CKD Venofer EPO* Only (N=75) (N=46) % %

78.8

76.3

73.4

72.0

65.2

0

2.2

0.7

0

0

0.4

0

0

2.7

0

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

Involving caregivers at all levels and providing frequent, regular feedback on infection rates to hospital staff are two key elements that have made these programs a success, experts said.

Matthias Walz, MD, chief of vascular anesthesiology at UMASS Medical Center, said the guidelines at his facility were developed by a small task force and then approved by the institution’s Critical Care Operations Committee

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

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

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

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

0

0

0

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

0

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

*EPO=ERYTHROPOIETIN 6.2 Adverse Reactions from Post-Marketing Spontaneous Reports In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following additional adverse reactions have been identified with the use of Venofer from postmarketing spontaneous reports: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Symptoms may respond to IV fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

7 DRUG INTERACTIONS Drug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Venofer should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers It is not known whether iron sucrose is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness of Venofer in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE No data are available regarding overdosage of Venofer in humans. excessive dosages of Venofer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. do not administer Venofer to patients with iron overload.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL).

16.2 Stability and storage Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Do not freeze. Do not dilute to concentrations below 1 mg/mL. Do not mix Venofer with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION Prior to Venofer administration: • Question patients regarding any prior history of reactions to parenteral iron products.

• Advise patients of the risks associated with Venofer • Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems.

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

IN2340BS, Rev. 6/2011

prior to implementation. “From the ICU physicians to the ICU nurses, respiratory therapists, pharmacy team, occupational therapists ... everybody is at the table.” Because all disciplines were involved in creating the guidelines, all caregivers feel they have a stake in the process, he said.

Although the landmark study by Peter Pronovost, MD, and colleagues is an example of a success story—a reduction in central-line infection rates of 66% in 18 months (N Engl J Med 2006;355:27252732)—the UMASS project is unique for its long follow-up, Dr. Walz said.

Infection rates steadily declined throughout the study period, from 5.86 per 1,000 catheter-days in 2004 to 0.6 per 1,000 days in 2011. Studies have shown that although programs can be successful in reducing the number of central-line infections, compliance can drop off over time (Arch Surg 2004;139:131-136). The new study demonstrates a program with stamina.

In the UMASS program, ICUs receive data on their infection rates on a

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Pharmacy Practice News • March 2012

Clinical 37

Infectious Disease ‘Now, you can go to the nurse who drew the blood culture and you can go to the physician who put in the line and ask them questions about the event, because it is still fresh in everyone’s mind.’

Trish Perl, MD, professor of medicine, pathology and epidemiology at Johns Hopkins University, in Baltimore, said the two studies add to the growing evidence that teamwork monthly basis, allowing for timely reaction. The program includes elements of the Pronovost study, such as the use of a dedicated catheter cart for supplies, checklists to ensure adherence to infection-control procedures, empowering nurses to halt a procedure if checklist elements are not followed and removal of unnecessary catheters.

Clinicians also rely on a preprocedural time-out, and they use chlorhexidine sponges and catheters impregnated with antibiotics. Re-education is key. “If you don’t continue to re-educate your staff and monitor progress, rates will creep back up again,” Dr. Walz said.

The Ohio State approach includes weekly surveillance of infection rates from its clinical epidemiology unit.

There the infection rates fell from 2.9 per 1,000 catheter-days in 2009 to 1.95 per 1,000 in 2010. Data for 2011 were incomplete but appeared to indicate further reductions in infections.

“Previously, we would get quarterly data and you would hear that you had three central-line infections, but you wouldn’t hear who the patients were, and you were so far removed from the events that no one could remember what actually happened,” said Mathew Exline, MD, associate director of the ICU at the institution. “Now, you can go to the nurse who drew the blood culture and you can go to the physician who put in the line and ask them questions about the event, because it is still fresh in everyone’s mind.”

Ohio State also incorporates components of the Pronovost study with an emphasis on re-education regarding line insertion and maintenance, the use of daily checklists to increase adherence to guidelines and identifying noncompliance with evidence-based guidelines.

“Unless you really have someone who is a champion who says, ‘This is really important, we need to focus on it,’ there are so many things going on in the ICU, that it is easy for the checklist to fall by the wayside,” Dr. Exline said.

In both the UMASS and Ohio State approaches, researchers investigate any identified infections to see if opportunities to prevent them were missed.

—Mathew Exline, MD can reduce central line–related bloodstream infections. “I think the use of teams works so well because there is a lot of wisdom that you can get from individuals with different experiences.

For example,” she said, “my perspective may be very different from somebody who is in the trenches.”

Dr. Perl also echoed the importance of having a champion. “If you have a really good and engaged champion, it makes a lot of difference,” she said. “If people really believe low rates are achievable ... and the institution and employees have accountability and hence really facilitate the interventions, it makes a lot of difference.”

—Kate O’Rourke

38 Clinical

Pharmacy Practice News • March 2012

Infection Control

Hand and Glove Hygiene Keys to Safe Compounding New Orleans—Improper hand hygiene is a common factor in the spread of hospital-acquired infections.

Prevention programs typically hammer away at making sure that clinicians wash their hands as they move among patients’ rooms. Yet, harmful microorganisms can just as easily find their way to patients when pharmacy staff don’t follow best practices when compounding sterile preparations.

To reduce the transmission of pathogens, pharmacists at NewYork-Presbyterian Hospital, Columbia University Medical Center, in New York City, launched a plan to improve compliance among pharmacy staffers who make compounded drugs in IV admixture clean rooms. They presented their findings at the 2011 Midyear Clinical Meeting of the American Society of HealthSystem Pharmacists (ASHP).

“We wanted to reduce the potential risk of transmission from the staff who are making sterile products for patients,” said Vickie L. Powell, MS, RPh, FASHP, site director of the pharmacy and coauthor of the study. “That can happen in many ways, such as not washing your hands, then touching the wrong thing and then touching the compound you’re making. You can contribute to infection risk. Numerous organisms can grow and potentially be transmitted. We decided that even though we put people through extensive training about sterile compounding safety, we would conduct random

cultures of gloved fingers to see how clean they were as a way to monitor, evaluate and document compliance.”

About 100 pharmacy staff participated in the testing.

The random culturing revealed that only 30% of the staff had no colony-forming units of microorganisms growing on their gloved fingertips before beginning compounding procedures. The low percentage suggested inadequate compliance with procedures as described

by US Pharmacopeia (USP) Chapter <797>, which details the requirements for compounding sterile preparations.

Its intent is to decrease the contamination of sterile products and protect the compounder from unwanted exposure to pharmaceutical products.

Staff members who were noncompliant—as judged by microbial growth on their cultures—were required to undergo re-education and training on proper procedures, a process that took about a week. (The microbes detected included Corynebacterium; coagulase-negative Staphylococcus; Micrococcus; Pseudomonas; Streptococcus; and Kytococcus.)

“We have them review videos and conduct one-on-one instruction, then we observe them at their work, which is

followed by another culture,” Ms. Powell said. “I think people are inclined to do the right thing, but sometimes they take shortcuts if you’re not watchful. It’s in our best interest to do what we can to assure that our patients are safe.”

Since the program’s initiation in 2010, an average of 95% of the pharmacy staff’s cultures have been free of microbial growth. Ongoing monthly monitoring, which includes random cultures and training, has resulted in compliance with USP <797> and Joint Commission medication management standards, according to Ms. Powell.

The team concluded that “strict adherence to proper hand washing and sterile compounding procedures decreases microbial growth and virtually eliminates the risk for nosocomial infections from compounded admixtures.

Developing strict policies and procedures can ensure quality outcomes for our patients.”

‘I think people are inclined to do the right thing, but sometimes they take [infection control] shortcuts if you’re not watchful.’

—Vickie L. Powell, MS, RPh, FASHP

Angela Cassano, PharmD, BCPS, president of Pharmfusion Consulting in Midlothian, Va., commented that it is “encouraging to see” that programs such as the one at Columbia University Medical Center “are paying attention and taking seriously USP <797>,” and recognizing that any reduction in contamination rates are an improvement.

“I’m not surprised to see that in this study, compliance rates among staff increased after a formalized program was put in place,” she added. “When employees see that you’re serious about an initiative, you’re likely to get greater buy-in. Going from 30% compliance to 95% is significant and shows that their efforts have been very effective.”

Dr. Cassano added that managers who are responsible for compounding operations often assert that the only way to effectively reduce contamination is to invest millions in rebuilding the clean room, but this program shows clearly that a difference can result from a structured training program, and more importantly, regular compliance oversight.

Break Out the Gloves: A Battle Between Sterile And Nonsterile Garb The USP <797> mandate also was the impetus for research conducted at Indiana University Health North Hospital near Indianapolis—more precisely, a 2007 change to the standard that requires the use of sterile gloves when compounding sterile products for hospital use.

“We were having problems obtaining supplies of sterile gloves from the manufacturers,” said Shawn Van Scoik, RPh, a pharmacist at the hospital and study coauthor. “At first, it was an availability issue. With all the hospitals wanting to be in compliance, you couldn’t get sterile gloves for a while.”

In addition, the new mandate for sterile gloves contributed significantly to increased pharmacy costs.

Ms. Van Scoik and her colleague, Stacy Snyder, PharmD, BCPS, lead study author, wondered whether the use of sterile gloves significantly decreased contamination rates. A literature search turned up a single study of gloves and contamination rates that found beneficial effects (Am J Health Syst Pharm 2007;64:837-841). The two pharmacists decided to conduct a pro-

Pharmacy Practice News • March 2012

Clinical 39

Infection Control spective study to find out if they could replicate those results.

The study’s objective was to compare the contamination rates between sterile and nonsterile gloves using tryptic soy broth (TSB) mini-bags and tryptic soy agar (TSA) fingertip plates. Contamination rates were evaluated to assess if proper aseptic technique and routine sanitization are comparable for both scenarios.

Four experimental arms were created: new non-sterile gloves with routine disinfection, non-sterile gloves that had been used in compounding for at least an hour with routine disinfection, new sterile gloves with routine disinfection and sterile gloves that had been used in compounding for at least an hour with routine disinfection.

Sterile 70% isopropyl alcohol (IPA) was the disinfectant used throughout the study, the agent mandated by USP <797>. With the exception of the type of gloves used, all other aspects of the trial were performed according to the same guidelines. All compounding and testing was completed by pharmacy technicians who were trained in aseptic sterile technique and who routinely worked in the IV room, compounding sterile products.

