The January 2012 Digital Edition of Pharmacy Practice News

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pharmacypracticenews.com

Volume 39 • Number 1 • January 2012

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Programs Bridge Gap In Care Between The Hospital and Home New Orleans—The transition between the hospital and the patient’s home is notorious for discontinuities that too often result in rehospitalization. According to published data, one in five discharged Medicare patients are readmitted within 30 days, with adverse drug events (ADEs) the major culprit in sending patients— especially older Americans—back to the hospital (Ann Intern Med 2003;138:161-167; N Engl J Med 2011;365:2002-2012).

In 2013, Medicare will begin to penalize hospitals that have high rates of preventable readmissions. Hospitals, strongly averse to the prospect of lost income, are paying more attention to this tenuous phase of patient recovery.

Increasingly, they are enlisting pharmacists to fill some of the gaps in care that can lead to

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see BRIDGE, page 18

Demonstration Project Cuts Some Risk From Hydromorphone Use

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demonstration project at nine hospitals in southern Pennsylvania, aimed at improving the safe use of hydromorphone through a combination of educational programs, computerized order entry improvements and enhanced prescribing oversight, has yielded mixed results, according to its developers.

The nine-month project, developed in part by the Institute for Safe Medication Practices (ISMP), found that practitioners’ knowledge about prescribing differences between hydromorphone and morphine improved, and the number of patients who required a rescue agent or rapid response call decreased. But the percentage of cases in which concomitant medications contributed to adverse drug reactions (ADRs) increased from 20% before the initiative to 41% afterward.

“Education is not a long-term strategy to effect change,” said Matthew Fricker, RPh, ISMP’s program director, “but it’s a starting point.”

•

see HYDROMORPHONE, page 34

in this issue Up Front

Medication Safety Drug mishaps remain a leading cause of ER visits.

6

Practice Models

10

Leadership in Action Ernie Anderson Jr., MS, RPh, on doing more with less.

14

Clinical

Hem/Onc Pharmacy New drug for advanced breast cancer ‘practice-changing.’

26

Critical Care Can bar-code scanning fix the ‘black hole’ of drug safety—the operating room?

30

Technology

Guest Editorial The case for casting a wider BCMA net.

48

Informatics The growing appetite for health care apps.

A closed-loop med management system streamlines investigational drug handling.

As supply gap continues, caregivers struggle to meet basics of feeding

Y

Operations & Mgmt Reducing heart failure readmissions.

Parenteral Nutrition Shortage Hits Patients, Providers Hard ears of chemotherapy, radiation and surgery for a childhood cancer left 41-year-old San Francisco health planner Frances Culp with gastrointestinal damage and malabsorption issues. To remedy this, in 2005, Ms. Culp began receiving nightly infusions of home total parenteral nutrition (TPN) to provide her body with enough calories and nutrients to keep her not only alive, but thriving.

The change was remarkable. Ms. Culp felt stronger and became more active than she had been in years. But in spring 2011, she learned that there was a shortage of the vitamins that form a key component of her nutritional support.

“I can absorb some vitamins orally, so I tried to make it work, but my hair has been falling out in clumps, my weight is way down and my energy level has dropped dramatically. The effects of malnutrition have really started to show,” Ms. Culp said. “Other ingredients are now going into shortage as well. There is no ingredient in TPN that I can do

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51 54

Educational Review

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations See insert after page 28.

see TPN SHORTAGE, page 8

Opioid Gene Variants Linked To Cancer Survival in Women

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ounting laboratory and epidemiologic data suggest a link between opioid exposure during cancer surgery and metastasis of, and eventual death from, the disease. Now, a major genetics study has turned up some of the most compelling evidence yet for a connection between the pain killers and malignancy—even beyond the operating room.

T h e n e w wo r k , by researchers at the University of North Carol i n a, i n Ch ape l H i l l , found that breast cancer patients with variants of the µ-opioid receptor that make their cells less responsive to the analgesic are as much as fourfold less likely to die of

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see GENES, page 22

New Products FIRST® ‘Magic Mouthwash’ Compounding Kits now available.

EXPAREL™ from Pacira Pharmaceuticals, Inc.

See page 32.

See page 32.

6 Up Front

Pharmacy Practice News • January 2012

Medication Safety

Drug Mishaps Still a Leading Cause of ED Visits D espite persistent medication safety efforts, nearly 100,000 people aged 65 and older are hospitalized on an emergency basis in the United States each year for adverse drug events (ADEs), nearly two-thirds due to unintentional overdoses, according to a study in The New England Journal of Medicine (2011:365:2002-2012).

The researchers found that four medications or medication classes accounted

for more than two out of three emergency admissions, with warfarin leading at 33.3%, followed by insulins (13.9%), oral antiplatelet agents (13.3%) and oral hypoglycemic drugs (10.7%).

To carry out the study, the investigators, from Emory University and the Centers for Disease Control and Prevention, both in Atlanta, examined 2007-2009 data from the National Electronic Injury Surveillance System-

Cooperative Adverse Event Surveillance project, identifying 5,077 cases that met the study criteria. Extrapolating from the sample number, they estimated 99,628 annual ADE-associated emergency hospitalizations among adults aged 65 and older. Nearly half of the hospitalized patients were at least 80 years of age.

Asked to comment on the study, Nicole Acquisto, PharmD, BCPS, emer-

gency medicine clinical pharmacy specialist at the University of Rochester Medical Center, in New York, said the medications reported “are what you would expect to cause the most harm in this patient population. Many of these agents have a narrow therapeutic window, require close monitoring and dose adjustments and have several drug interactions associated with them.”

Dr. Acquisto noted that “elderly

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Pharmacy Practice News • January 2012

Up Front 7

Medication Safety patients often have several providers prescribing medications, leading to a higher potential for drug interactions or additive adverse effects. Furthermore, they have a higher likelihood of acute changes in health that can affect their renal function, oral intake and use of over-the-counter medications that could lead to medication-related adverse events and hospitalizations.”

ISMP’s Take Michael R. Cohen, RPh, MS, ScD, president of the Institute for Safe Medication

‘There is some [patient] counseling [on safe medication use] that goes on, and certainly there are individual pharmacists who really take this seriously. But … nationwide, this is not something that we’ve bought into in community practice.’

—Michael R. Cohen, RPh, MS, ScD Practices (ISMP), also was not surprised at the problematic medications identified in the study. “They almost exactly match

our list of community pharmacy highalert drugs,” Dr. Cohen said.

To help patients avoid ADEs, Dr. Cohen

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said ISMP has developed a series of highalert medication safety sheets, each containing a checklist of the top 10 tips that pharmacists can use during counseling.

“They really help pharmacists not to overlook any key points when they’re educating patients,” he said.

But finding pharmacies willing to help ISMP expand its patient education project has been a challenge, he said. “I think state pharmacy boards should mandate that this be done,” Dr. Cohen said.

“Isn’t this a public health issue? Isn’t that where state board efforts should be directed? And it isn’t being done.”

Dr. Cohen said ISMP had spoken to state pharmacy boards and to pharmacy organizations, “and to some extent, there is some counseling that goes on, and certainly there are individual pharmacists who really take this seriously and do it on their own. But, no, nationwide this is not something that we’ve bought into in community practice.”

In The New England Journal of Medicine study, researchers underscored the need to focus on improvements most likely to have “sizable, clinically significant and measurable effects, such as improving the management of antithrombotic and anti-diabetic drugs.” Both are areas in which clinical pharmacists excel.

Barriers Cited But pharmacists often face barriers, including a lack of access to patient health records, pointed out Victor Cohen, PharmD, BCPS, clinical pharmacy manager at Maimonides Medical Center Department of Emergency Medicine, and Samantha P. Jellinek-Cohen, emergency medicine clinical pharmacy specialist at Beth Israel Medical CenterPetrie Division, both in New York City, in a joint comment. “This information should be readily available to all health care providers,” they noted.

One solution, they suggested, would be to include geriatric education in training programs for all health care providers engaged in managing elderly patients, “with a particular emphasis on age-related physiologic changes and how they can impact medication use.” Another would give pharmacists a greater role as “physician extenders,” allowing them more opportunities to conduct home visits or see patients in the ambulatory clinic or emergency department (ED) for see DRUG MISHAPS, page 34 

8 Operations & Management

Pharmacy Practice News • January 2012

Drug Supply

TPN SHORTAGE

an enormous amount of time trying to find products, paying out-of-contract prices for the products, and so on,” Mr. Mirtallo said. “And it takes away from clinical time because you really have to have a team working on this issue.

You can’t just have one person saying, ‘Use this product until the shortage is resolved.’ You need input from dietitians, nurses, physicians, compounders—everyone involved.”

continued from page 1

without. It’s got every ingredient I need to survive. I cannot have bits taken out of it and stay a productive person with any kind of quality of life.”

Unfortunately, that’s exactly what’s happening for Ms. Culp and many other PN patients across the country. A nationwide shortage of virtually every component of IV nutrition—from multivitamins, IV fat emulsions and amino acids to concentrated electrolyte and mineral injections—has left hospitals and home PN providers scrambling to find enough of the needed nutrients to keep their patients alive and healthy.

“About 100,000 people in the country receive home parenteral nutrition, and at any point, about 5% of the hospital population is getting their nutrition intravenously,” said Mark DeLegge, MD, global medical director for Baxter Healthcare Corporation and former professor of gastroenterology and hepatology at the Medical University of South Carolina, Charleston. “In the pediatric unit, the percentage is higher—about 20%, and in the neonatal unit, pretty much 100% of the patients receive IV nutrition. These are all lifesaving therapies.”

Every Component Affected Over the past two to three years, an increasing number of drug shortages have affected various components of the carefully balanced solutions these patients require. “It really started in spring 2010, beginning with fat emulsions and then progressing to every component of IV nutrition,” said Jay Mirtallo, MS, RPh, associate professor of clinical pharmacy at the Ohio State University College of Pharmacy, Columbus, and executive director of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), which put together a task force to address the supply shortages and has been issuing frequent updates and guidances to help its members prioritize, substitute and manage the limited supplies they have.

The shortage was one of several factors that prompted Baxter to sponsor the first-ever nutrition shortage safety summit in September. The meeting included representatives from the FDA, the Institute for Safe Medication Practices, the American Society of Health-System Pharmacists (ASHP), the National Home Infusion Association and industry representatives.

The factors behind the shortage are similar to those that have led to the ongoing supply crisis involving chemotherapy drugs: consolidation of industry, a limited number of suppliers, low supplies of raw materials and low profit margins on many of the products involved.

The shortage has left hospitals and

Suppliers Scrambling To Respond

‘In the pediatric unit, the percentage [of patients needing TPN] is ... about 20%, and in the neonatal unit, pretty much 100% of the patients receive IV nutrition. These are all lifesaving therapies.’

—Mark DeLegge, MD

More information on the parenteral nutrition shortage is available from A.S.P.E.N. at http://www.nutritioncare.org/Index.aspx?id=6068 and the Oley Foundation at http://oley.org/PN_Product_Shortages.html.

home providers facing impossible choices. “We’re having to ration our nutritional components, diluting product and putting people on oral therapies when they really should be on IV,” Mr. Mirtallo said.

In a hospital setting, for example, neonates receive top priority for IV nutrition because they have no reserves. “But what if there’s a baby with a cardiac problem who is not doing well and needs calcium?” Mr. Mirtallo asked. “If the hospital has a limited supply of the product, they may need to take the calcium from one baby’s nutritional IV because in the short term the damage is not as drastic as not getting calcium for the heart. But a baby needs calcium for bone growth and stability, so this really isn’t an acceptable alternative.”

Community Hospital Hit Hard At Community Regional Medical Center in Fresno, Calif., neonatal intensive care unit (NICU) pharmacist Tsung-Chi (George) Lien, MS, PharmD, BCPS, has been juggling shortages of sodium phosphate, potassium phosphate, calcium gluconate and zinc sulfate. “We had a shortage of potassium phosphate several months ago; now we have that in stock and there’s a shortage of sodium phosphate. Calcium glu-

conate was back ordered for months, but now we have a temporary supply in stock. Zinc sulfate went on back order several months ago and we can’t get more, so we switched to a different product. It’s very complicated.”

With fragile NICU babies, Dr. Lien and his team are constantly calculating tradeoffs. “A shortage of potassium phosphate meant that we had to use sodium phosphate to provide adequate phosphorus in parenteral nutrition.

However, with excess sodium ion in the solution, if the baby’s sodium level is otherwise normal or mildly elevated, the increased sodium supplement may result in some consequences like increased water retention which could lead to pulmonary and systemic edema.”

So far, Dr. Lien counts himself lucky: Community Regional hasn’t seen any serious consequences as a result of the shortage. “But it’s putting an enormous strain on the entire pharmacy staff,” he said. “We have to communicate very diligently with the nurses and physicians to make sure that everyone’s aware which products are on shortage, and modifying the orders for babies that can’t yet tolerate oral feeds.”

That stress is hitting pharmacists and other clinicians who deal with PN all across the country. “They’re spending

Michael Fadeyi, PharmD, a director of clinical pharmacy for national IV nutrition supplier American Outcomes Management, said that he and his colleagues are now frequently buying higher concentrations of macronutrients like amino acids, and then diluting them to maximize supply. But even then, that’s often not enough. “We had a patient, a young man with complications from leukemia treatment, who was severely dehydrated,” Dr. Fadeyi said. “He was on IV nutrition but we were about to run out of potassium phosphate. We informed the physician a week before we ran out, and he discontinued the drug after the end of that week and placed the patient on oral therapy. He then transferred the young man from his home in the Dallas area to MD Anderson Cancer Center in Houston for a continuation of his therapy, because we couldn’t get what he needed anywhere that allowed him to stay home.”

PN suppliers and patient advocates, like the Oley Foundation, are urging support for U.S. Senate Bill 296 (SB 296), the Preserving Access to LifeSaving Medications Act, introduced by Sens. Amy Klobuchar (D-Minn.) and Robert Casey (D-Pa). SB 296 directs the FDA to address drug shortages by requiring manufacturers to notify the FDA about manufacturing problems or when a drug is to be discontinued. The bill also requires that the FDA maintain an online list of drugs in shortage situations, and revises the agency’s definition of “medically necessary.”

Time is of the essence, Mr. Mirtallo stressed. “Yes, generic manufacturers are now ramping up production and beginning to make sure inventories are adequate,” he said. “But that will take years. What about patients who need to get adequate nutrition now?”

One possible source of products: Europe, where no apparent shortage exists. “I’ve traveled there and none of those professionals have any drug shortage issues,” Mr. Mirtallo said. “They are quizzical, asking why we have this problem when they have more than adequate supplies.” But since the Europeans’ products use different components that are not generically equivalent to U.S. products, current regulations would

Pharmacy Practice News • January 2012

Operations & Management 9

Supply Chain

New AMA Policy Addresses Drug Shortages New Orleans—The American Medical Association’s (AMA) House of Delegates has introduced a policy backing existing measures to address what it is calling the “national public health emergency” of drug shortages. With the policy’s adoption at the AMA’s Semi-Annual Policy-Making Meeting in November, the association is lending its support to Congressional efforts that, if passed, would require manufacturers to provide six-month advance notification of any impending drug shortages.

Bona Benjamin, BS Pharm, director of Medication-Use Quality Improvement for the American Society of HealthSystem Pharmacists (ASHP) Practice Development Division in Bethesda, Md., said the AMA’s policy is a significant step toward resolving drug shortages.

“We are encouraged by the AMA’s support, which sends a strong message about the importance of this issue and lends strength to the collective efforts of others, including Congress, to resolve drug shortages,” Ms. Benjamin told Pharmacy Practice News. “It is a critical first step for Congress to pass legislation that requires manufacturers to report problems that may cause shortages to the Food and Drug Administration as soon as possible.”

Added Dr. Benjamin: “Will the bills that have been introduced eradicate drug shortages? Of course not. But advance notification is something that can be done in the short run and we know it will work. In November, the FDA said 101 shortages had been prevented in 2011 so far by voluntary advance notification.”

The AMA policy does not specify whether the association backs penalties for manufacturers who fail to provide adequate advance notice. AMA delegates at the meeting voted against a measure that would have penalized drug manufacturers that fail to remedy a shortage within 30 days (http://www.

ama-assn.org/amednews/2011/11/28/ prl11128.htm). Louisiana State Medical Society delegate K. Barton Farris, MD, told other AMA delegates that financial penalties would only discourage manufacturers from producing generic drugs.

However, Ms. Benjamin believes penalizing companies is necessary to ensure they abide by the rule.

“The ASHP supports penalties for failing to notify the Food and Drug Administration of interruptions in production, such as those included in H.R. 2245 by Rep. [Diana] DeGette [D-Colo.] and S. 296 by Sen. [Amy] Klobuchar [D-Minn.],” she said. Neither of these proposals had received Congressional approval at the time of this writing Ms. Benjamin added that “currently, manufacturers are required to notify the FDA six months in advance only of a decision to discontinue a sole source of medically necessary materials, but there’s no penalty for noncompliance.

The FDA needs this time to seek alternative sources and care providers need it to plan for patient care.”

AMA Supports Obama Plan For Battling Drug Shortage The new AMA policy states the association’s support for recommendations issued at the FDA’s 2010 Drug Shortage Summit. Participants there called for manufacturers to confidentially notify the FDA of factors that may cause shortages, such as an interruption in the supply of raw materials, and also called on the FDA to expedite approvals of manufacturing redundancies and of production of drugs in short supply.

The AMA policy also specifies the association’s “appreciation to the President of the United States for issuing an Executive Order intended to assist in mitigating ongoing drug shortages.”

President Obama’s Nov. 1 order mir-

rored the recommendations of Ms. Klobuchar’s proposed legislation in asking for advance notification, and like recommendations from the 2010 Drug Summit, ordered the FDA to expedite approvals for companies seeking to fill manufacturing gaps when shortages do occur.

The AMA’s policy, which had not yet been published online at press time, also calls on the FDA and Congress to require manufacturers to establish contingency plans for continuity of supply of “vital and life-sustaining medications and vaccines” and to avoid production shortages “whenever possible.”

The AMA recommendations would indeed help mitigate the drug shortage crisis, Ms. Benjamin said. However, she believes it is unrealistic to identify and address all the variables that contribute to shortages in the near future.

“The biggest challenge is the urgency of the situation and the perception that shortages have one predominant cause

‘We’re having to ration our nutritional components, diluting product and putting people on oral therapies when they really should be on IV.’ —Jay Mirtallo, MS, RPh

require the drawn-out process of a New Drug Application (NDA) with the FDA before such importation could occur. Mr. Mirtallo said

that A.S.P.E.N. is trying to work with the ASHP to advocate a change in the Klobuchar–Casey bill that would allow the FDA to permit importation of products from Europe that are not generically equivalent, but “therapeutically

that a single change could fix,” she said. “The factors influencing shortages are enormously complex, not completely understood and not likely to be resolved quickly.”

Ms. Benjamin said she is encouraged that some manufacturers and other stakeholders “have been forthcoming and candid in our consultations with them on shortages” and noted that Hospira had signed on in support of H.R. 2245.

In early December, the ASHP’s Kasey Thompson testified at a Capitol Hill hearing on drug shortages. He cited data from the Institute for Safe Medication Practices and other sources to illustrate that the shortages are causing adverse drug events, delayed treatment and cancelled procedures, all of which can compromise patient care.

—David Wild Ms. Benjamin reported no relevant conflicts of interest.

equivalent,” without an NDA. In the meantime, patients like Frances Culp and their caregivers wage daily battles against the latest shortages. Mr. Mirtallo’s advice to pharmacists coping with their own IV nutrition limitations: Be vigilant. “If you have to lower dosages, dilute or substitute, you need to monitor for the deficiency symptoms that are likely to occur,” he said. “If you don’t normally monitor certain lab parameters, like trace elements or vitamin levels, you need to start doing that in patients who aren’t getting adequate dosages.”

—Gina Shaw

10 Operations & Management

Pharmacy Practice News • January 2012

Practice Models

Pharmacists at Heart of HF Program Heart failure readmissions slashed via patient outreach efforts

W

hen the Centers for Medicare & Medicaid Services (CMS) announced a substantial new penalty for hospitals with high readmission rates among heart failure (HF) patients aged 65 years or older, Thomas Jefferson University Hospital took a proactive approach to lower its numbers. In November 2010, the Philadelphia institution launched a pilot program that uses the clinical skills of pharmacists to keep patients healthy and at home.

Although outcomes data from the initial 436 patients are still being analyzed, the HF program already has proven to be enough of a success that it has triggered the development of pharmacist outreach programs in several other disease states, according to Patrice Miller, MSN, MBA, vice president for clinical resource management, who oversees the program.

“It’s unique for the extent of our pharmacists’ involvement,” said Ms. Miller, who did extensive research before planning began. Impressed by Boston University Medical Center’s RED (ReEngineered Discharge) program, in which pharmacists call patients after discharge to discuss their medications, she recommended borrowing and building on RED’s concept. (The RED program reduced readmissions by 30%; Ann Intern Med 2009;150:178-187).