After routine hygiene and garbing with personal protective equipment, an ampoule of TSB growth medium was opened and transferred to a vial of TSB growth medium. Twenty 1-mL aliquots of the growth medium were then transferred to a TSB mini-bag. The technicians placed fingertips of each hand on the TSA plates. When testing was completed, the TSB mini-bags (considered the final product) were stored and incubated at room temperature for 14 days, based on manufacturer guidelines. The TSA plates were stored and incubated at room temperature for a minimum of three days. The TSB minibags were assessed for clarity and evidence of particulates. The agar fingertip plates were assessed for evidence of microbial colonies.

For the mini-bag aseptic technique verification, 83 gloves (45 nonsterile, 38 sterile) were tested; for the agar fingertip testing, 184 gloves (104 nonsterile, 80 sterile) were tested. The overall contamination rate of the agar plates was 18.2%, and overall contamination rate of the mini-bags was 5.1%.

No significant difference in bacterial growth in TSB mini-bags was found between the use of sterile versus nonsterile gloves (P=0.855), and there was no significant difference in contamination risk in the mini-bags (P=0.293) or on TSA plates (P=0.21) based on whether the test was completed with new gloves or gloves used for at least one hour of compounding. The likelihood of finding bacterial growth on nonster-

contamination and infections. It’s critical to make sure we’re giving patients the safest, best opportunity to have the lowest risk for contamination from compounded sterile preparations.”

Criticisms Deemed Valid, but Study Design May Be at Fault

‘I’d say that their rate of contamination is totally unacceptable. And it’s hard to differentiate if it was the result of the gloves or because of the clinicians’ aseptic technique.’

—Eric Kastango, MBA, RPh, FASHP

ile gloves was 1.3 times that of finding growth on sterile gloves. However, that glove contamination did not appear to transfer to the TSB mini-bags: No statistically significant association was found between fingertip contamination and contamination of the mini-bags, according to the investigators.

“Using nonsterile gloves had no negative effect in our study, which is what we had anticipated,” Ms. van Scoik said.

“We found that if you have fingertip contamination but use good aseptic techniques, the contamination doesn’t translate to the final product. Nonsterile gloves may therefore be an economical and safe alternative to sterile gloves for medium risk–level compounding.” She strongly emphasized that the study’s small size means its findings must be validated in a larger population.

Kudos for Study, But Approbation On Contamination Rate Eric Kastango, MBA, RPh, FASHP, president and CEO of Clinical IQ, LLC, a health care consulting firm in Madison, N.J., and a member of the 2010-2015 USP Compounding Expert Committee, applauded the researchers’ initiative. He agreed with them that the sample size is too small to reach any meaningful comparison between sterile and nonsterile gloves with regard to contamination rates in this context.

And the study clearly demonstrates

that nonsterile gloves are “dirty right out of the package,” he noted.

But what most concerned him was the overall contamination rate of 5.1% reported in the study, which he said is far higher than the industry standard rate of 0.1% for pharmaceutical compounding. “I’d say that their rate of contamination is totally unacceptable,” Mr. Kastango said. “And it’s hard to differentiate if it was the result of the gloves or because of the clinicians’ aseptic technique. I would have to say that the fingertip contamination from the nonsterile gloves did get transferred to the final product.”

More generally, he emphasized that the widespread zeal to save money by using nonsterile gloves is understandable but misplaced. In a typical compounding operation, the additional cost of sterile gloves ranges from $10,000 to $12,000 annually, he noted. “In this day and age, that’s not an insignificant amount of money. But it’s the equivalent of two drug vials or perhaps three days’ worth of IV drug waste, and one-third of the cost of a hospital-acquired infection, which has been estimated at $34,000.”

Mr. Kastango added, “The decision the USP committee made in requiring sterile gloves over nonsterile gloves is that you start with a pair of gloves with zero microbial bioburden and that it’s a very inexpensive way to maintain a state of control and prevent the risk for

The authors acknowledged the validity of Mr. Kastango’s criticism, although they hesitated to extrapolate any potential contamination rate based on their small sample size.

“One particular reason is that we were extremely conservative in how we interpreted the TSB bags,” Dr. Snyder said.

“Any evidence of fibrils or turbidity that could be due to protein agglomeration or denaturation, rather than microbial growth, were interpreted as having positive microbial contamination. We did not plate out or speciate the contents of the bags.” She said they incorporated fingertip testing because “the new version of USP <797> states that all personnel who compound sterile preparations must complete a ‘gloved fingertip sampling’ procedure as part of periodic competency evaluations.

“After completing our pilot study, we did identify that the majority of our failures were possibly associated with a particular technician,” Dr. Snyder continued, noting that the study involved only four technicians, because it was simply a pilot study.

“Following the completion of this study and reviewing the results, all of our technicians went through extensive direct observational study, as well as didactic training and retesting.”

The authors also examined the possibility of expanding the study to achieve statistical significance to match the industry standard contamination rate of 0.1% for aseptically produced preparations; however, their statisticians calculated that more than 2,400 samples per study arm would be required, which was not feasible.

“We are encouraged that our small pilot study presented as a poster at the ASHP Midyear meeting has stimulated discussion,” said Dr. Snyder. “We hope that larger studies can be conducted to fully elucidate the impact of sterile versus nonsterile gloves with routine disinfection in parallel with the adherence to rigorous sterile technique on the part of technicians.”

—Steve Frandzel

40 Spotlight on Bleeding Management

Pharmacy Practice News • March 2012

SPE C IAL SECTION

Pharmacists Need To Set Up Heparin Protocols New Orleans—Heparin protocols vary widely among medical centers, but in light of national patient safety goals issued by the Joint Commission that encompass the use of standardized anticoagulation practices, it is increasingly important for pharmacists to develop and maintain heparin protocols at their institutions.

Three studies presented at the American Society of Health-System Pharmacists’ Midyear Clinical Meeting highlighted the importance of pharmacists in creating heparin protocols and making sure they are followed, two showing specific benefits of weight-based heparin dosing protocols and a third showing that even when weight-based protocols are in place, vigilance is needed to make sure they are used.

thromboembolism (VTE), the average time to therapeutic range was 13 hours in the weight-based group and 33 hours in the non–weight-based group.

The January 2011 analysis of 85 patients found that weight-based dosing continued to be helpful, resulting in a mean time to therapeutic aPTT of 20

Dr. Agi set out to educate her colleagues on protocol compliance. She met with internists and other physician groups about unnecessary lab reports, educated nurses about the proper protocol, distributed educational materials about the protocol, put up flyers in break rooms discussing how to manage

Table. Outcomes With Weight-Based and Non–Weight-Based Dosing Number of Patients

Mean Time to Therapeutic aPTT, h

Patients in Therapeutic Range at 24 h, %

Lahey Clinic Medical Center

282

Weight-based: 17 Non–weight-based: 31 (P=0.0001)

Weight-based: 65 Non–weight-based: 34

Cleveland Clinic Weston

52

Weight-based: 12.5 Non–weight-based: 44 (P<0.001)

Weight-based: 49 Non–weight-based: 34 (P=0.007)

Institution

Goals Reached Sooner With Weight-Based Dosing “Despite the demonstrated benefit of using weight-based heparin protocols, many places still do not use them,” explained Mary Amato, PharmD, MPH, lead author of a study conducted at Lahey Clinic Medical Center in Burlington, Mass. At the Lahey Clinic, she said, “we were using a protocol that was non–weight-based and found that it took a long time—sometimes more than 30 hours—to reach therapeutic range.”

Dr. Amato, associate professor at the Massachusetts College of Pharmacy and Health Sciences in Boston, and her colleagues implemented weightbased heparin dosing protocols for inpatients in April 2009. They then compared records for patients treated with IV unfractionated heparin in February 2009, when non–weight-based protocols were used, with those treated in June 2009, two months after initiation of weight-based protocols.

They assessed heparin dose; the time it took to reach an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times mean control; the percentage of patients achieving therapeutic range within 24 hours; and the dose needed to achieve therapeutic goals. They conducted a similar review of records again in January 2011.

Overall, 134 patients received weightbased heparin dosing and 148 had non– weight-based dosing. The weight-based group had a mean time to therapeutic aPTT of 17 hours, vs. 31 hours in the non–weight-based group (P=0.0001) (Table). Also, 65% of patients in the weight-based group were in therapeutic range at 24 hours compared with 34% of patients in the non–weightbased group.

For patients treated for acute venous

from 34% to 49% (P=0.007) (Table).

Supratherapeutic values decreased from 22% to 13% (P=0.036), and the number of aPTT tests per patient was cut in half (P=0.0012). Additionally, five patients had evidence of a bleed before the protocol was implemented, whereas none showed evidence of

‘There’s a heightened need for re-examining hospital practice in anticoagulants. It appears that many hospitals still have a huge need for improvement.’

—Edith Nutescu, PharmD hours, with 65% of patients reaching the therapeutic range at 24 hours.

Additional Benefits Of Weight-Based Dosing After performance improvement auditors found problems with use of IV heparin therapy at the Cleveland Clinic’s Weston, Fla., location, the hospital’s pharmacy set up a pharmacy-monitored heparin weight-based protocol in May 2010. Pharmacists used the protocol to improve anticoagulation patient safety practices and address the problems that had been identified, such as inappropriate dose adjustments, omitted documentation and timing of aPTTs. With the new system, pharmacists were involved in evaluating every aPTT value. The protocol was documented through the hospital’s electronic medical records (EMRs), which created a trail that allowed any health professional to see how many patients were taking heparin as well as up-todate aPTT results.

Martha Espinoza-Friedman, PharmD, BCPS, clinical pharmacist at Cleveland Clinic Weston, and her colleagues reviewed the charts of 52 patients, some seen before the protocol was implemented (January 2009 to May 2010) and some after (June 2010 to March 2011).

The mean time to achieve therapeutic aPTT decreased from 44 hours to 12.5 hours (P<0.001) and the percentage of therapeutic aPTTs increased

bleeding after implementation.

The program had an additional benefit, Dr. Espinoza-Friedman said, noting that the “staff learned that morbidly obese patients were often being overtreated [and] pharmacists to be re-educated about switching to an adjusted weight-based dosing for this special patient population.”

Adherence to Protocols Can Be Lacking But even when such weight-based protocols are in place, they are not always followed, and this can have negative consequences, such as increased adverse drug events (ADEs).

Harris County Hospital District, a community hospital in Houston, established a weight-based dosing protocol for heparin in 2005 that was updated in 2009, with nurses as the primary drivers. But Rose Agi, PharmD, MBA, clinical pharmacist in internal medicine, and her colleagues found that discrepancies in adherence were affecting the hospital’s rates of ADEs. The investigators reviewed 316 patient charts and found protocol forms that were filled out incorrectly, wrong dosing weights, unnecessary heparin drip orders, inappropriate lab draw times and unnecessary or unordered prothrombin time (PT)/international normalized ratio (INR) tests. Additionally, many nurses were still using the outdated 2005 heparin protocol forms.

warfarin and heparin patients, went unit by unit (with the help of nurse managers) to remove all 2005 order forms as well as remove the forms from the forms department’s reorder list.

“I’ve found that putting protocols in place is not the issue—it’s following the protocols,” she said. The updat-

•

see HEPARIN, page 46

Inside Advice for teasing out the best antiplatelet regimen for various patient populations.

42

Anticoagulation experts Paul Dobesh, PharmD, and Michael Gulseth, PharmD, debate the merits of rivaroxaban versus dabigatran for VTE prophylaxis.

44

Dabigatran saves New Jersey hospital money despite its higher upfront costs compared with warfarin.

48

Ohio State pharmacists use algorithm to improve safety of argatroban dosing in critically ill patients.

50

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February 2012

42 Spotlight on Bleeding Management

Pharmacy Practice News • March 2012

Selecting Appropriate Antiplatelet Therapy Is Challenging U

ntil fairly recently, physicians and pharmacists had more or less two choices when it came to antiplatelet therapy in patients with conditions such as valvular disease, ischemic stroke, cardiovascular disease and peripheral arterial disease: clopidogrel (Plavix, BristolMyers Squibb), approved by the FDA in 2002, and that ancient mainstay, aspirin.

But with the 2009 approval of prasugrel (Effient, Lilly) and the 2011 approval of ticagrelor (Brilinta, AstraZeneca), the menu of options for thrombosis prevention has effectively doubled—and the array of questions and considerations for clinicians has grown exponentially.

What are the factors that should guide the choice of therapy? Which patients are best suited for which agents?

The ninth edition of the American College of Chest Physicians’ guidelines for Antithrombotic Therapy and Prevention of Thrombosis (AT9), published in February (Chest 2012;141:2:7s-47s), offers a basic road map. Aspirin and/ or clopidogrel remain the recommended mainstays for valvular disease, ischemic stroke and peripheral arterial disease, although there is more debate about which is the antiplatelet of choice when it comes to cardiovascular disease—particularly for acute coronary syndrome (ACS).

“While clopidogrel has been the primary agent of choice over the previous decade for dual-antiplatelet treatment, prasugrel and ticagrelor are now approved choices that the clinician has to consider in ACS,” said Charles E. Mahan, PharmD, professor of pharmacy at the University of New Mexico College of Pharmacy, in Albuquerque.

The complexity of choices in antiplatelet therapy is further highlighted by two recent papers: one in the January 2012 issue of Expert Opinion in Pharmacotherapy, and another in the Dec. 26, 2011 supplement to Current Opinion in Cardiology.

“Both of these papers highlight the fact that each of these drugs is still trying to find a niche, and we’re still trying to tease out which drug is right for which patients based on the available data,” said Robert L. Page, PharmD, MSPH, BCPS, associate professor in the Department of Clinical Pharmacy at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of Colorado-Denver. “The studies we have don’t all have the same end points, and aren’t all conducted in the same population. We have the broader picture, but the details are unclear. We’re also trying to figure out factors such as the ideal duration of therapy.”

Aspirin and clopidogrel have some obvious advantages. “They have a tre-

mendous amount of real-world use that has accumulated, as well as large numbers of patients who have been assessed in clinical studies. Both will be inexpensive, with clopidogrel becoming generic in May 2012,” said Dr. Mahan. On the other hand, prasugrel and ticagrelor have a more rapid onset than clopidogrel because they do not require hepatic breakdown to an effective metabolite. Additionally, “these agents appear to not be impacted to the same degree by genetic polymor-

bottom line is that ticagrelor has been found to be superior.”

But trial data are just one factor in treatment choice. “Ticagrelor is a twicedaily drug, plus there is some debate about the aspirin dosing that comes with that,” said Dr. Page. There is some question as to whether patients will “adhere as well to that type of regimen compared with clopidogrel once a day.”

When it comes to PCI, both prasugrel and ticagrelor are possible choices.

“Patients who are at high risk for stent

‘While clopidogrel has been the primary agent of choice over the previous decade for dual-antiplatelet treatment, prasugrel and ticagrelor are now approved choices that the clinician has to consider in ACS.’

—Charles E. Mahan, PharmD

‘Each of these [antiplatelet] drugs is still trying to find a niche, and we’re still trying to tease out which drug is right for which patients based on the available data.’

—Robert L. Page, PharmD, MSPH, BCPS phisms that may increase the thromboembolic or bleeding risk in patients receiving clopidogrel,” he added. But that potency and efficacy comes at the price of a slightly higher risk for bleeding. The newer agents also have limited Phase IV information and only niched indications at this point—and they are more expensive.

In contemplating antiplatelet therapy for ACS, where the data is least clear, Dr. Page advised clinicians to consider what type of ACS is involved and what the overall treatment approach would be. “If you’re just dealing with medical management,” he said, “that really leaves out prasugrel; most of its data is in percutaneous [coronary] intervention [PCI]. So that focuses you on ticagrelor and clopidogrel, and here the

thrombosis due to multiple stents or previous thrombosis while on clopidogrel may best benefit from prasugrel or ticagrelor,” said Dr. Mahan. “Prasugrel may be the best option in patients with diabetes mellitus or patients with a previous myocardial infarction. Clopidogrel is still likely the mainstay in patients who are elderly or at high risk for bleeding when prasugrel may not be an option.”

Both Drs. Mahan and Page said that in the current era of more potent antithrombotics, using the minimum number of various agents necessary to treat the patient will become an imperative.

“For instance, two antithrombotics may be better than three in patients who may be on warfarin or the newer drugs dabigatran [Pradaxa, Boehringer Ingel-

heim], rivaroxaban [Xarelto, Janssen], or [the investigational agent] apixaban [Bristol-Myers Squibb] for other indications,” Dr. Mahan said. “I compare this to the analogous reduction over time of glycoprotein IIB/IIIA use in PCI. We have much more conservative use of these agents as compared to a decade ago. I believe clinicians are beginning to recognize higher ‘real-world’ bleeding rates than what we have seen in clinical trials, and this deserves further investigation to ensure appropriate patient care.”

In the past, relatively little weight was given to bleeding outcomes in the selection of antiplatelet therapy, Dr. Mahan noted, but that appears to be changing. “There is a clear paradigm shift in many of the chapters of the new AT9 guidelines toward risk stratification for bleeding as well as thromboembolic or ischemic events, which promotes a more individualized approach to patient care. Case fatality rates of both bleeding and thromboembolic/ ischemic events should be taken into consideration, along with downstream morbidities … that occur due to these respective outcomes.”

What will be the role of pharmacogenomic testing in selecting appropriate antiplatelet therapy? It’s promising, but not yet ready for prime time, said Dr. Page. “People who may benefit from pharmacogenomic testing, particularly with clopidogrel, will be those undergoing stents. That’s where the most robust data is. It’s exciting and a whole new frontier for pharmacists. But we’re not there yet.” Dr. Mahan concurs. “While genetic polymorphisms may impact up to 30% of patients given clopidogrel, it is too preliminary to recommend the routine use of platelet function and genetic testing in guiding treatment choices for antiplatelet agents in the care of patients with cardiovascular disease,” he said. “Data is really lacking as to whether implementation of functional or genetic testing has a strong impact on clinical outcomes at this point. The availability of newer agents may also reduce the drive to pursue these studies.”

And that’s the other X factor: new agents. Those in various stages of development include elinogrel (Portola), terutroban (Servier Labs), cangrelor (The Medicines Company), vorapaxar (Merck) and atopaxar (Eisai). As complex as the choices of antiplatelet therapy in the cardiovascular setting may be today, they may be even more so if and when some of these new agents enter the market.

—Gina Shaw

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44 Spotlight on Bleeding Management

Pharmacy Practice News • March 2012

Which New Agent Is Better for Prophylaxis of VTE? Paul P. Dobesh, PharmD, FCCP, BCPS

Michael P. Gulseth, PharmD, BCPS

Associate Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

Program Director for Anticoagulation Services Sanford USD Medical Center Sioux Falls, South Dakota Adjunct Assistant Professor South Dakota State University College of Pharmacy Brookings, South Dakota

Rivaroxaban

R

Dabigatran etexilate

C

ivaroxaban [Xarelto, Janssen] is a better agent than dabigatran etexilate for several reasons. To begin, rivaroxaban and dabigatran have different mechanisms of action. Dabigatran is a direct thrombin inhibitor (DTI), whereas rivaroxaban is a direct factor Xa inhibitor. The coagulation cascade centers around factor Xa, the location of rivaroxaban’s pharmacologic action. Rivaroxaban very efficiently blocks both free factor Xa and factor Xa that is inside the prothrombinase complex. DTIs such as dabigatran block both free and bound thrombin.

However, because it is in the center of the coagulation cascade, factor Xa is a better target than thrombin. For every molecule of factor Xa that you inhibit, you could inhibit the production of hundreds and possibly even thousands of molecules of thrombin from being produced. This upstream targeting is one of the reasons why we have seen drugs that focus on factor Xa to be more effective than those focusing on thrombin.

In the RECORD1 study of total hip replacement surgery, rivaroxaban provided superior protection against venous thromboembolism (VTE) compared with enoxaparin (N Engl J Med 2008;358:2765-2775). In RENOVATE, a similar study, dabigatran was only non-inferior (not superior) to enoxaparin (Lancet 2007;370:949-956).

In studies of patients undergoing total knee replacement surgery using European enoxaparin dosing (40 mg SQ once daily), rivaroxaban was superior to enoxaparin (RECORD3; N Engl J Med 2008;358:2776-2786) and dabigatran again was only non-inferior to enoxaparin (RE-MODEL; J Thromb Haemost 2007;5:2178-2185). In patients undergoing total knee replacement surgery using North American enoxaparin dosing (30 mg SQ twice daily), rivaroxaban again was superior to enoxaparin (RECORD4; Lancet 2009;373:1673-1680) and dabigatran was inferior (not even non-inferior) to enoxaparin (RE-MOBILIZE; J Arthroplasty 2009;24:1-9). Bleeding did not differ significantly for either agent compared with enoxaparin, regardless of surgery type.

There also have been studies demonstrating that rivaroxaban can be reversed using prothrombin complex concentrates, whereas there are no such studies for dabigatran.