Immediately, Ms. Miller recruited another Jefferson executive to the multidisciplinary planning group—Brian G. Swift, PharmD, MBA, vice president/ chief of pharmacy and accreditation.

“When Jefferson’s leadership called on the pharmacy department to support the program, we were ready,” Dr. Swift said. “I knew that our pharmacists were well trained to provide services beyond their usual team roles.”

The low-cost program emphasizes educating patients and caregivers about each aspect of their condition and treatment, especially medications.

Inpatients keep a medication log and learn which prescriptions they should be taking and the correct time to take them. At discharge, a pharmacist reviews medications the patient will take at home, who to contact if they run out, how to reorder and which signs and symptoms should trigger a call to the physician.

“We always encourage patients to take ownership of their treatment,” Ms. Miller said. “We stress the risk of not taking a medication exactly as prescribed, and what problems can occur.”

The family is alerted to possible side effects and reactions.

Jefferson’s pharmacists make five fol-

low-up calls during the patient’s first 30 days at home, an unusually high number. “Involving our pharmacists in not only inpatient care but in postdischarge communication utilizes their expertise well,” Ms. Miller said. “With their clinical knowledge, pharmacists are able to further educate patients and reinforce their understanding about their medications. Another big benefit of pharmacists making these calls is that they review meds and address any clinical symptoms related to heart failure.”

Joanne Heil, PharmD, RN, BCPS (AQ Cardiology), director of Thomas Jefferson’s Advanced Practice Heart Failure/ Transplant Pharmacy department, said that pharmacists in the HF outreach program take an early and aggressive role in patient care. “Our approach is very different [from other programs] because we provide much of the initial education to patients and their caregivers,” she said.

“Up front, we see doctors’ orders to enroll the patients

and we activate them into the program.

We’re able to enroll patients into the program ourselves.” The pharmacists assess patients’ medication regimens, lab values, chest x-ray results and echocardiogram results. Based on these assessments, “we determine if the patient qualifies for our program. Our pharmacists are also making the follow-up calls and intervening on behalf of the patient, if need be. Most programs have nurses doing all of this,

except for medication education.”

Pharmacist Activities During discharge sessions, pharmacists discuss diet, activities and other at-home factors. Each patient gets a seven-day pillbox. After discharge, pharmacists call each patient on days 2, 7, 14, 21 and 30. They confirm upcoming scheduled doctor’s visits, review all discharge instructions and check patients’ understanding of their current medication regimen, including adherence to time and dosage instructions.

Dr. Heil coordinates pharmacists’ calls and questions to patients. “We all learned how to do a

•

see HF OUTREACH, page 12

‘Medication-related problems, including errors and nonadherence, are common as patients transition between care settings. Pharmacists are ideally suited to work with patients and other health care providers to prevent these drug therapy issues.’

—Cynthia Reilly, BSPharm

Main Contributors to Increased 30-Day Readmission Rates Poor communication among health care providers between sites Systemic flaws in discharge process

Inaccurate medication histories and reconciliation

HOSPITAL READMISSION Lack of plan for appropriate medical follow-up after discharge

Deficiencies in patient self-care education

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The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in one subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in one subject (in PI), and myocarditis in one subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP). *CIDP=Chronic inflammatory demyelinating polyneuropathy; PI=Primary immunodeficiency; ITP=Idiopathic thrombocytopenic purpura.

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12 Operations & Management

Pharmacy Practice News • January 2012

Practice Models

HF OUTREACH continued from page 10

proper medication history and standardize our approach,” she said. “Jefferson pharmacists have substantial patient contact, so they’re comfortable with that aspect.” But for the HF program, a more challenging goal needed to be achieved—“attaining uniformity about how and at what level we provide medication education, so that patients understand,” she explained.

Dr. Heil updates her team on any

changes to the program and provides training if any further education is needed. Additionally, she is the liaison between pharmacists and pharmacy/ hospital administration.

Four rotating pharmacists work with the HF patients, full-time, for a week.

Three others rotate the weekend shift.

Since 2010, approximately 600 patients have enrolled. During a typical week, in late October, Dr. Heil’s team was covering 35 patients throughout enrollment, discharge and follow-up.

Program responsibilities are timeconsuming for pharmacists, she conceded. Postdischarge calls average three to 15 minutes, followed by documentation and evaluation of the phone discussion. Assessing and enrolling a patient can require 45 minutes.

Several times a week, pharmacists encounter a medication problem. “For

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• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients.

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

• For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.

• GAMUNEX-C is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent.

• Passive transfer of antibodies may confound serologic testing.

----------------------------ADVERSE REACTIONS---------------------------• PI – The most common adverse reactions ( 5%) with intravenous use of GAMUNEX-C were headache, cough, injection site reaction, nausea, pharyngitis and urticaria. The most common adverse reactions ( 5%) with subcutaneous use of GAMUNEX-C were infusion site reactions, headache, fatigue, arthralgia and pyrexia.

• ITP – The most common adverse reactions during clinical trials (reported in 5% of subjects) were headache, vomiting, fever, -------------------------INDICATIONS AND USAGE------------------------nausea, back pain and rash.

GAMUNEX-C is an immune globulin injection (human) 10% liquid • CIDP – The most common adverse reactions during clinical indicated for treatment of: trials (reported in 5% of subjects) were headache, fever, chills, hypertension, rash, nausea and asthenia.

• Primary Humoral Immunodeficiency (PI) • Idiopathic Thrombocytopenic Purpura (ITP) • Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

To report SUSPECTED ADVERSE REACTIONS, contact Talecris Biotherapeutics, Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

----------------------------CONTRAINDICATIONS-------------------------------------------------------DRUG INTERACTIONS---------------------------• Anaphylactic or severe systemic reactions to human • The passive transfer of antibodies may transiently interfere with immunoglobulin the response to live viral vaccines, such as measles, mumps • IgA deficient patients with antibodies against IgA and a history and rubella. Passive transfer of antibodies may confound of hypersensitivity serologic testing.

---------------------WARNINGS AND PRECAUTIONS--------------------• IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available immediately to treat any acute severe hypersensitivity reactions.

• Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output in patients at risk of developing acute renal failure.

• GAMUNEX-C is not approved for subcutaneous use in ITP patients. Due to a potential risk of hematoma formation, do not administer GAMUNEX-C subcutaneously in patients with ITP. • Hyperproteinemia, with resultant changes in serum viscosity and electrolyte imbalances may occur in patients receiving IGIV therapy.

--------------------USE IN SPECIFIC POPULATIONS -------------------• Pregnancy: no human or animal data. Use only if clearly needed.

• Geriatric: In patients over 65 years of age do not exceed the recommended dose, and infuse GAMUNEX-C at the minimum infusion rate practicable.

Talecris Biotherapeutics, Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1716

08939771/08939782-BS Revised: October 2010

example, someone may skip a water pill when they’re out all day at a social event, or say, ‘I’ll take it at night—I’m at work all day,’” Dr. Heil said. “We educate them about diuretics, explaining what can happen when they miss a day, the danger of fluid gain, that taking it near bedtime interferes with needed sleep, and the risk of taking one outdoors in hot weather: If they suddenly pass out, they’re back in the hospital!

We help patients find a specific time of day when they’ll have enough hours at home to take that water pill.”

A pharmacist following up discovered that a patient started on furosemide by her cardiologist in the hospital had previously been taking bumetanide, prescribed by her nephrologist. “We called to verify exactly what the cardiologist wanted the patient to take,” Dr. Heil recalled. “It wasn’t so much lack of communication between doctors—it’s the patient not understanding to stop a previous medication after getting home.”

Several elderly patients on diuretics live in two-story homes, with the only bathroom on the upper floor. Pharmacists arranged for commodes, through consulting with caseworkers.

Pilot study data are still being analyzed, according to Ms. Miller. Among the outcomes being tracked are number and type of pharmacist interventions and the impact of the program on hospital readmission rates. Initial results are “promising,” she noted— so much so, that the HF program’s approach to reducing hospital readmissions is being rolled out to patients diagnosed with pneumonia and with myocardial infarction.

Other Programs Document Success Other health-systems already have documented success with similar outreach programs. Wishard Health Services in Indianapolis, for example, documented the value of having pharmacists on the HF team in a study published in the Annals of Internal Medicine (2007;146:714-725). In the National Institutes of Health­­–funded trial, lowincome patients with HF were randomly assigned to a pharmacist intervention group (n=122) and a “usual care” group (n=192) that did not see a pharmacist targeting HF. The most marked effect was observed in emergency department visits and hospital readmissions—both occurred 19.4% less frequently (incidence rate ratio, 0.82; 95% confidence interval, 0.73-0.93) in patients seen by pharmacists.

Jim Young, PharmD, CPHQ, quality assurance/process improvement pharmacist for Wishard Health and a coauthor of the Annals study, praised the Thomas Jefferson University Hospital program. “It’s great to see a hospital

Pharmacy Practice News • January 2012

Operations & Management 13

Practice Models

‘I want more [clinical] involvement and gratification.

My attitude is “let’s move ahead and see what else we can do.” Machines can count pills!’

—Joanne Heil, PharmD, RN, BCPS

integrate pharmacists into a heart failure program and use their strengths to follow up on patients’ pharmaceutical care,” Dr. Young said.

The American Society of Health-System Pharmacists (ASHP) will feature Jefferson’s pharmacist outreach efforts in HF and other disease states in its online Practice Spotlight section. The hospital is being profiled because its clinical programs illustrate the type of innovation promulgated by the Pharmacy Practice Model Initiative (PPMI), a joint effort by the ASHP and the ASHP Foundation to promote practice change. The HF program was cited as an outstanding PPMI example at the Pennsylvania Society of Health-System Pharmacists’ 2011 meeting, where Jefferson showed a slide presentation about its efforts.

“Expanding pharmacist involvement in the transition of care is evolving here, as at many other institutions,” said Dr. Swift. “I’m happy to report that our pharmacists are playing an important role in our enterprise-wide efforts to improve patient care and reduce hospital readmissions. Pharmacists are uniquely qualified to provide much-needed services like the ones in our heart failure program.”

Colleagues concur. “Multidisciplinary programs, such as Jefferson’s Heart Failure Readmission Reduction Program, are essential to improving patient outcomes and the overall efficiency of health care,” said Cynthia Reilly, BSPharm, ASHP’s practice development division director. “Medicationrelated problems, including errors and nonadherence, are common as patients transition between care settings. Pharmacists are ideally suited to work with patients and other health care providers to prevent these drug therapy issues.”