Head-to-head trials comparing rivaroxaban and dabigatran have not been conducted. A solid-gold answer on which of these agents is better does not exist. We have to make decisions based on the data we have. In a pooled analysis, enoxaparin was favored over dabigatran, and rivaroxaban was favored over enoxaparin (Circ Cardiovasc Qual Outcomes 2010;3:652-660). In a systematic review, adjusted indirect comparison indicated that rivaroxaban was superior to dabigatran for the prevention of VTE (J Clin Pharm Ther 2011;36:111-124). If you undergo orthopedic surgery, do you want the non-inferior drug or the superior drug?

onsider this case: A 90-kg, 72-inch, 60-year-old man just underwent total hip arthroplasty. His history includes coronary artery disease, hypertension, benign prostatic hyperplasia and atrial fibrillation. He takes dabigatran 150 mg orally twice daily for stroke prevention. His kidney function is good. Dabigatran [Pradaxa, Boehringer Ingelheim] had been held two days prior to the procedure.

His baseline hemoglobin was 11 g/dL and is 9 post-surgery. What would be appropriate VTE prophylaxis after his procedure: rivaroxaban (10 mg orally once daily), warfarin (5 mg today titrated to an international normalized ratio of 2-3), enoxaparin (40 mg SQ once daily) or dabigatran (150 mg orally once daily, increasing back to his twice-daily dose in two to three days)?

The point of this case is that these kinds of situations may not be so black-andwhite. This is a realistic type of scenario that many of us are going to see.

It is true that dabigatran was non-inferior to enoxaparin in two trials (RENOVATE and REMODEL), and inferior to enoxaparin in another trial (RE-MOBILIZE). But we can delve into these data a little bit more.

In REMODEL, dabigatran was dosed within four hours after surgery, whereas in RE-MOBILIZE, it was dosed six to 12 hours after surgery. That is an important point. Furthermore, in RE-MOBILIZE, there were lower levels of major bleeding, although this finding was not significant.

In RECORD1, rivaroxaban showed a little higher major bleeding (0.3% vs. 0.1% for enoxaparin). It was not statistically significant, but the same trend is present in RECORD3 and RECORD4. Compared with symptomatic VTE rates, 0.3% is a big deal. A bleeding complication after orthopedic surgery can be devastating to the patient and everybody else involved. So, I think that is something that we have to be careful to minimize. Notably, there was no difference between dabigatran and enoxaparin in symptomatic VTE in the hip trial and both knee trials. Additionally, surgical site bleeding, which was not included in the RECORD trials’ definition of major bleeding, also trends higher for rivaroxaban. Orthopedic surgeons care about surgical site bleeding.

Consider the trials of apixaban (ADVANCE-1; N Engl J Med 2009;361:594-604) and fondaparinux (e.g., Lancet 2002;359:1721-1726). The same thing happened: If you dose closer to surgery, you get more efficacy but also more major bleeding. So, are these drugs really that different or was it just the clinical trial design that led to the differences?

Additionally, dabigatran has been found to be superior to warfarin for stroke prevention in patients with atrial fibrillation (RE-LY; N Engl J Med 2009;361:1139-1151). Rivaroxaban has not been found to be superior (ROCKET AF; N Engl J Med 2011;365:883-891). Finally, RECORD4 data were intentionally not included in the package labeling for rivaroxaban, which does make one worry about the integrity of the data.

In conclusion, look back at the case in which the patient is taking dabigatran successfully for stroke prophylaxis. What would I do for VTE prophylaxis after surgery? I think I would be comfortable with using dabigatran.

Dr. Dobesh reported that he is a consultant for Johnson & Johnson.

Dr. Gulseth reported that he is a consultant for Ortho-McNeil-Janssen, is on the speakers’ bureau for Boehringer Ingelheim and is a Johnson & Johnson stockholder.

Based on a presentation at the 2011 ASHP Midyear Clinical Meeting.

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46 Spotlight on Bleeding Management

HEPARIN continued from page 40

ed heparin protocol is now available through the hospital’s electronic order entry system. Dr. Agi estimated that by reducing unnecessary PT/INR labs, venipuncture-related infections, hospital lengths of stay and ADEs, the protocol resulted in a cost avoidance of approximately $300,000. She plans to review adherence annually.

Harris County Hospital District is not alone in having protocols that are

‘I’ve found that putting protocols in place is not the issue—it’s following the protocols.’

—Rose Agi, PharmD, MBA not followed. “Hospitals may have several processes and protocols in place to manage medications, but in the hustle and bustle of day-to-day work it can get lost,” explained Edith Nutescu, PharmD, director of the Antithrombosis Center at the University of Illinois at Chicago (UIC) Hospital and Health System. “This speaks to the constant need for re-evaluation and re-education of processes,” Dr. Nutescu, clinical professor of pharmacy practice at UIC College of Pharmacy, told Pharmacy Practice News.

Although her hospital had a weightbased protocol in place for several years, the task of ensuring compliance had been left to the medical staff. An internal review conducted after the Joint Commission goals were issued found that UIC was not very compliant. Dr. Nutescu and her col-

leagues created a multidisciplinary program using a computerized EMR system with a weight-based protocol for heparin that is managed by nursing staff with oversight from medicine and pharmacy.

A review comparing data from 229 patients treated with heparin before and after the implementation of the system in 2009, the results of which were presented in May 2011 at the Anticoagulation Forum’s national meeting in Boston, showed that the new program resulted in better compliance

Pharmacy Practice News • March 2012

with institutional clinical care and dosing guidelines and better heparin anticoagulation control.

The average time to reach therapeutic aPTT among patients treated with the newer protocol was significantly improved—15 versus 24 hours for those in the usual-care group (P=0.0005).

Compliance with dosing guidelines, as evidenced by appropriateness of initial loading and maintenance doses, was significantly better in the newer group compared with the usual-care group (loading dose: 73.2% vs. 6.8%,

P<0.0001, respectively; maintenance dose 75% vs. 16.2%, P<0.0001, respectively). Major bleeding significantly decreased, from 11% in the usual-care group to less than 2% in the nursemanaged group (P=0.004).

“There’s a heightened need for reexamining hospital practice in anticoagulants. It appears that many hospitals still have a huge need for improvement,” said Dr. Nutescu, adding, “interventions work, specifically, pharmacy interventions work.”

—Karen Blum

47

Pharmacy Practice News • March 2012

In April

Next Issue: Spotlight on in Medication Safety The April issue will feature a special section on medication safety. Here’s a preview of featured content:

Educational Reviews 1. Drug Safety in the ICU Steven J. Martin, PharmD, BCPS, FCCP, FCCM, professor and chair, Department of Pharmacy Practice, University of Toledo Medical Center, describes a number of technologies and processes that are in place to improve medication safety. Bar code administration systems, smart pumps, computerized prescriber order entry (CPOE) and error reporting systems are all covered; workarounds, system failures and other barriers to good performance are detailed.

2. Medication Errors—A Year in Review This annual review by the Institute for Safe Medication Practices (ISMP) offers details on how to set up an errorreduction program, with a focus on building a multidisciplinary team approach and employing bar coding, CPOE and other medication safety technologies.

• Florida hospital makes a cultural transformation to improve patient safety.

• North Carolina VA offers tips for preventing med errors with investigational drugs.

Articles

• Pharmacists at GA medical center develop strategies for safe use of oxytocin.

Medication Safety Pearls from ASHP Midyear Clinical Meeting:

ED Pharmacists: How They Are Improving Medication Safety in the ICU.

• Duke pharmacists improve use of intrathecal products after methotrexate near-miss.

ISMP Webinar—Challenges in Oncology Medication Safety: Identifying Risk and Opportunity.

48 Spotlight on Bleeding Management

Pharmacy Practice News • March 2012

Despite Up-front Costs, Dabigatran May Be Economical New Orleans—Although the anticoagulant dabigatran has higher acquisition costs, it can save hospital costs overall through less need for monitoring and reduced length of stay (LOS) for patients, a hospital in New Jersey has found.

In a retrospective study, Lauren McCarthy, PharmD, BCPS, pharmacy clinical coordinator at Cape Regional Medical Center, in Cape May Court House, N.J., and her colleagues found

that the average cost of anticoagulation therapy for hospitalized patients with atrial fibrillation was significantly lower for those receiving dabigatran (Pradaxa, Boehringer Ingelheim) than for those receiving warfarin, and that patients taking dabigatran stayed in the hospital one less day.

During the study, Dr. McCarthy and her team compared the charts of 53 patients with atrial fibrillation who

received dabigatran at their hospital between December 2010 and May 2011 with those of 53 patients treated with warfarin during the same period. They collected information on drug interactions, hospital LOS, doses and duration of anticoagulant drugs dispensed, laboratory markers of bleeding or recorded bleeding, interruptions in therapy, international normalized ratio for warfarintreated patients, creatinine clearance

for dabigatran-treated patients and pharmacist therapeutic interventions.

The results, presented at the American Society of Health-System Pharmacists’ 2011 Midyear Clinical Meeting, showed that the acquisition costs of dabigatran were much higher—$9.70 per patient versus $0.16 for warfarin for the length of admission. However, the average cost of anticoagulation therapy was significantly lower for those receiving dabigatran ($36

‘Despite the lack of required daily lab monitoring, it remains important for pharmacists to actively follow dabigatran patients to monitor for correctness of dose based on renal function, identify drug interactions and minimize bleeding risk.’

—Lauren McCarthy, PharmD, BCPS per patient) than for those receiving warfarin ($51 per patient; P=0.011). Twentyfive warfarin patients required heparin bridging, with a mean duration of 3.52 days of heparin therapy. When heparin bridging was excluded, the total cost of anticoagulation therapy was still lower for the patients treated with dabigatran ($28.30 vs. $35.79), but the difference was not statistically significant (P=0.08).

The investigators also found that hospital LOS was 3.9 days for dabigatrantreated patients and 4.9 days for patients given warfarin (P=0.028). One minor and one major bleeding event occurred among dabigatran-treated patients, and

Spotlight on Bleeding Disorders 49

Pharmacy Practice News • March 2012

there were no cases of bleeding among warfarin patients.

The need for pharmacist interventions was similar in the two groups: 13 interventions among the dabigatrantreated patients (11 for drug interactions and two for bleeding events) and 14 among the warfarin-treated patients (12 for drug interactions and two for the administration of a reversal agent).

Dose adjustments by a pharmacist were necessary for eight patients taking dabigatran.