The ASHP featured a story on another HF outreach program in the Dec. 1 issue of its AJHP News. The program, known as Steward Healthy Transitions, employs clinical pharmacists who conduct home visits and telephone follow-up calls to patients who are diagnosed at discharge with HF, acute myocardial infarction or pneumonia. Before the program began, hospital readmission rates for these conditions ranged between 5.56% and 32.5%.

Post-rollout, “we’ve seen re-admission rate for enrolled patients hold steady at about 5%,” Ernest R. Anderson Jr., MS, RPh, system vice president of pharmacy at Steward Health Care System, Boston,

said in an interview with Pharmacy Practice News. Moreover, “patient survey data show a high acceptance rate of the pharmacists’ recommendations (100% agree-

ing) and a 90% rate of changed behavior.”

Although the Healthy Transitions program “is still in its infancy,” Mr. Anderson added, “the data are encouraging and

should have a positive financial impact.”

For Dr. Heil, although such financial considerations are important, it is the clinical benefits of these outreach programs that truly resonate. “We’re getting much more involved in the full spectrum of a patient’s care, which is what we’re trained to do: assess, listen, talk, and educate,” she said. “I want more [clinical] involvement and gratification. My attitude is ‘let’s move ahead and see what else we can do.’ Machines can count pills!”

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14 Operations & Management

Pharmacy Practice News • January 2012

Leadership in Action

Leadership in Pharmacy: When the Going Gets Tough I just returned from a busy ASHP Midyear Clinical Meeting full of wonderful presentations. A theme of doing more with less became apparent in the presentations, but more so in private conversations. Colleagues admitted to having never worked so hard in their lives or having faced so many work challenges at once. One pharmacy manager told an audience that we have to set a good example and work a few Saturdays if we expect other managers to do the same. Many changes have driven the current climate, including reduced reimbursements via health care reform, new regulations concerning value-based purchasing, denials of reimbursement for hospital-acquired conditions and the difficult economy.

to those around us. Moral authority defines servant leadership where both

the leader and the follower serve one another and are guided by truth and shared values. The result is a high level of shared trust.

The Covey preface identifies the following four dimensions of servant leadership: 1. The essence of moral authority or conscience is sacrifice. This means looking outside of ourselves, thinking of others, approaching situations

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, Mass.

Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ steward.org.

Ernest R. Anderson Jr., MS, RPh

Work Smarter, Not Harder As leaders, we have all been told that we need to work smarter, not harder, and that we need to have balance in our lives. To foster that line of thinking, in this issue I begin a new series based on Robert K. Greenleaf ’s “Servant Leadership: A Journey into the Nature of Legitimate Power and Greatness, 25th Ed.” (Paulist Press, New York). Greenleaf is considered to be the inspiration of the servant leadership movement in the United States. Servant leadership entails leading people to greatness by determining how best to serve them.

In the foreword to the book, Stephen R. Covey writes, “The deepest part of human nature is that which urges people—each one of us—to rise above our circumstances and to transcend our common nature. If you can appeal to it, you tap into a whole new source of human motivation.” To sustain and surpass the present levels of motivation in pharmacy, we have to tap into our people in a way that will empower and inspire them to greatness. Empowerment requires great trust in those you supervise. It means not micromanaging or being a top–down dictator.

It means unleashing your employees’ creativity and problem-solving abilities, as well as enabling them to reach goals in ways that will exceed your expectations. Empowerment requires an external vision that will inspire internal motivation toward achieving the common goal.

The Core Within Covey has concluded that servant leaders differ from regular leaders by the way they live their lives according to an enduring sense of conscience, that moral code or compass that stands firm no matter the tide. The core values of honesty, respect, fairness and contribution provide an unwavering confidence

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

IMPORTANT SAFETY INFORMATION: • Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving Venofer ® (iron sucrose injection, USP).

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

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

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

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

Leading anemia management.™

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

Pharmacy Practice News • January 2012

Operations & Management 15

Leadership in Action open-mindedly and showing deep respect and love toward others.

Conscience is discerning: It tells you when to speak and when to hold your tongue. Conscience responds appropriately and positively to circumstances, and it encourages feedback because it is interested in truth.

2. Conscience inspires us to become part of a cause worthy of our commitment. The focus shifts

from what you want to what is being asked of you.

3.

Conscience teaches us that ends and means are inseparable. To appreciate the ends, we must be intimately involved with the means. We have to earn whatever we attain— wealth, power, respect—to

appreciate and preserve it.

4. Conscience introduces us to the world of relationships. Shared vision and values are necessary to forge ahead.

Vision identifies what we are trying to accomplish, but conscience tells us why we must accomplish it. Conscience is our empathy and sympathy in caring for others and building strong bonds of trust.

Moral Authority and Servant Leadership The ultimate authority is one that

The science behind the molecule behind the formulation...

The efficacy behind the safety behind the trust A distinctive hydrogel core...a long history of clinical excellence... over 260 million units*1 prescribed...and counting

There’s CORE Experience in every drop ™

Millions prescribed. Millions treated.

®

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

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

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

Reference: 1. Data on file. American Regent, Inc. Shirley, NY.

Please see brief Prescribing Information on adjacent page.

is granted by those who are led, and they grant it in proportion to their leader’s attitude and nature of service.

As Covey states, “Those who accept this principle will freely respond only to individuals who are chosen as leaders because they are proven and trusted as servants.”

Over the coming months, we will explore the value of servant leadership as a means of accomplishing greater productivity and achieving higher levels of satisfaction, passion and success.

16 Clinical

Pharmacy Practice News • January 2012

Practice Models Resources for Obstetric And Teratogen Information

In Obstetrics, Opportunity E

ach year, there are more than 6 million pregnancies in the United States that result in more than 4 million live births, and approximately 875,000 women experience complications of pregnancy. These figures indicate plenty of opportunity for pharmacists to use their specialized training in medication management to provide input on care, yet experts say there is a dearth of clinical pharmacists who specialize in work-

ing with obstetric patients.

The demand for obstetric care is a missed opportunity for pharmacists, whose first reaction to questions from pregnant patients is often to refer them to their obstetricians, according to Denise Ragland, PharmD, CDE, associate professor in the Department of Pharmacy Practice at the University of Arkansas for Medical Sciences College of Pharmacy, in Little Rock.

“In retail and community pharmacy, automatically referring the patient to her obstetrician is understandable, as there are legal and medical risks involved and pharmacists behind the counter don’t have access to the patient’s whole history. But clinical and health-systems pharmacists do [have access],” she said. “There is a tremendous potential for pharmacist input not only in areas specific to pregnancy, such

American Congress of Obstetricians and Gynecologists www.acog.org Organization of Teratology Information Specialists (OTIS) www.otispregnancy.org OTIS provides evidence-based, clinical information to patients and health care professionals about exposures during pregnancy and lactation.

Diseases, Complications, and Drug Therapy in Obstetrics: A Guide for Clinicians (Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

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

78.8

76.3

73.4

72.0

65.2

0

2.2

0.7

0

0

0.4

0

0

2.7

0

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

Gerald G. Briggs and Michael P. Nageotte, eds. Bethesda, MD: American Society of Health-System Pharmacists; 2009.

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

Drugs in Pregnancy and Lactation.

9th ed.

Gerald G. Briggs, Roger K. Freeman, and Summer J. Yaffee. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.

as hyperemesis gravidarum and patient counseling about medication safety and risk to the fetus, but also in areas where pharmacists already have specialized knowledge, such as anticoagulation, hypertension, infectious disease, diabetes and HIV medication management.”

Gerald G. Briggs, BPharm, FCCP, pharmacist clinical specialist at Women’s Hospital, Long Beach Memorial Medical Center in Long Beach, Calif., and clinical professor of pharmacy at the School of Pharmacy at the University of California, San Francisco, stresses the opportunities pharmacists have in obstetrics as part of multidisciplinary teams. “There are at least two areas for clinical pharmacists, inpatient care in hospitals and ambulatory care in clinics,” said Mr. Briggs, who is also adjunct professor of pharmacy practice at the University of Southern California and Washington State University, in Seattle. He noted two special considerations in managing drug therapy in obstetrics: Women metabolize drugs differently when they are pregnant, and the risk to the developing fetus must be balanced with the benefit to the mother.

Obstacles in Obstetrics If there is such a great demand for pharmacy practice in obstetrics, why aren’t there more specialists? According to Mr. Briggs, there is a general lack of awareness in the health care community. But pharmacists may be their own worst enemies with missing opportunities. “They may think that obstetricians, as specialists themselves, don’t really need pharmacists. And I agree: They don’t need pharmacists to help them deliver babies. But when more than 10% of pregnancies have complications that

Pharmacy Practice News • January 2012

Clinical 17

Practice Models are treated with drug therapy, yes, they do need pharmacist involvement.”

Mr. Briggs noted that managing drug therapy is labor- and time-intensive for certain conditions, such as diabetes and hypertension, and for certain therapeutic regimens, such as anticoagulation. Physicians do not necessarily have the time that pharmacists have for appropriate monitoring and dose adjustment, he said.

Nardin Samuel, BScPhm, with the Motherisk Program, Division of Clinical Pharmacology and Toxicology at the Hospital for Sick Children in Toronto, Canada, cited a lack of focus in academia. “Usually if there is education about obstetrics in pharmacy school, it’s one class, and it’s an elective.” She added that there is a paucity of data and lack of consensus with respect to medication management in pregnancy. “We do know that certain medications can be inherently harmful [to a pregnant woman or developing fetus], but if the focus is evidence-based care, often there isn’t sufficient information for any kind of formal conclusion. For some drugs, the data out there can be as little as one case study.”

Taking the Reins Pharmacists and pharmacy students who want to carve out a niche in obstetrics need to be proactive, Ms. Nardin said. “It’s the pharmacists who should be initiating this, going to their institutions and making their leadership aware of the need.”

According to Mr. Briggs, the onus is on clinical pharmacists to demonstrate their value in obstetrics, as it is in other areas of care, by being readily available to provide information to other clinicians on the risks and benefits of drug therapy in pregnancy and by assisting in the selection of the most cost-effective therapies.

He added that it is up to pharmacists as medication specialists to develop evidence-based treatment guidelines. At Long Beach Memorial, there are formally written guidelines on hyperemesis gravidarum, diabetes in pregnancy, infectious diseases such as endometritis, theophylline for asthmatics, prophylactic antibiotics and anticoagulation, among others. The guidelines are approved by the medical staff and allow physicians to order treatment “per pharmacist.”

Acknowledging the lack of published research, Mr. Briggs added, “Areas where there is not a lot of established data are opportunities for research for those who are inclined.”

He encourages pharmacists to immerse themselves in learning and to build relationships with other clinicians with whom they work directly. “You have to build credibility with physicians and nursing staff so they trust you to make good decisions for the patients,” he said.