Although dabigatran does not have specific monitoring requirements, Dr. McCarthy told Pharmacy Practice News that her team remained very involved with patients and was able to prevent many adverse effects. The pharmacists measured serum creatinine as a baseline and looked at hemoglobin/hematocrit for the first three days of inpatient therapy. They monitored patients for bleeding, ordering fecal occult blood testing on day 3 of therapy. In one patient, they noticed gastrointestinal bleeding and were able to discontinue dabigatran before the bleeding became serious.

“Being able to catch small changes in renal function and acute changes in the patient is really where pharmacy plays a definite role,” Dr. McCarthy said.

“Despite the lack of required daily lab monitoring, it remains important for pharmacists to actively follow dabigatran patients to monitor for correctness of dose based on renal function, identify drug interactions and minimize bleeding risk. Teaching patients to recognize the signs and symptoms of thrombosis also is key, she said.

Ann Wittkowsky, PharmD, CACP, director of anticoagulation services at the University of Washington Medical Center and a clinical professor at the University of Washington School of Pharmacy, both in Seattle, said the study highlights how the role of traditional anticoagulation services is changing with newer-generation anticoagulants, including dabigatran, rivaroxaban (Xarelto, Janssen) and the investigational drug apixaban (Pfizer), which are intended to be given at

The decreased need for monitoring opens new avenues and ‘allows for a more nuanced approach for drug selection, taking into account individual patient characteristics and drug characteristics.’

—Ann Wittkowsky, PharmD, CACP fixed doses without monitoring. “Traditionally, inpatient services are very hands-on and involved in monitoring,” Dr. Wittkowsky said, although the

decreased need for monitoring [with the newer drugs] opens new avenues.

It’s “a very positive development clinically. Pharmacy doesn’t just have to

be about changing doses based on lab values. … It allows for a more nuanced approach for drug selection, taking into account individual patient characteristics and drug characteristics.”

Hospital pharmacy managers may think that because the newer anticoagulants don’t require monitoring they don’t need pharmacy involvement, but “that’s not true,” Dr. Wittkowsky said.

Pharmacists “still need to be involved in patient education and drug selection.”

—Karen Blum

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50 Spotlight on Bleeding Management

Pharmacy Practice News • March 2012

In critically ill patients ...

Low-Dose Argatroban Offers Improved Safety, Equal Efficacy tically significant. The rate of major bleeding was 2.2% among those treated according to the new dosing algorithm versus 9.6% among those treated with the conventional dosing regimen (P=0.15); the rate of minor bleeding was 4.4% among those treated according to the new dosing algorithm versus 12.3% among those treated with conventional dosing (P=0.12).

Additionally, lower doses were as effective as higher doses, with 6.8% (5 of 73) and 6.7% (3 of 45) of patients in the two groups, respectively, experiencing thromboembolic events (P=0.99).

Although the analysis only included ICU patients, Dr. Doepker noted that now they also treat non-ICU patients with renal failure, hepatic failure or a body weight of 110 kg or greater with lower doses.

Commenting on the findings, Sarah Spinler, PharmD, professor of clinical pharmacy and residency programs coordinator at the Philadelphia College of Pharmacy, University of the

Risk Range a

Low (aPTT 40-60 sec) b

If Goal aPTT is 60-80 sec and Measured Rate is:

Standard (aPTT 60-80 sec)

Sciences, said that although the results show important outcomes, they do not justify a change in established dosing algorithms. “There are standard evaluations of the performance of a nomogram that the authors did not conduct,” noted Dr. Spinler, who was not involved in the study. “For example,” she told Pharmacy Practice News, “it is unclear whether the aPTT ranges for the nomograms, which included a low target range for patients at higher perceived bleeding risk, were derived from data collected from the same or different retrospective data the authors used as part of this study’s historical control.

If they were the same data, that would bias the results in favor of less bleeding.

They also did not report the percentage of patients meeting or not meeting the target aPTTs of each nomogram.

That is a standard outcome to evaluate a nomogram’s performance.” Dr. Spinler added that “a comparison to identify whether or not use of the current algorithm led to other meaningful

outcomes apart from bleeding events, such as length of hospital stay” also would be useful.

In response to Dr. Spinler’s comments, Dr. Doepker said, “The low target range used in patients with a high risk for bleeding was derived from expert opinion at our institution and not from the same cohort evaluated in this study.” He explained that “typically, after initial bleeding is ruled out over a 24 -to 48-hour period, these patients’ goal aPTT ranges are increased to a full systemic aPTT range, if indicated.

There was no difference in the number of patients who reached the target aPTT range in the pre-algorithm group [59 of 73 (80.8%)] compared to the post-algorithm group [38 of 45 (84.4%); P=0.62].”

Dr. Doepker further noted that the algorithms they developed were “derived based on institution-specific goals and are not intended to be directly applied at other institutions.”

Critically Ill, Renal Failure, c Hepatic Failure,d Body Weight ≥110 kg

Standard Dosing

0.1 mcg/kg/min

0.5 mcg/kg/min

0.25 mcg/kg/min

1 mcg/kg/min

<60

Increase rate 20%

<40

60-80

No change

40-60

81-95

Decrease rate 20%

61-75

96-120

• If infusion rate ≤0.1 mcg/kg/min, HOLD INFUSION and draw aPTT q6h until within goal range, then decrease rate 40%. If infusion rate ≤0.5 mcg/kg/min but >0.1 mcg/kg/min, hold infusion 60 min, then decrease rate 40%. If infusion rate >0.5 mcg/kg/min, hold infusion 30 min, then decrease rate 40%.

76-105

>120

• If infusion rate ≤0.1 mcg/kg/min, HOLD INFUSION and draw aPTTs q6h until within goal range, then decrease rate by 50%.

• If infusion rate >0.1 mcg/kg/min, HOLD INFUSION and draw aPTT every 3 h until within goal range, then decrease rate by 50%.

Figure. Post-algorithm regimen.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRRT, continuous renal replacement therapy; DVT, deep vein thrombosis; GGT, γ-glutamyl transferase; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; PE, pulmonary embolism a

—David Wild

High risk for bleeding or prophylaxis with remote history of HIT.

b

Suspected or confirmed HIT or DVT, PE, atrial fibrillation.

c

Renal failure is defined as hemodialysis, CRRT, or creatinine clearance ≤30 mL/h or serum creatinine >2 mg/dL

d

Hepatic failure is defined as any elevation of INR, ALT, AST, GGT, or bilirubin.

Adapted with permission. © 2005-2012. The Ohio State University Medical Center.

>105

If Goal aPTT is 40-60 sec and Measured Rate is:

Houston—Low-dose argatroban is as effective as a higher dose of the drug in treating or preventing thromboembolic events and is associated with a 70% drop in the incidence of bleeding among critically ill patients with heparin-induced thrombocytopenia (HIT), according to a retrospective study presented at the Society of Critical Care Medicine’s 2012 Critical Care Congress (abstract 692).

“At Ohio State University, we use critical illness as a risk factor for administering lower initial starting doses of argatroban,” lead investigator Bruce Doepker, PharmD, clinical assistant professor in the university’s Department of Pharmacy in Columbus, told Pharmacy Practice News. He said the approach is based on findings from several studies concluding that a more conservative titration algorithm in critically ill patients with organ dysfunction is necessary, given that up to 29% of these individuals develop argatroban-related bleeding (Pharmacotherapy 2009;29:1073-1081).

Established dosing regimens recommend an initial argatroban dose of 0.5 to 2 mcg/kg per minute, but Dr. Doepker and his colleagues employ an algorithm in which they initiate therapy at 0.1 to 0.25 mcg/kg per minute in critically ill patients and modify activated partial thromboplastin time (aPTT) target ranges (Figure).

To document the algorithms’ safety and efficacy, they compared 73 intensive care unit (ICU) patients who were treated for confirmed or suspected HIT with conventional doses of the drug (mean initial argatroban dose, 0.54±0.35) with 45 similar patients administered more conservative doses using the algorithm (mean initial dose, 0.23±0.06); P=0.0001). The patients were treated between 2007 and 2011 and were similar in age, weight and pretreatment APACHE II scores.

Major bleeding events were defined as hemoglobin reductions of 2 g/dL requiring transfusion of two units of blood in a 24-hour period, or any retroperitoneal, intracranial or other life-threatening bleeding. Any cases of venous or arterial thrombosis that occurred during argatroban administration were assumed to be treatment-related.

The researchers found a significant reduction in overall bleeding events with the new algorithm-based dosing regimen, from 21.9% (16 of 73) to 6.7% (3 of 45) in the high- and low-dose groups, respectively (P=0.029). When the results for major and minor bleeding were looked at separately, there were differences between the two dosing groups, but they were not statis-

Pharmacy Practice News • March 2012

Policy 51

FDA Watch

FDA Warning Links PPIs to C. difficile–Associated Diarrhea Expert offers tips for using PPIs in light of FDA warning

I

n a safety alert dated Feb. 8, the FDA warned that proton pump inhibitors (PPIs) may be associated with an increased risk for Clostridium difficile– associated diarrhea (CDAD). The alert affects both prescription and over-thecounter (OTC) PPI products.

symptoms could represent CDAD.” The FDA says it is working with manufacturers of PPIs to expand drug labels to include information about the increased risk for CDAD with PPI use.

The FDA also is reviewing the risk for CDAD associated with the use of hista-

‘It’s a good time for clinicians to start looking at their own practice, to scrutinize their use of these medicines.’

Evidence of a potential association between PPI use and risk for CDAD has been accumulating for some time.

“The FDA reacted to a string of publications showing that PPI therapy is associated with C. difficile and C. difficile colitis,” said Ronnie Fass, MD, professor of medicine, University of Arizona College of Medicine, and director, GI Motility Laboratory, University of Arizona Health Sciences Center, both in Tucson. “It makes sense to me, and I think it is timely.”

Despite the warning, the FDA cautioned that patients should not stop taking prescription PPIs without first consulting their health care providers. Patients taking OTC PPIs should pay careful attention to the directions for use in the package inserts of those drugs, the FDA advised.

“Recommendations to avoid PPIs as a therapeutic class are unwarranted,” stated Karen R. Mahoney, an FDA representative, in an email. “Since there are many causes of diarrhea, FDA is recommending that PPI users with diarrhea that does not improve should contact their health care professional to be evaluated for the possibility that their

Current file:

—Mark Reid, MD Full name of project

FILE SLUG CMezone qtrpg.indd

1ST PROOF LAYOUT APPROVeD InITIALS AnD DATe MAX sign-off

mine H2 receptor blockers.

Senior editor “PPIs are a therapeutic class of drugs fits the level of information we have.”

Style chges fr.and prev. safety Copy“it’s editor reasonable to that have known efficacy Dr. Reid added that profiles, having a therapeutic suspect, with the information we have Revision # benefit for R2 Sales many patients with the labeled indica- now, that a patient on PPIs may be more Layout Date/Time March 5, 2012 9:37 AM Production tions,” Ms. Mahoney noted. likely to get C. difficile infection than a editorial Date/Time The FDA recommends that clini- patient who is not onCreative these medications. cians consider a diagnosis of CDAD It’s a good time for clinicians to start COMMENTS: Trim Size Half Vertical in patients taking PPIs who develop looking at their own practice, to scrutiColor Specs 4C diarrhea that does not improve. The nize their use of these medicines.” agency also advises that patients taking Dr. Fass speculated that the FDA alert PPIs seek immediate medical care if was not more specific because more they develop watery stool that does not studies need to be done. For example, resolve, abdominal pain and fever. PPI therapy should be limited to the lowest dose and the shortest duration appropriate for the condition being treated, according to the FDA. Mark Reid, MD, a hospitalist at Denver Health Medical Center, and associate professor of medicine, University of Colorado Health Sciences Center, both in Denver, observed that the FDA alert is “worded very gently.” He believes this is appropriate because at present only an association exists between PPI use and C. difficile; causation has not been proven.

“It’s a notification of a possibility of increased risk,” he said. “The wording

Suggestions for Treating Patients With PPIs

I

n light of the recent FDA warning of an increased risk for Clostridium difficile– associated diarrhea in patients taking proton pump inhibitors (PPIs), Ronnie Fass, MD, professor of medicine, University of Arizona College of Medicine, and director, GI Motility Laboratory, University of Arizona Health Sciences Center, both in Tucson, recommended the following guidelines:

PROOF 1 12/10 ReV 1 12/17 ReV 2 ReV 3 ReV 4 age, high dosing and duration of PPI ReV 5 therapy also are suspected risk factors, ReV 6 he said, but there is “no ReV sufficient evi7 dence to state that clearly.ReV 8 “This warning will be the ReV 9 impetus for FInAL OK InITIALS AnD DATe

further research,” he predicted.

—George Ochoa

Drs. Fass and Reid reported no relevant financial disclosures.

www.CMEZone.com

Your premier source for practical, relevant and timely continuing medical and pharmacy education

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1. Reassess whether patients truly need PPI treatment.

2. Ensure that patients receive the lowest dose possible, and avoid prescribing more than once-daily dosing.

3. Consider switching to a different PPI. As an example, for cases of gastroesophageal reflux disease, instead of doubling the PPI dose, consider switching to a different PPI, or a PPI in combination with another anti-reflux therapy.

4. Consider alternative approaches to chronic PPI treatment. For example, think about on-demand or intermittent dosing.

5. Discuss long-term PPI use and adverse events with patients.

6. If patients taking PPIs have diarrhea that is not self-limiting, consider a diagnosis of C. difficile infection.

Applying Recent evidence in Hereditary Angioedema: Optimizing Individual Care

Mn1111

Expires October 1, 2012

Tailoring Therapy in Metastatic Breast Cancer: novel Clinical Approaches Expires October 1, 2012

Mn1113

PICKeD UP APPLIeD T

52 Policy

Pharmacy Practice News • March 2012

Practice Pearl

Organizing and Documenting Are Keys To Providing and Getting Paid for MTM A

s the medication therapy management (MTM) practice at Mayo Clinic in Jacksonville, Fla., has grown and been applied to different medical specialties, we have found that a good documentation template is critical in the organization of the MTM consult and the speedy documentation of the consult after it has been performed.

As to the consult itself, structuring it with a Microsoft Word template allows the provider to cover the targeted areas he or she wishes to cover in an efficient, organized way, helping to ensure

Michael J. Schuh, PharmD, MBA Ambulatory Pharmacist Assistant Professor of Family and Palliative Medicine Assistant Professor of Pharmacy School of Health Sciences College of Medicine Mayo Clinic Jacksonville, Florida

Time Started:

Time Ended:

blue areas are “wildcards” that can either change (e.g., patient name) or only are included in the initial workup to make recommendations but are not needed in the final note because they repeat what the physician already knows (vitals, labs), does not need (instructions for pharmacist/students/ residents) or can easily access in the patient’s chart (labs). We learned that including too much redundancy might prevent the physician from reading the note fully because they are busy and

•

see MTM, page 54

Pertinent Laboratory Data

Follow-up appointment: Pharmacist consult recommendations for: Patient name here Age: XXXX

all salient points are reviewed with the patient and that nothing is missed (Figure). Labs unrelated to the original chief complaint and secondary issues discovered during the patient interview were many times overlooked, so these areas were included on the template to help guide the pharmacist to remember to address these issues.

After the consultation, areas used to organize the consult can be deleted from the final document, leaving the remaining areas to be used for documentation and billing purposes. The

Sex: XXX

Clinic #: XXXXXXX

Date: XXXX

Pharmacist Name and Credentials: XXXXXXX The reason for today’s consult as requested by Dr. XXXXX: Reason for consult here Self Referral yes_____ no_____

General Chemistry

Blood Cell Counts

Lipid/Liver Panel

Miscellaneous Labs

Na (135-145)

WBC (3.5-10.5)

TG (<150)

DIG (0.8-2) TSH (0.3-5)

K (3.6-5.2)

Hgb (13.5-17.5)

TC (< 240)

Cl (100-108)

Hct (38.8-50)

HDL (M >40,F>50)

HCO2 (22-29)

Plts (150-450)

LDL (< 160)

BUN (8-24)

RBC (4.32-5.72)

Cholest/ HDL

Ser. Cr. (0.8-1.3)

B12 (180-914)

Alk phos (45-115)

CK (52-336)

Calc. Cl.

Fol (>3.5)

AST (8-48)

Fe (35-145)

Allergies:

Glu (70-100)

INR

ALT (7-55)

Fe % sat (14-50)

Problem List

HbA1c (3.9-6.1)

PT

Uric Acid (2.4-6.0 F) (3.4-7.0 M)

Ferritin (11-307)

Ca (8.9-10.1)

Phos (2.5-4.5)

Mg (1.8-2.5)

TIBC (250-400)

SOCIAL HX:

EtOH:

TOB:

Corr. Ca (8.8-10.5) Albumin (3.5-5)

Current Medications: Medication Dose Time/Frequency Indication How Long?

Info/recommendations

Bili tot 0.1-1.1) TP (6.3-7.9)

Summary of Primary Recommendations/Observations (see below for details): Observations/Recommendations:

PRESCRIPTION

All medications, including over-the-counter medications and herbal remedies, were reviewed as to indication, dose, and administration.

OTC/HERBALS

1. The first observation/recommendation should always be directly related to the indication for the consult, even if it is not the most clinically important point.

Pertinent Vital Signs: Height:

BP:

Weight:

HR:

Ideal Body Weight:

RR:

Pain Assessment:

Temperature:

Adjusted Body Wt:

2. Subsequent observations/recommendations should relate to each disease state and/or medication-related problem in descending order of clinical relevance.

3. Recommend time frame for pharmacy follow-up.

These are the major recommendations at this time. All questions were answered to (Patient’s name) satisfaction, and the patient was provided with my business card for future questions. # minutes were spent in face-to-face consultation. (If written materials were provided to the patient, document that here.) I appreciate the opportunity to have spoken with (Patient’s name) , and will gladly provide future assistance if necessary.

Alk phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bili tot, total bilirubin; BUN, blood urea nitrogen; Ca, calcium; Calc Cl, calculated clearance; CK, creatine kinase; Corr Ca, corrected calcium; DIG, digoxin; Fe, iron; Fe % sat, percent saturated iron; Fol, folate; Glu, glucose; HCO2, serum bicarbonate; Hct, hematocrit; HDL, high-density lipoprotein cholesterol; Hgb, hemoglobin; INR, international normalized ratio; LDL, low-density lipoprotein cholesterol; Mg, magnesium; Na, sodium; OTC, over-the-counter medications; Phos, phosphorus; Plts, platelets; PT, prothrombin time; RBC, red blood cell count; TC, total cholesterol; TG, triglyceride; TIBC, total iron-binding capacity; TP, total protein; TSH, thyroid-stimulating hormone; WBC, white blood cell count

Figure. Template for MTM polypharmacy/pharmacotherapy consultation.

Reprinted with permission. © 2011 Mayo Foundation for Medical Education and Research.

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54 Policy

Pharmacy Practice News • March 2012

MTM Pearl Table. MTM Services Provided at Mayo Clinic, Jacksonville, FL

MTM continued from page 52

have limited time to read it before making clinical decisions.

The different-colored inks used in different areas of the template help delineate what areas of the document to keep and what areas to delete from the template for documentation. It is quick and easy to delete unneeded fields, and this format is compatible with our electronic medical record.

Much time is saved in training students and residents because everyone knows how to use Microsoft Word before they start rotations and writing SOAP (sub-

Patient Population

MTM Services Provided

Kidney, liver, lung transplant patients

Education and postoperative monitoring

a

Polypharmacy

Can include any patient referred due to any drug-related inquiries.

In one recent example, a neurologist referred a patient with an uncommon neurological condition to obtain a clinical pharmacist opinion and recommendations regarding possible side effects or interactions.

CMR, education on herbals, supplements, adherence, ADRs, drug interactions etc

Bariatric surgery patients

Polypharmacy, determine crushable medications needed postoperatively

Pain rehabilitation patients

Polypharmacy,a taper schedules, ADRs, drug interactions

Patients with HIV infection taking protease inhibitors

Education, polypharmacy,a CMR, ADRs, drug interactions; medication administration (for the patient) and medication interactions (for the prescribing physician) are emphasized

ADR, adverse drug reaction; CMR, comprehensive medication review a Polypharmacy includes anything drug-related from any department that concerns either the patient or the referring physician. It is very broad and can be anything one can and sometimes can’t imagine regarding medications, including counseling a patient at the low end of complexity to counseling a patient taking 35 herbal supplements with 20 prescription medications at the other end of the complexity spectrum.

We have gotten tremendously positive feedback from patients, evidenced by reactions we get after the service has been performed—surprise that pharmacists know so much, hugs, kisses, thank you notes, follow-up calls, repeat business, and referrals from patients.

jective, objective, assessment, plan) notes on patient charts. Using templates not only organizes the patient visit by standardizing it by service rendered, it minimizes nonreimbursed documentation time and makes training pharmacy students and residents

much easier. Students and residents can be trained in the use of these templates in just a day or two and they can perform consultations expertly by the end of their rotation.