Then it’s time to branch out. “Maybe

will enjoy a career that provides not only employment opportunities in a vastly understaffed area of pharmacy practice, but also personal fulfillment. “One of the rewards of working in obstetrics comes when you see one of one of your patients coming toward you with her baby, and she thanks you for your help in bringing her child into the world.” you are in infectious disease or diabetes care. Read the literature of groups that publish literature on obstetrics, like ACOG [American Congress of Obstetricians and Gynecologists]. Then

start looking for obstetrics patients in your area of expertise—infectious disease or diabetes.”

Mr. Briggs said that for their effort, pharmacists specializing in obstetrics

—Terri D’Arrigo The sources had no relevant financial relationships to disclose.

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18 Operations & Management

Pharmacy Practice News • January 2012

Continuity of Care

BRIDGE continued from page 1

medication errors and noncompliance with drug regimens.

“We know that the main drivers for readmissions are drug-related, especially among the elderly. That means pharmacists at health systems and in the community are well positioned to address some of the problems,” said Patricia C. Kienle, RPh, MPA, FASHP, director of Accreditation and Medication Safety Quality Services, Cardinal Health Pharmacy Solutions.

Ms. Kienle spoke at the symposium, “Transitions of Care: Building Bridges Between the Hospital and the Community,” held during the 2011 American Society of Health-System Pharmacists Midyear Clinical Meeting.

Topping the list of factors that disrupt the transition after discharge and precipitate medication-related errors is haphazard and uncoordinated communication and recordkeeping among clinicians, patients and caregivers, according to another speaker, Marialice S. Bennett, RPh, FAPhA, professor of clinical pharmacy and residency director with the ambulatory and community care residency programs at the Ohio State University College of Pharmacy, Columbus. “There’s often no, or insufficient, medication reconciliation and no appropriate postdischarge medication management. Comprehensive medication reviews are not happening, nor are follow-up appointments,” she said. Once home, she continued, many patients and their caregivers don’t recognize red flags that should prompt a phone call to a pharmacist or physician, such as drug-related side effects or weight gain in a patient with congestive heart failure.

The sort of pharmacist consultation that Ms. Bennett and Ms. Kienle have in mind has been shown to reduce preventable ADEs. A 2006 study in the Archives of Internal Medicine (2006;166:565-571) reported that pharmacist counseling at discharge and a follow-up telephone call three to five days later were associated with a nearly 90% lower rate of preventable ADEs 30 days after patients returned home. Ms. Kienle and Ms. Bennett also emphasized the importance of creating the most complete medication record possible at the time of hospital admission. “Without that, things aren’t going to go well,” said Ms. Bennett.

“The key piece of the medication reconciliation is having a good admission record as the patient enters the system.” That level of thoroughness requires more than simply questioning patients—who are notoriously unreliable witnesses when it comes to their own health—about what drugs they’re

taking. The pharmacist or pharmacy technician assembling the medication list must dig deeper, perhaps calling pharmacies, physician offices and family members. “Reconciliation goes well beyond just matching drug lists,” and an accurate assessment may take an hour to complete, but the potential payoff after discharge is well worth it, Ms. Bennett said.

One seemingly mundane barrier can arise when newly discharged patients (regardless of age) go to a retail pharmacy to fill their prescriptions. Ms. Kienle recalled the time she was driving her husband home from the hospital after his surgery, with a stop at the pharmacy. “There was a huge snowstorm and I thought, this is bizarre.

How do other people handle it if I’m having trouble?”

Ms. Bennett added, “There’s nothing more eye-opening than to go through this process with a loved one.”

reduce readmissions. The two-pronged initiative will work like this: The hospital pharmacy will email him the discharge prescriptions for a patient being readied to leave. Mr. Schieber will fill the order and deliver it to the patient’s bedside, and a hospital staff pharmacist will conduct a discharge consultation.

(Patients can decline the delivery and fill their prescriptions at any pharmacy, but they’ll still be eligible to receive the consultation and subsequent followup. A second independent pharmacy, Circleville Apothecary, has also partnered with Berger Hospital. Funding for the program is possible because it is set up as a 340B drug purchase plan under the Department of Health and Human Services.)

Mr. Schieber or the hospital pharmacist will be able to address issues such as prior authorization and noncompliance stemming from concern over drug costs on the spot. For example,

he can contact the prescriber to see if a less-expensive substitute is acceptable; explain to a patient the importance of a costly drug to his or her longterm health; or help a patient arrange terms through a drug manufacturer’s discount program.

A week or so after dispensing the medications, Mr. Schieber will call patients to check on their progress and schedule an in-store comprehensive medication therapy management (MTM) session.

“During the MTM, I’ll verify again that the patient understands what drugs they’re taking, how they should take them, and why it’s important to follow the regimen.” If problems are evident, he’ll alert the patient’s physician and begin an intervention to avert readmission to the hospital.

The last major piece of the puzzle— linking the pharmacies to the hospital’s electronic medical record—is now

•

see BRIDGE, page 21

Follow-through Lacking Patients may decide to head straight for the comfort of home and delay a pharmacy visit—and there’s a good chance they won’t follow through and pick up their medications, even if the prescriptions were filed electronically (Am J Med 2011; 124:1081.e9-1081.e22). If and when they do reach the pharmacy, patients may be stymied by unexpected twists, such as prior authorization requirements for some medications. Patients may abandon a prescription because of high cost, even if the medication had been a crucial factor in their inpatient treatment.

“Many times, patients have come in and found out that the drug used to stabilize them in the hospital is expensive, and their first words are, ‘I’m not going to take that, forget it,’” said Larry Schieber, RPh, owner of Schieber Family Pharmacy in Circleville, Ohio, who spoke at the symposium. Patients may just be overwhelmed by the number of prescriptions they’ll have to keep up with or startled by the sudden realization that their insurance doesn’t adequately reimburse for a costly drug.

“At that point the whole system is breaking down, and that’s what we’re trying to prevent. That’s when we can act as advocates for the patient,” he added.

Mr. Schieber said that he expects that his nascent collaboration with the nearby 94-bed Berger Hospital in Circleville will ease many of the common problems related to discharge and care transition, and, ultimately, will

‘These types of programs show that pharmacists are right at the heart of the care transition, which is where so many misadventures happen.’

—Marialice S. Bennett, RPh, FAPhA

20 Operations & Management

Pharmacy Practice News • January 2012

Continuity of Care

Pharmacists’ Follow-up Found To Improve Patient Care Pittsburgh—Health-system pharmacists can improve patient care by resolving medication-related problems during the transition from hospital to home, according to a new study by researchers at the University of Pittsburgh.

The research shows how clinicians can foster “continuity of care”—that is, taking care of patients not only during the hospital stay, but also after discharge. The preliminary results of the ongoing study, begun a year ago and funded by the Jewish Healthcare Foundation, were presented at the 2011 annual meeting of the American College of Clinical Pharmacy.

Hospital-based pharmacists, using a standardized telephone script, spoke with 45 patients discharged to home to make sure they were complying with their medications and to uncover any other problems with their drug therapy. Seventy-eight percent of patients discharged to home were successfully contacted and evaluated. The pharmacists made 88 medication-related interventions in 45 of the patients in the pilot program. Pharmacists conducted the standardized telephone medication evaluation within 72 hours after their patients were discharged home and spent an average of 23 minutes on each patient interview. The pharmacists followed one general-medicine hospitalist team, which included an attending internal medicine doctor, a nurse practitioner, a social worker, and a nurse care liaison. The patients had many prevalent disorders, including hypertension, diabetes and kidney disease. The most common types of medication-related interventions were therapeutic drug monitoring and resolution of missing medications incorrectly omitted by the patients.

Pharmacists’ interventions most often were related to antibiotic and gastrointestinal medications.

Pharmacists counseled patients and contacted their physicians, pharmacies and health plans as needed. In one case, a patient was at risk for serious bleeding because his dose of warfarin was too high. The pharmacist immediately contacted the patient’s doctor so

the dose could be lowered, according to lead researcher Rima A. Mohammad, PharmD, BCPS, assistant professor of pharmacy and therapeutics and director of the internal medicine pharmacy residency program at the University of Pittsburgh.

Dr. Mohammad said the study was unique. “No one has categorized interventions in as detailed a fashion as we’re doing. Having the same pharmacist who cared for the patient conduct the followup also is a new concept.”

Medication Discrepancies Are a Common Problem The study classified the interventions into several categories: resolution of missing medication by patient

Ambulatory Clinical Pharmacy Services and director of the managed care residency program at Henry Ford Health System and Health Alliance, in Detroit.

“We need to classify interventions by level of urgency,” she said.

Dr. Pindolia is involved with the launch of a post-hospital discharge medication management program conducted by ambulatory clinical pharmacists for five hospitals and all payers. It’s based on a pilot she conducted earlier in 2011. “The key is to characterize who is at highest risk for rehospitalization due to medication errors, and to develop a transition of care from inpatient to outpatient,” she said.

Dr. Mohammad said she chose to focus on categorizing interventions and

in penalties expands in later years. Dr. Pindolia added, “Because Medicare is doing this, some private insurers are already following suit.”

For Cindy Kunzendorf, RPh, MBA, general manager of Critical Care Systems, Inc., a national home infusion company, the study provides further proof of how invaluable it is that pharmacists follow up with patients after they’ve been discharged. That concept was painfully illustrated by a recent experience she had involving her parents. When Ms. Kunzendorf’s 83-year-old father fell in September, he was given a muscle relaxant in double the dose that would normally be prescribed for a patient that age. This resulted in him having hallucinations and being readmitted to the

‘It’s hard to find a payer who’ll acknowledge the value of follow-up,“ she said. “It’s such a tragedy. It could prevent rehospitalizations and other problems that have even greater costs.’

—Cindy Kunzendorf, RPh, MBA or due to prescribing error, addressing wrong dose or wrong medication taken by patient, therapeutic drug monitoring, medication and adherence counseling, and identification and addressing of adverse drug events (ADEs) and drug interactions. According to the study, 33% of interventions were due to therapeutic drug monitoring, 22% were resolution of missing medication by the patient, and 18% involved medication and adherence counseling—which often occurred because patients had trouble tolerating a drug’s side effects or understanding the importance of taking their medications.

Nearly 13% of the interventions were related to ADEs or drug interactions.

Preventing Readmissions Some researchers are going a step farther. “The literature already shows that errors can be reduced and patient care improved when pharmacists follow up after hospital discharge. The problem is they’re not affordable,” said Vanita K. Pindolia, PharmD, vice president of

finding out which of them are most common, rather than looking primarily at rehospitalization data. But she agreed that the patient-stratification approach makes sense. “This is an ongoing study, so we may address that later,” she said.