Although MTM services are affiliated with Mayo Clinic’s outpatient pharma-

We Want Your Pearls Do you have an interesting practice pearl you’d like to share? If so, send it to smtilyou @mcmahonmed.com.

Pearls should: • Focus on a clinical or operational problem at your institution, with tips (“tricks of the trade”) on how to manage the problem via an innovative system or strategy

cy, they are performed on an outpatient basis in physician exam rooms, not in the pharmacy. This has been advantageous because it promotes a collaborative practice between pharmacists and physicians. Charges are calculated using a formula that is based on the MTM current procedural terminology (CPT) codes and is designed to cover costs. We have gotten tremendously positive feedback from patients, evidenced by reactions we get after the service has been performed—surprise that pharmacists know so much, hugs, kisses, thank-you notes, follow-up calls, repeat business, and referrals from patients. Our initial MTM program targeted pharmacotherapy/polypharmacy patients. Then shortly after, we added liver and kidney transplant patients, and then bariatric surgery patients and others (Table). We also are planning to expand the service into other clinical areas. and we encourage physicians to send us any medication-related issues for which they don’t have time or with

•O ffer insights that are not widely known, understood or published •E xplain why the pearl should be implemented on a widespread basis •N ot exceed 1,000 words Readers whose Practice Pearls are accepted for publication will be paid a $100 honorarium.

which they need help. I am convinced that most physician specialties can use the help of pharmacist expertise in one form or another because our skill sets and training are synergistic.

Overall feedback from patients and physicians has been very good. Some physicians are unsure or don’t refer.

That is natural, and we will keep trying to convince them to try our services. But feedback from surveys and personal communication feedback has been very favorable from other providers (physicians, nurses, physician assistants) at the clinic. We try to have ongoing communications with many physician groups throughout the Mayo Clinic regarding either initiation or expansion of MTM services. Additionally, we have developed many professional relationships with physicians in the clinic, and by and large the physicians are fairly honest in their assessments (good and bad) of the service.

This helps the service evolve to serve both them and their patients better.

Pharmacy Practice News • March 2012

Technology 55

Informatics

Hospital Record Systems: A Failure To Communicate?

E

lectronic medical record systems in hospitals are spreading, but seldom communicating.

“It’s a huge problem,” said Richard P. Dutton, MD, MBA, executive director of the Anesthesia Quality Institute, an offshoot of the American Society of Anesthesiologists. Lack of integration across hospital departments increases the cost of care; results in duplicate tests; reduces billing; and can undermine compliance with insurance, regulations and quality guidelines such as those from the Surgical Care Improvement Project, experts said.

Installing electronic record systems incurs substantial capital cost and requires additional personnel, said Ronald A. Kahn, MD, professor of anesthesiology and surgery at Mount Sinai Medical Center, in New York City. The three main obstacles, he said, “are cost, cost, cost.” A 2009 study found that only 1.5% of U.S. hospitals had a comprehensive electronic record system across all major clinical units, with an additional 7.6% possessing a basic system in at least one clinical unit (N Engl J Med 2009;360:1628-1638).

The anesthesiology department is particularly in need of integrated digital medical records “because we care for all kind of patients, from neonates to nonagenarians,” Dr. Dutton said. “We have to interface with multiple systems.” Yet, anesthesiology has been the “last part of the hospital to get touched by this.”

No System Is an Island Jesse M. Ehrenfeld, MD, MPH, assistant professor of anesthesiology and biomedical informatics and director of Perioperative Data Systems Research for the Department of Anesthesiology at Vanderbilt University Medical Center, in Nashville, Tenn., said that “in spite of some recent progress in moving toward the adoption of common, interoperable standards, the notable lack of integration across EHR [electronic health record] systems remains a problem for anesthesiologists and other clinicians who work across the perioperative environment.”

According to Dr. Ehrenfeld, lack of integration causes inefficiency, undermines clinical decision support and increases chances of data entry–related mistakes.

Such failure to communicate “can be downright dangerous.” For example, a patient who is allergic to penicillin might have the allergy noted only in a hospital EHR, without the information transferring to the anesthesia information management system. The result would be that the operating room team would not have this needed information. “Lack of EHR integration, in my mind, is a clear patient safety issue,” Dr. Ehrenfeld said.

Dr. Kahn, however, said integration of

EHR systems was not as important as having electronic medical records in the anesthesia department. “Anesthesia is a different work environment. The record we require is much different.”

Outside Looking In Another pressing problem, experts said, is a lack of integration between hospitals and outside clinicians. “The inability to transfer information from one

provider or clinic to another represents a cumbersome reality that all patients face when they see physicians in more than one practice setting. This lack of integration leads to redundant forms, questions, time and effort, and in some cases a bad game of telephone, in which key pieces of information are incorrectly transmitted.”

Robert Rowley, MD, chief medical officer for the EHR company Practice Fusion, in San Francisco, said that stan-

dards are not yet mature. “There is no single easy way to connect all players,” Dr. Rowley said. “Many locally installed systems don’t have the ability to connect with hospitals without an upgrade, which means additional cost.”

Make Demands Dr. Dutton said that the connection between the hospital and the providers

•

see RECORD SYSTEMS, page 58

56 Technology

Pharmacy Practice News • March 2012

Informatics

Kiosks May Be Key to Improved Medication History Capture Washington—Touch screen computer kiosks may help patients better recall their medications than paper charts or sitting in front of a clinician or pharmacist, two recent pilot studies suggest.

The kiosk results, paired with a drug review by a health professional, could lead to more accurate medication reconciliation practices.

The studies, presented last fall at the American Medical Informatics

Association Annual Conference, found that most patients with diabetes who tried such kiosks found them easier to use than filling out paper charts, even if they took longer to complete and even if the patients rarely or never used computers. The kiosks also were found to detect incidences of hypoglycemia better than a standard medical interview.

The work was funded by the Agency for Healthcare Research and Quality.

The investigators, from Emory University School of Medicine and Mercer University College of Pharmacy and Health Sciences, both in Atlanta, designed and developed the computer kiosk program, which they dubbed My Medication Helper, as an aid for lowliteracy patients with diabetes. The goal of the program was to help those patients report current medications, adherence to medications and hypogly-

Presents

Bridging the gap between the hospital and post-discharge care

Volume 1 • Number 1 • Winter 2012 A Supplement to Pharmacy Practice News

In This Issue

Embracing Rather Than Fighting Specialty Pharmacy

Ask the Expert

4

I

nfusion centers and other community practice sites that manage patients post-discharge share a common lament: Why do so many of those patients often struggle with the basics of care after they leave the (usually) safe confines of the hospital?

One glaring contributing factor is a lack of collaboration between hospitals and the community sites of care, according to Dennis Street, RPh, lead pharmacist at Mercy Home Infusion, which is affiliated with Mercy Hospital in St. Louis. “It’s a big enough transition to get patients out of the hospital, much less getting them out of the hospital and starting them on

Tips for partnering with managed care organizations, plus cost-saving strategies.

Q&A

5

Stephanie Holliday, PharmD, discusses REMS, self-administered oral chemotherapy and other hot topics in specialty pharmacy.

Opinion

6

N. Lois Adams, BPharm, on reining in the high cost of drug therapy.

Operations & Mgmt

9

Aetna Specialty Pharmacy, other providers offer drug adherence strategies.

Educational Review

18

Antimicrobial Efficacy

Policy

24

Patient assistance programs, plus a projection that specialty pharmacy drug spending will soar by 26.5% in 2012.

Building a Better Care Transition: What Works Now

•

University of Illinois clinical staff pharmacist Nehrin Khamo, PharmD, educates a patient on self-injection techniques.

A

lthough many health-system pharmacists bristle at limited distribution networks and other restrictions placed on some specialty medications, more and more of them are deciding to embrace specialty pharmacy rather than fight it, and thus join the ranks of smaller and larger specialty operations providing that segment of care.

To offer insights into this new source of competition, Specialty Pharmacy Continuum profiled three hospitals that are bolstering their presence in the market: The University of Illinois Hospital and Health Sciences System, Chicago; Fairview Pharmacy Services, Minneapolis; and Duke University Hospital, Durham, N.C. The health systems cite revenue loss as one reason for their recent efforts: they simply can’t afford to continue seeing patients siphoned off to specialty pharmacy providers. But finances aren’t the only motivation; another key driver is the need to provide for patients’ total health needs across transitions of care, as the era of accountable care organizations and payments based on quality standards gets under way.

For Kyle Skiermont, PharmD, director of specialty infusion operations at Fairview Pharmacy Services, improving patient care is the No. 1 reason health systems enter or expand into the specialty pharmacy area. His operation, a part of Fairview Health Services, a large regional network of hospitals, already is well established as a

•

see EMBRACE, page 11

FDA Approvals Kalydeco approved for cystic fibrosis patients with CFR gene mutation.

See page 26.

see CARE TRANSITION, page 8

Tips for Surviving The TPN Shortage

T

hings have been heating up on the IV nutrition shortage front. Last fall, Baxter hosted the first-ever nutrition shortage safety summit, and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), which put together a task force to address the supply shortages, has been issuing frequent updates and guidances to help its members prioritize, substitute and manage the limited supplies they have.

But such regulatory and policy efforts only go so far in mitigating the effects of the shortage on patient care. Here are several practical strategies that home infusion centers are using right now to weather the storm.

•

see TPN SHORTAGE, page 10

The Book Page

A new quarterly publication from the editors and publisher of Pharmacy Practice News.

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

Our goal: to help foster high-quality, cost-effective treatment across the entire patientcare continuum.

To subscribe, visit pharmacypractice news.com

MedInfoNow Subscription

See page 27.

Bridging the gap between the hospital and post-discharge care

cemic episodes. Kiosks were placed near the registration desk of Grady Memorial Hospital’s Diabetes Center periodically from September 2010 to August 2011.

Physicians from Emory and a pharmacist from Mercer staff the diabetes center.

The kiosk featured a voice reading questions to the patient. It listed names of all diabetes medications in the center’s formulary and had photos of insulin bottles from which patients could select, as well as pop-up keyboards patients could use to enter data on medication adherence.

In one study, 19 patients (average age, 55 years) coming to the diabetes center were asked to use the kiosk and two paper forms to record medication history. Nearly two-thirds of the patients (63%) said they rarely or never used a computer. They took an average of seven regular medications and saw two to three health care providers.

According to the researchers, 79% of patients reported that the kiosk was easier to use than paper forms, and 89% said the kiosk was more helpful to their recalling medications than paperbased forms.