“But for now, we’re considering whether to implement follow-up into our pharmacists’ activities or to hire one or two pharmacists to do it.”

Hospitals Incentivized To Lower Rehospitalization Rates Concerns about readmission rates are beginning to take center stage. Medicare payments soon will be reduced for hospitals with higher than expected numbers of patients who are readmitted within 30 days of discharge, and who were treated for heart failure, heart attack or pneumonia. Beginning in October 2012, payments will decrease by up to 1% for hospitals with these events; the reductions will be up to 2% in 2013, and up to 3% in 2014. The list of medical conditions that can result

hospital. “It was very scary for him and my mom,” Ms. Kunzendorf said. “There are so many opportunities for failure with the current system.” Additionally, Ms. Kunzendorf discovered that her mother was discharged from the same hospital with a drug that she was allergic to—even though that information was clearly stated on her discharge sheet.

Ms. Kunzendorf said that she believed that if a pharmacist had checked with her parents after they were discharged from the hospital, the medication errors might have been averted. But she said that she did not see that happening anytime soon.

“It’s hard to find a payer who’ll acknowledge the value of follow-up,” she said.

“It’s such a tragedy. It could prevent rehospitalizations and other problems that have even greater costs.”

—Dana Hawkins-Simons Drs. Mohammad and Pindolia and Ms. Kunzendorf reported no relevant conflicts of interest.

Pharmacy Practice News • January 2012

Operations & Management 21

Continuity of Care

BRIDGE continued from page 18

being put into place. Mr. Schieber said that he expects the first patients to participate in the program within 30 days.

Safe Med Program Another program to prevent readmissions, Novant Health’s Safe Med program, has dramatically reduced readmission rates among older patients, according to speaker Terri Cardwell, RPh, PharmD, MHA, director of Safe

Med at the Novant Medical Group in North Carolina. At nine of its 11 hospitals, pharmacists receive a weekly list of patients aged 65 years and older who are discharged to a home setting. After discharge, a hospital pharmacist provides a drug consultation by telephone to ensure that the patient understands his or her drug regimen, to answer ques-

tions and to probe for any irregularities and signs of trouble. After the call, the patient receives a packet that includes an updated medication list, educational materials and key phone numbers.

The pharmacist also sends an assessment, a record of medication changes and updated laboratory results to the patient’s primary care provider and discusses any concerns about the patient’s medication regimen

in Your Inbox Pharmacy Practice News is available as an E-newsletter.

with the provider. A pharmacist or technician calls the patient a second time 30 days after discharge.

“The purpose is to work with the patient to ensure understanding of what their medications are once they get home,” Ms. Cardwell said. “That’s when questions come up: ‘Oh, I still have these other medication bottles I forgot to ask about; this new bottle looks the same as the old one.’ We want to make sure that any concern the patient brings up with the pharmacist is taken care of, including making an appointment for them with a physician, if necessary.”

Data collected in two years after Safe Med’s 2006 launch showed that 13.1% of Novant patients who did not participate in the Safe Med program were readmitted within 30 days, compared with 6% of Safe Med participants—a decrease of 54% (P<0.0001). Among patients not followed by a Safe Med pharmacist, 7.7% were readmitted compared with 2.7% of Safe Med participants (P<0.0001). Since its inception, Safe Med has involved nearly 10,400 patients. Ms. Cardwell estimated cost avoidance of $3.3 million in 2009—a figure based on 305 averted readmissions (out of nearly 3,700 Safe Med patients) and an average Medicare cost per readmission of about $11,000.

Safe Med has expanded to include referral patients who have not been hospitalized. Additionally, a hospitalist or primary care physician can refer discharged patients of any age if they are deemed to be at high risk for readmission. “We want to empower patients to take an active role in their health care and keep them from being admitted to a hospital due to adverse drug events or medication nonadherence,” Ms. Cardwell said.

“These types of programs show that pharmacists are right at the heart of the care transition, which is where so many misadventures happen,” Ms. Bennett said. “So many people are trying different ways to solve the problem right now; eventually we’ll settle on what truly are the best practices. In the meantime, people will continue to design systems that work in their organizations and hopefully lead us to those best practices for the future.”

—Steve Frandzel What are your thoughts?

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22

Hem/Onc Pharmacy

Pharmacy Practice News • January 2012

In Focus

GENES continued from page 1

their tumors as those with the most widespread form of the receptor.

The findings, presented at the 2011 annual meeting of the American Society of Anesthesiologists (ASA; abstract JS05), came as “pretty much of a surprise” to the investigators, said study leader Andrey Bortsov, MD, PhD, assistant professor of anesthesiology at UNC. “We think this is a very strong association.”

Dr. Bortsov and colleagues analyzed the genetic makeup of 2,039 women diagnosed with breast cancer, who had participated in the Carolina Breast Cancer Study—a longitudinal population analysis of the disease that began in 1993.

Opioid Genetics The researchers wanted to see if variations in the G allele of the µ-opioid receptor gene, OPRM1 A118G, affected a woman’s risk for death from breast cancer. In particular, because the 118G form of the allele ratchets down the receptor’s responsiveness to opioids, the UNC team hypothesized that women with one or more of these variants would be more likely to survive their cancer.

The results of the study supported that hypothesis. According to Dr. Bortsov’s group, women who had at least one variant copy of the allele were twice as likely to survive breast cancer by 2006 as those with the typical form.

Women with two copies of the 118G variant were four times as likely to survive the disease (Table).

Samuel McLean, MD, said OPRM1 is the best understood opioid gene. “We know that if you have a G allele, you respond less well” to the drugs. “If you have cancer, you will need more opioids over time if you have a G allele. If it takes more opioids, that’s bad for you for controlling your pain, but it may be good because of the other effect,” he said.

Most Americans of European and African ancestry have an A allele of the OPRM1 gene, Dr. McLean noted.

The G allele is less common, appearing in about 30% of European Americans but only about 7% of African Americans. That difference might help explain why black women are significantly more likely to die of breast cancer than women from other racial and ethnic groups with the malignancy, the researchers suggested.

Dr. McLean cautioned that although opioids appear to play an important role in the growth and spread of cancer, how they do so remains unclear.

Indeed, it’s not even known if the opioids that patients take for cancer pain have an effect on cancer cells beyond that of the endogenous opioids that the body already produces. “We’re a long way from having any evidence that opioids patients take for cancer pain are harming them,” Dr. McLean

said. “There is animal data that’s provocative, but obviously we can’t take humans and not give them opioids if they have cancer. That’s the last thing we want to do.”

Mouse Data Bolster Link New cellular evidence backs the UNC findings. In an unrelated study also presented at the ASA meeting (abstract JS08), researchers from the University of Chicago showed that

cancer cells modified to overexpress the µ-opioid receptor are far more likely to grow and spread than those with normal levels of the protein.

Using a line of human lung cancer cells that they transplanted into nude mice, the researchers found that overexpression of the opioid receptor caused the growth rate of the tumors to rise 2.5-fold. Metastasis of the tumors spiked by a factor of 20.

Jonathan Moss, MD, PhD, professor of anesthesia and critical care at the University of Chicago, said the North Carolina work “confirms a growing body of in vitro and animal data from several laboratories, including our own, suggesting a role of the µ-opioid receptor in cancer progression.”

However, Dr. Moss said, too many questions remain to consider altering clinical practice. “We don’t want to scare patients,” Dr. Moss said. “Our paper and theirs did not address giving opioids and may relate to endogenous opioids. While I may personally believe there could be effects that would change practice. ... There are no direct, prospective, randomized controlled [trial] data suggesting that opioids influence cancer progression in humans, but several studies contribute to the debate.”

Jeffrey L. Apfelbaum, MD, professor of anesthesia at the University of Chicago, who was not involved in the studies, agreed. “They need some prospective studies to clearly delineate what major practice changes might need to take place,” Dr. Apfelbaum said. “But they’re working on that.”

—Adam Marcus

‘We’re a long way from having any evidence that opioids patients take for cancer pain are harming them. There is animal data that’s provocative, but obviously we can’t take humans and not give them opioids if they have cancer. That’s the last thing we want to do.’

—Samuel McLean, MD

Table. Double-A Genotype Strongly Associated With Cancer Deaths A118G Genotype

Number of Participants

Breast Cancer Deaths

% of Breast Cancer Deaths

P Value

A/A

1,682

296

17.6

0.0001

A/G

323

28

8.7

G/G

22

1

4.6

A/A

1,332

290

21.8

A/G

233

28

12

G/G

13

0

0

All cases

Invasive cases 0.0006

24

Hem/Onc Pharmacy

Pharmacy Practice News • January 2012

In Focus

Zoledronic Acid Controversy in Breast Cancer Continues SABCS studies largely positive, although not unanimous San Antonio—A growing body of evidence backs the contention that bisphosphonates can improve survival in breast cancer patients with low estrogen levels. The results of three studies of bisphosphonates in this setting presented at the recent San Antonio Breast Cancer Symposium (SABCS) support the low estrogen hypothesis, whereas interim results of a fourth trial presented there were negative.

Some experts, including James

Bowel Project (NSABP)-34 trial—as well as the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a subanalysis of which demonstrated that zoledronic acid can improve diseasefree survival (DFS) in postmenopausal breast cancer patients.

ABCSG-12 According to Dr. Ingle, the long-term results of ABCSG-12 (abstract S1-2) provide level 1 evidence of the benefit of zoledronic acid in the specific population studied.

receptor–positive breast cancer who were postmenopausal or amenorrhoeic due to cancer treatment. Eligible patients had a bone mineral density (BMD) T score of at least two standard deviations below normal. All patients received letrozole (Femara, Novartis) for five years.

Patients were randomized to receive zoledronic acid immediately and for the duration of the trial or to delay the start of the drug until their BMD T score decreased to more than 2 standard deviations below normal, they had a clinical nontraumatic fracture or an asymptom-

‘We believe we can effectively silence dormant tumor micrometastases with this treatment.’

—Michael Gnant, MD

Ingle, MD, a professor of oncology at the Mayo Clinic in Rochester, who served as a discussant for the trials at SABCS, consider there to be “mounting evidence ... that bisphosphonates will become established as efficacious in adjuvant therapy of postmenopausal women with earlystage breast cancer.”

However, others have concerns. Steven Vogl, MD, a medical oncologist in New York City, said, “Before I sprinkle this stuff around, I want a randomized prospective trial in whatever population they claim it works.” Dr. Vogl also pointed out that bisphosphonates are not without side effects, such as osteonecrosis of the jaw, and that zoledronic acid (Zometa, Novartis) is “expensive.”