Another Kiosk–Clinician Face-off In a second study, 39 patients with diabetes were asked to complete three medication reports: the voice-enabled kiosk checklist, the American Pharmacists Association’s (APhA) standard form and a clinic-specific customized checklist.

These were compared with the patients’ paper medical charts and a gold standard medication history taken by a pharmacist.

Participants were diverse in education (44% had less than a high school education; 36% had at least some college); age (range, 32 to 84 years); and computer use (24% were frequent users; 68% rarely or never used computers). The average user time was 23 minutes at the kiosk, eight minutes for the custom checklist and seven minutes for the APhA model.

Most subjects (80%) reported the kiosk was easier to use. Compared with the gold standard, the kiosk was correct 79% of the time, ahead of the custom checklist (correct 68% of the time; P=0.01) and the APhA model (correct 62% of the time; P<0.001). The kiosk missed 12% of drugs, compared with the checklist (missed 8% of drugs), APhA forms (missed 18% of drugs) and the chart (missed 7% of drugs).

The kiosk detected hypoglycemia better than a standard medical interview, at a cost of increased false-positives. (In the charts, hypoglycemia questions were unanswered for 26% of patients.)

Researchers tried the kiosks because nurses and others were spending a lot

•

see KIOSKS, page 58

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2012/2013 Top 300 Pharmacy Drug Cards Jill M. Kolesar; Lee Vermeulen

McGraw-Hill, January 12, 2012 These cards are a fun, fast way to learn essential information about the top 300 drugs. They are essential for pharmacy school courses and NAPLEX® preparation.

Scan here for our complete catalog of medical books.

ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com.

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If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

2

Currents in Pharmacy Teaching & Learning Elsevier

Elsevier Health, 2012 This quarterly publication is devoted to the dissemination of high-quality, peer-reviewed scholarship relevant to all areas of pharmacy education. It endeavors to attract and publish manuscripts from a variety of disciplines and educational settings to promote excellence in educational research.

3

Fundamentals of Pharmacognosy and Phytotherapy, Second Edition

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

4

Manual for Pharmacy Technicians, Fourth Edition Bonnie S. Bachenheimer, ASHP

ASHP, August 30, 2010 As technicians are assuming more responsibilities and are taking on greater leadership roles, quality training material is increasingly important for new technicians entering the field, and current ones looking to advance. The best-selling Manual for Pharmacy Technicians helps technicians to master the practical skills and gain the foundational knowledge they need to be successful.

5

MedInfoNow Subscription

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Pharmprep: ASHP’s Naplex Review, Fourth Edition

Doody Enterprises, Inc., 2012

Through MedInfoNow’s customizable literature update service, you can now easily and efficiently stay up to date with the medical literature published in your field. Since 2001, more than 70,000 health care professionals have been receiving weekly custom emails that introduce and link them to specialty-specific journal article citations and abstracts published in Medline®, the premier index of biomedical literature, as well as reviews of important new books in their specialty. So make the power of the Internet work for you. Subscribe to MedInfoNow today.

Lea S. Eiland; Diane B. Ginsburg ASHP, May 10, 2011 Using real patient cases accompanied by questions that address all NAPLEX® competency statements, the new fully updated fourth edition of PharmPrep: ASHP’s NAPLEX® Review, gives you the flexibility to review information by specific disease state and provides 78 sample cases, as well as calculations and law review sections. As drug therapy becomes more complex, PharmPrep has continued to update and revise cases so they reflect contemporary clinical practice.

7

The APhA Complete Review for Pharmacy, Ninth Edition

American Pharmacists Association APhA, January 15, 2012

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

8

Understanding Pharmacy Calculations, Second Edition

Teresa A. O’Sullivan APhA, March 1, 2012 Written in easy-to-understand language and emphasizing practical calculations that pharmacists do every day, this revised and updated edition guides student pharmacists through the sometimes overwhelming introduction to the subject.

PPN0312

58 Technology

Informatics

KIOSKS continued from page 56

of time conducting medical histories, according to Gina J. Ryan, PharmD, coauthor of the studies and clinical associate professor at Mercer whose practice site is the diabetes center. Only about half of patients would bring in their medication bottles or an accurate medication list.

“We think it’s definitely worth more research and more refining,” Dr. Ryan said. “The kiosk can be a great teaching tool, and, with repeated exposures, help patients learn their medications.”

Researchers have pulled the kiosks while they wait for additional funding.

VA Medical Center’s Experience Kiosks also have become part of the landscape at the Portland Veterans Affairs (VA) Medical Center in Oregon, where researchers have been using their own check-in kiosks, called the Automated Patient History Intake

Pharmacy Practice News • March 2012

An Educational Tool as Well

C

omputer kiosks can be used for patient education, too. Rhode Island researchers recently tested the technology’s utility as an add-on to two other teaching tools: pharmacist counseling of patients and paper documents, including drug labels and package inserts.

Researchers placed a computer kiosk near the cashier in a semi-private area of a community pharmacy in Charlestown, R.I. The kiosk was programmed to bring viewers to the National Library of Medicine (NLM) MedlinePlus Web site, which contains comprehensive information on prescription and nonprescription drugs, including reasons for prescribing the drug, how to use the drug, precautions, dietary issues, side effects, what to do in the event a dose is missed and storage conditions.

The team hired pharmacy students to serve as research assistants; they sat near the kiosk and invited patients to learn more about the medications they purchased. Following a prepared script, the students offered to guide patients through the Web site. The kiosk software prompted patients through survey questions and to the NLM Web site. Patient interactions were studied over a four-week period in the fall 2009.

During the study, 198 pharmacy patients viewed the Web site and completed the survey. The majority (63%) were women and most (48%) were between 46 and 65 years old. About 45% of patients reported receiving counseling or information from the pharmacist that day; 86% said they ask their physicians for medication information when needed, 38% reported asking family and friends, 87% reported reading written materials and 62% reported seeking information on the Internet.

Only 8% of participants had used the NLM Web site before but 92% said they would use it again. The average encounter with the kiosk was four minutes, six seconds. Most participants had access to the Internet in their homes. Results were published in November in the Journal of Consumer Health on the Internet (2011;15:347-360).

“I think it was a no-brainer,” said Tamar Lasky, PhD, an epidemiologist who designed the study. “People like seeing things on an electronic screen more than getting paper with fine print.” They also liked having contact with the pharmacy students, said Dr. Lasky, president and owner, MIE Resources, Kingston, RI. “It made the pharmacy more of an experience.”

—K.B.

RECORD SYSTEMS continued from page 55

should be seamless. “It’s a tough nut to crack,” he said. National integration may be needed. Dr. Dutton said that there is a trend in hospital purchasing toward enterprise systems (from vendors such as Epic, Cerner and General Electric), in which all systems are seamlessly integrated and acquired from a single vendor. However, his prediction is that the

Device (APHID), in seven primary care clinics since 2008.

APHID allows patients to review the names, dosages, frequency and pictures of their medications before their appointments. The software then inserts the medication list and patient responses into the electronic health record as a text note for clinicians to review during appointments.

During a 2007 pilot of the kiosks, VA researchers found that although more than 50% of patients reported being unfamiliar with computers, 75% indicated that the kiosk was easy to use; 67% said it was easy to navigate. Most patients

(94%) thought the medical information was easy to understand, and 67% believed the program improved their medication recall (J Am Med Inform Assoc 2009;16:300-304). Yet despite these responses, researchers found that adoption of the technology across their practice sites varied greatly, in large part due to the attitudes of mid-level management.

Although more than 90% of patients can use the kiosks, the average use is about 50%, and the output is documented in about 70% of kiosk encounters.

A survey of primary care providers in the clinics showed that although most providers agreed that the kiosks represented an important safety intervention, 43% did not believe they had the necessary resources to manage dis-

future lies in buying individual components to take advantage of evolution in different technological niches. “It’s better to have an umbrella where you can plug in and out,” Dr. Dutton said.

a hospital adversely affected by gaps in EHR integration. The fact that there is no agreed-upon standard for communicating allergy information, for example, cuts across multiple care settings. And pharmacy organizations cannot even come up with agreement on what a drug is, he noted. There also is a lack of agreement on how to represent any drug between EHR systems.

“A group from NCPCP has proposed an allergy standard to the Office of

Pharmacy Perspective John Poikonen, PharmD, director of clinical informatics at University of Massachusetts Memorial Medical Center, in Worcester, said that anesthesiology departments are not the only areas of

crepancies. Approximately one third felt the technology “takes a lot of mental effort” and thought work schedules did not easily accommodate routine use of the kiosks. Others thought there weren’t incentives to using the kiosks, or the results were challenging to process, according to a report on the data, which the investigators say has been accepted for publication in Informatics in Primary Care.

Blake Lesselroth, MD, assistant professor of medicine and medical informatics for the Portland VA, and lead author of the studies, said they are working through these barriers. Although some providers think the kiosk is too timeintensive a transaction, he noted, the average patient–kiosk interaction is just 4.5 minutes: “It is totally feasible, from a workflow perspective, from a patient utilization perspective and from a care perspective.”

Brian Wilcox, PharmD, pharmacy informatics program manager for the VA center, said the kiosks help patients recall questions or issues about drugs they otherwise might forget in a face-to-face encounter. The outpatient setting “gives patients a lot of opportunities to wait,” he said. The kiosk “gives them a task to do and tells patients, ‘We care about you and what you’re thinking, and we want to know your input on your medication therapy.’ Intuitively, I would think that it would increase patients’ satisfaction.”

Added Gordon Wong, RPh, clinical applications coordinator for the project, “Patients are feeling more comfortable with kiosks as a way to deliver information. It gives them a chance to think about their medications, and to use their waiting room time in a productive manner.”

Dr. Lesselroth said another version of the kiosk questionnaire offered to inpatients on a tablet computer has gathered clinical information about drugs like diuretics, hypertensives and narcotics they otherwise might not have.

The group plans to study the accuracy of data collected by the kiosks, and they’re working to roll out the technology to other VA centers nationwide.

—Karen Blum

National Coordinator for Health Information Technology,” Dr. Poikonen noted. “The National Library of Medicine has an exceptionally robust drug name standard, RxNorm, that has yet to get traction with pharmacy organizations and vendors. It is the hope that these become part of Meaningful Use, phase II in order to get organizations and vendors to adopt these naming standards for better interoperability.”

—George Ochoa

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

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.

Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients.

• Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%).

Reference: 1. Market Rx 2010.

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

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on previous page.

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850.

US Patent Nos: 5,258,510 and 5,753,677.

Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

©2011 Otsuka America Pharmaceutical, Inc.

February 2011

0711A-2015C