Bisphosphonates have multiple potential anti-tumor effects in bone, researchers said. They include reducing the release of bone-derived tumor growth factors, modifying levels of circulating tumor cells, affecting tumor vasculature and having direct effects on tumor cells themselves.

More specifically, noted Michael Gnant, MD, a professor of surgery at the Medical University of Vienna, who led the ABCSG-12 trial, “We believe we can effectively silence dormant tumor micrometastases with this treatment.”

Data from four trials now support the hypothesis that bisphosphonates have value as an anticancer agents, 3 presented at SABCS—ABCSG-12, by the Austrian Breast and Colorectal Cancer Study Group, the Zometa-Femara Adjuvant Synergy Trial (ZOFAST), and the National Surgical Adjuvant Breast and

In the study, 1,803 premenopausal patients with endocrine receptor–positive early breast cancer who received goserelin to shut down their ovarian function were randomized to receive either tamoxifen with or without zoledronic acid or anastrozole with or without zoledronic acid. The treatment duration was three years.

After a seven-year follow-up, investigators identified a 28% relative reduction in the risk for relapse in patients who received zoledronic acid (P=0.01). Earlier analyses also had shown similar improvements in DFS: 26% after 48 months (P=0.01), 32% at 62 months (P=0.008) and 27% after 76 months (P=0.02). Overall survival (OS) seven years out also was increased with zoledronic acid (hazard ratio [HR], 0.64; confidence interval, 0.390.96; P=0.033). The absolute difference was about 4% in progression-free survival and 1.6% in OS, according to Dr. Ingle.

Dr. Gnant said that the four- to fiveyear posttreatment follow-up suggests that zoledronic acid may have “a sustained anticancer effect.”

Although the evidence from ABCSG-12 seems solid, few women with breast cancer in the United States are currently treated with goserelin as in the ABCSG-12 trial, making extrapolation of the results questionable.

“There is a study called SOFT [Suppression of Ovarian Function Trial] where they are trying to add ovarian ablation to tamoxifen,” said Dr. Vogl. “If that study is positive, we may have a large number of such patients, but if it’s not, nobody is going to be treating a patient like this except in Austria.”

ZOFAST Results of the ZOFAST trial involved 1,065 women with stage I to IIIa hormone

atic fracture detected via x-ray when assessed at 36 months. The median age was less than 60 in both arms.

Zoledronic acid increased patients’ BMD, the study’s primary end point. “We can see the benefit in the immediate therapy group occurring early on, when bone turnover or bone loss is at its greatest, and continuing out to the five-year time point, with a net difference of 10% favoring the immediate zoledronic acid group,” said Richard de Boer, MD, of the Royal Melbourne Hospital in Australia, who presented the study (SABCS abstract S1-3).

With a follow-up of five years, patients given immediate zoledronic acid had a 34% improvement in DFS (HR, 0.66; P=0.0375), resulting in a 3.6% absolute difference. An exploratory analysis of DFS and OS showed that women who had been postmenopausal for at least five years or were older than 60 had greater benefits. “As per the improved diseasefree survival results seen in both the Austrian and AZURE trials, these data support the hypothesis that the anti-cancer potential of zoledronic acid might best be realized in a low-estrogen environment,” said Dr. de Boer.

NSABP-34 In the NSABP-34 trial (abstract S2-3), investigators compared adjuvant clodronate with placebo in 3,323 patients with early-stage breast cancer who had received systemic chemotherapy and/ or tamoxifen or no therapy. Clodronate, importantly, is not approved in the United States. Only 3% of patients had received no prior adjuvant therapy, and 78% were positive for the estrogen and/or progesterone receptor. Patients were stratified by age—younger than 50 years or 50 years and older—and roughly 65% of patients were older than

50 years. The study failed to show that clodronate improved DFS, the study’s primary end point (HR, 0.91; P=0.27).

In the overall study population, the only secondary end point that was improved was non–bone metastasis–free interval (HR, 0.743; P=0.046).

In a subanalysis, however, secondary end points were improved in women aged 50 years or older who received clodronate. These included recurrence-free interval (HR, 0.76; P=0.05), bone metastasis–free interval (HR, 0.61; P=0.024), and non-bone metastasis–free interval (HR, 0.63; P=0.015). Breaking patients into age groups of younger than 50 years, between 50 and 59 years and older than 60 years, showed a stepwise increasing benefit for clodronate in older patients in terms of skeletal metastases and nonskeletal metastases, according to Alexander H. G. Paterson, MD, professor of medicine and oncology at the University of Calgary in Alberta, who led the study.

“Similar beneficial results in older postmenopausal women are seen in other studies involving bisphosphonates,” he said.

GAIN However, not all studies presented at SABCS bolstered the claim that bisphosphonates can improve survival in a lowestrogen environment. The first interim results from the GAIN (German Adjuvant Intergroup Node Positive) trial (abstract S2-4) were negative. The study showed that the bisphosphonate ibandronate (Boniva, Roche) did not increase survival in women with node-positive, primary breast cancer, whether or not they had low estrogen levels.

GAIN included 3,023 patients who were first randomized between two different dose-dense chemotherapy regimens (epirubicin, paclitaxel and cyclophosphamide [ETC]) or to the same three drugs plus capecitabine (Xeloda, Roche).

After completing chemotherapy, patients were then randomized to either the oral drug ibandronate 50 mg per day for two years or observation. Patients aged 65 years or younger were eligible for the trial if they had untreated primary breast cancer, no distant metastases, an Eastern Cooperative Oncology Group (ECOG) status of less than 2 and a life expectancy of at least 10 years.

At a median follow-up of 39 months, investigators did not identify an improvement in DFS (P=0.59) or OS (P=0.8) in patients who received ibandronate. There were no statistically significant differences in subgroup analyses based on hormone receptor or menopausal status. Although not

•

see ZOLEDRONIC, page 26

26

Hem/Onc Pharmacy

Pharmacy Practice News • January 2012

In Focus

Pertuzumab: Practice-changing for HER2+ MBC New antibody makes big splash at SABCS Meeting

80 70

Pertuzumab,

Placebo,

most predominant is ligand binding.

“When these ligands bind to receptors on the membrane, they induce receptor homodimerization, where two of the same kind of receptor bind to each other, or heterodimerization, where one type of receptor can bind with another family member,” Dr. Osborne said.

Trastuzumab works predominantly by inducing antibody-dependent cellmediated cytotoxicity (ADCC), preventing HER2 extracellular domain shedding and inhibiting signaling of HER2 homodimers; it interferes only slightly with HER1/HER2 and HER2/HER3 heterodimers. Pertuzumab activates ADCC and inhibits HER1/HER2 and HER2/HER3 heterodimer signaling, thus providing a more complete blockade of the HER signaling pathway.

“The two agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater anti-tumor activity than either agent alone,” said Dr. Baselga.

CLEOPATRA included 808 patients with HER2-positive, locally recurrent, unresectable or metastatic breast cancer with measurable or nonmeasurable disease. Eligibility criteria included left ventricular ejection fraction (LVEF) of at least 50% at baseline, no more than one hormonal regimen for MBC prior to randomization and no history of congestive heart failure or LVEF decline to less than 50% during or after prior trastuzumab therapy. Prior neoadjuvant systemic chemotherapy, including trastuzumab and/or taxanes, was allowed if followed by a diseasefree interval of at least 12 months. The median age was 54 years.

Patients were randomized to receive docetaxel, trastuzumab and pertuzumab or docetaxel, trastuzumab and placebo. The trial arms were well balanced in terms of performance status and prior therapy with anthracylines, hormones, taxanes and trastuzumab. “About 50% of patients were ER

trastuzumab, docetaxel trastuzumab, docetaxel and/or PR-positive,” Dr. 66.8 60 Baselga said.

Independently assessed 50 median PFS, the primary 46.3 40 end point, was 18.5 months 33.7 30 in patients receiving per27.8 tuzumab and 12.4 months 24.2 20 19.9 in the control arm (hazard 13.8 10 ratio [HR], 0.62; 95% con7.6 0 fidence interval, 0.51-0.75; Diarrhea Rash Mucosal Febrile inflammation neutropenia P<0.0001). Improvement was seen in all subgroups.

Figure. Comparison of key adverse The interim analysis of events (all grades). overall survival (OS) did not cross the prespecified stopping boundary for staHowever, Dr. Baselga had presented tistical significance, according to Dr. Baselga, but looked very promising an analysis of 88 patients who had with an HR of 0.64 (P=0.0053). An received prior trastuzumab and showed exploratory statistical analysis showed a PFS HR of 0.62 in favor of pertuzumthat pertuzumab also improved objec- ab. This was similar to the HR of 0.60 tive response rate (80.2% vs. 69.3%), in favor of pertuzumab in an analysis complete response rate (5.5% vs. 4.2%) of 288 similar patients who had not and partial response rate (74.6% vs. received trastuzumab.

Dr. Osborne also pointed out that the 65.2%) (P=0.0011).

Adverse events (AEs), including improved outcomes were less dramatic diarrhea, rash, mucosal inflammation in ER-positive patients than in ERand febrile neutropenia, were more negative patients (HR, 0.72 vs. 0.55). common in the experimental arm (Fig- Similar to many other clinical trials in ure). These primarily grade 1-2 AEs this patient population, he said, “Even occurred during docetaxel therapy though ER was present, it was not and were characterized by Dr. Baselga targeted. I suppose this is because we as manageable. No cardiac AEs were think that tamoxifen is antagonistic with chemotherapy, so we don’t comidentified.

“CLEOPATRA met its primary end bine them together, but I would point point and demonstrated a statistically out that we know very little about comsignificant and clinically meaningful bining chemotherapy with estrogenimprovement in PFS,” Dr. Baselga said. deprivation therapy.”

A trial adding an aromatase inhibitor “This new regimen may be practicechanging in HER2-positive first-line into the mix might yield better results, said Dr. Osborne. “This is something metastatic breast cancer.”

Dr. Osborne said the well-conducted that does need to be studied.” study provided convincing data that adding pertuzumab to the regimen of —Kate O’Rourke trastuzumab and docetaxel increased PFS, OS and response rate. He pointed out that 90% of patients had not Dr. Baselga disclosed that he is a received prior trastuzumab and outconsultant for Roche. Dr. Osborne comes likely would be worse in patients disclosed that he is a consultant for AstraZeneca, Novartis and Genentech. who had.

ZOLEDRONIC

dose-dense chemotherapy,” said Volker Möbus, MD, head of the Department of Obstetrics and Gynecology at Klinikum Frankfurt Höchst in Frankfurt, Germany. He pointed out that GAIN was quite different from the other three studies in that all patients received dose-dense chemotherapy.

“The anticancer effects of adjuvant zoledronic acid are now well established in endocrine-responsive patients,” said Dr. Gnant. Dr. Paterson added that “inhibition of osteoclast function with bisphosphonates has an effect on cancer growth in older women, and little effect in premenopausal women.”

For other doctors, however, the jury is still out. “Subanalyses are suspect,” said Dr. Vogl. “This is interesting, but we need to study it some more. But if they study it some more, Novartis will have lost its patent protection by the time

continued from page 24

statistically significant, the HR of 0.75 in women aged 60 years and older was identical to the HR of postmenopausal women in the AZURE trial. The interim futility boundary for chemotherapy was not crossed, and these data were not reported.

“The GAIN study demonstrated that adjuvant ibandronate improves neither DFS nor OS in node-positive early breast cancer after treatment with

Weighing the Evidence In recent years, some oncologists have been prescribing bisphosphonates offlabel to treat breast cancer, and the new studies may sway more doctors to do so.

Incidence, %

San Antonio—A new HER-targeted antibody, pertuzumab (Omnitarg, Roche), is poised to alter the treatment landscape of patients with HER2-positive metastatic breast cancer (MBC).

Adding pertuzumab to trastuzumab (Herceptin, Genentech) and docetaxel in this patient population improved progression-free survival (PFS) by six months, according to results from the CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial.

The Phase III, double-blind trial was presented at the recent San Antonio Breast Cancer Symposium (SABCS, abstract S5-1), where it was received as the biggest news coming out of the meeting, and simultaneously published in the New England Journal of Medicine.

“The magnitude of this effect is unprecedented. This is the most positive trial in the history of patients with HER2-positive advanced disease and for that matter in patients with advanced breast cancer,” said José Baselga, MD, associate director of the Massachusetts General Hospital Cancer Center in Boston, who presented the results.

Other experts in the field are similarly enthusiastic about the drug. “For patients meeting the eligibility criteria, pertuzumab may be a new standard,” said Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, during discussion of the trial at SABCS. However, cost is a concern for many oncologists. At press time, Roche had applied for approval, and a company spokesperson said a price had not yet been decided.

The combination of pertuzumab and trastuzumab works because the drugs have complementary mechanisms of action. The HER signaling pathway is a complex, redundant, evolvable, layered network that includes four membrane receptors—HER1 to HER4— and 11 ligands. The pathway can be activated in a variety of ways, but the

that study comes out. Novartis has some interest in it [being approved] now.”

—Kate O’Rourke Dr. Paterson is a consultant for GlaxoSmithKline, Amgen, Roche and Nicomed and has received a grant for a clinical trial involving denosumab. Dr. Gnant disclosed relationships with AstraZeneca, Novartis, Pfizer, Sanofi, Roche, Schering and Amgen. Dr. Möbus disclosed relationships with Amgen, Novartis and Roche. Dr. DeBoer disclosed a relationship with Novartis.

Drs. Ingle and Dr. Vogl have no relevant disclosures.

6 OZ 4 OZ

28 Clinical

Pharmacy Practice News • January 2012

Journal Scan

A Few Small APAP Overdoses Deadlier Than Single Large One From Journal of Clinical Oncology

C

hronic, slight overdoses of acetaminophen (APAP) can be more lethal than one-time massive overdoses, according to researchers at the Scottish Liver Transplant Unit (SLTU) and the University of Edinburgh in Scotland.

In a retrospective analysis of 663 patients who were admitted to the SLTU between November 1992 and October 2008 with APAP-induced liver toxicity, the researchers were able to determine the time course of APAP overdose in 611 cases (92.2%) (Craig D et al. Br J Clin Pharmacol 2011 Nov 22 [Epub ahead of print]). Among those, 450 (73.6%) had taken a single overdose, defined as more than 4 g of APAP taken at once, and 161 (26.4%) had taken a staggered overdose, defined as the ingestion

of two or more supratherapeutic APAP doses over more than eight hours, resulting in a cumulative dose of more than 4 g per day.

The team found that patients with a staggered overdose pattern had higher mortality rates compared with those with a single overdose (37.3% vs. 27.8%; P=0.025). Those who took staggered overdoses of APAP were more likely to have a history of alcohol abuse than those with single overdoses (48.9% vs. 29.2%, P<0.001). The most common reason for a staggered overdose was pain relief.

Among patients with single overdoses, 178 (44.9%) presented for medical care more than 24 hours after their overdose. This delayed presentation was independently associated with death and liver transplantation (odds ratio, 2.25; 95% confidence interval, 1.23-4.12; P=0.009).

COMMENTARY Heather Draper Eppert, PharmD, BCPS Clinical Specialist, Emergency Medicine Associate Professor of Clinical Pharmacy University of Tennessee College of Pharmacy Knoxville, Tennessee

Over the past five to 10 years, the health care community has seen that even therapeutic doses of APAP carry the possibility of toxicity and death when used chronically. This study hammers home points that were somewhat speculative and offers us some data to use to provide evidence-based care.

It is important to note that the majority of patients with a staggered overdose were taking the drug for its therapeutic benefits, so their overdoses can be considered accidental. Patients assume that if something

is over-the-counter (OTC), it’s safe.

As pharmacists, we need to counsel patients not only against taking more than 4 g over 24 hours but also about long-term use.

There are two groups of patients in particular that we need to educate: chronic users, such as those who take APAP for arthritis pain, and those who take prescription medications containing APAP, to drive home the point that if they also want to take an OTC medication, they should determine whether it contains APAP. One limitation of this study was the high rate of alcohol abuse in the staggered-dose population. The researchers’ definition of alcohol abuse was quite generous (>56 units per week for men and >42 units per week for women). That is a large consumption, and we might expect patients in that population to have worse outcomes.

Kidney Injury Is Top Risk Factor for Adverse Events in ICU From Critical Care Medicine

A

cute kidney injury is the major risk factor for adverse drug events (ADEs) among critically ill adult patients, according to a recent report published in Critical Care Medicine (Kane-Gill S et al.

2012;40 [Epub ahead of print]).

In a retrospective study designed to assess the critically ill population for risk factors for ADEs, researchers reviewed the records of 1,101 cases and controls admitted to the intensive care unit (ICU) at The University of Pittsburgh Medical Center-Presbyterian between July 1998 and January 2006.

The team found that critically ill 10

patients with kidney injury were 9.6 times more likely to have an ADE than patients in the control group (P<0.001).

Thrombocytopenia trailed a distant second to kidney injury as a risk factor for ADEs, with patients with thrombocytopenia being 3.4 times more likely to have an ADE than controls (P<0.001). Other significant risk factors were ICU length of stay (LOS; 2.64; P<0.001), hospital LOS (1.93; P<0.001), emergent admission (1.66; P<0.001) and having Medicare/Medicaid as insurance (1.31; P=0.033) (Figure). Administration of IV medications also was identified as a risk factor, with a 3% increase in the

9.6

Odds Ratio

8 6 4

3.4 2.64 1.93

2 0

Acute kidney injury

Thrombocytopenia

ICU LOS

Hospital LOS

1.66

1.31

Emergent admission

Medicare/ Medicaid

Risk Factor

Figure. Risk factors for ADEs in critically ill patients.

ADEs, adverse drug events; ICU, intensive care unit; LOS, length of stay

—Compiled by Terri D’Arrigo

likelihood of having an ADE for each additional drug administered.

In all, there were 499 ADEs among 367 cases, with 27% of patients having more than one. The most common drug classes related to ADEs were analge-

sics/anxiolytics/sedatives (23%), antimicrobials (20.2%) and anticoagulants (14.2%). The most common drugs associated with ADEs were heparin (9.2%), morphine (7%), fentanyl (5.6%), piperacillins (3.8%) and phenytoin (3.6%).

COMMENTARY John W. Devlin, PharmD, FCCM, FCCP Associate Professor Department of Pharmacy Practice Northeastern University Special and Scientific Staff Division of Pulmonary, Critical Care and Sleep Medicine Tufts Medical Center Adjunct Associate Professor Tufts University School of Medicine Boston, Massachusetts

This is one of the more important papers about medication safety. Its methodology is strong in terms of size and design, and cases and controls were very well matched. One of the strengths of the study is that it looked at the patients and their underlying characteristics, whereas most studies tend to focus on the drugs. Also, the focus is on straight ADEs, as opposed to lumping in drugs that are given in error.

In broad terms, the results with respect to kidney injury will make sense to ICU pharmacists because a lot of the medications given in the ICU rely on the kidneys for clearance. Many

patients in that setting will have some degree of renal injury or impairment.

The bias in the study is that ADEs tend to be underreported, and the ones that do get reported are more likely to be severe. But there is a strong take-home message here, which is that ADEs are prevalent in the critical care setting and that both patient characteristics and drug class influence the likelihood of an ADE. This highlights the importance of pharmacist input and care when optimizing drug therapy, dosing and monitoring for patients who have underlying renal impairment or who require a greater than normal number of IV drugs.

PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICENEWS.COM

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations JERRY SIEGEL, PHARMD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

C

hoosing an immune globulin (Ig) product is now more challenging because all products are available and in good supply. When Ig shortages were commonplace, it was often a matter of seeing what product you could get, with less concern paid to the best product for your patient.

For the past several years, the availability of Ig products has been very good, so product shortages have not played a major role in product choice. This gives clinicians the opportunity to match the best product to the patient based on the patient’s clinical condition and comorbidities. In the future, it is expected that some of the lyophilized products will be discontinued, but additional liquid products will be coming to the market, providing more treatment options. For example, there are now 3 Ig products indicated for subcutaneous use: Gammagard Liquid (Baxter) and Gamunex-C (Talecris), formerly Gamunex, come in 10% concentrations and can be administered subcutaneously or intravenously (subcutaneously for PID only), and Hizentra (CSL Behring) comes in a 20% concentration. It should be noted that dosing adjustments are required for all SC agents when converting from IV. Another area of change for Igs is the use of these products for various new indications. One product, Gamunex-C, has received approval for use in patients with chronic inflammatory demyelinating polyneuropathy (IV only). In addition, there is ongoing research in many other potential indications, including Alzheimer’s disease and complex regional pain syndrome.

The most common question regarding Ig products relates to whether they all are the same. Even though clinicians have considered all Ig products to have comparable efficacy, they are not pharmaceutically equivalent. It is imperative that Ig products not be interchanged without full consideration of the pharmaceutical differences.

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

The reasons for switching products may be clinical in nature and related to tolerability; they may be fiscal and based on contracting issues; or they may be due to product availability. It is best to consider product changes as if the patient is naïve to Ig use, with increased monitoring and conservative infusion times.

Whereas Tables 1 to 5 may help facilitate these decisions, it is important to understand the clinical impact of changing products. Although all of the products contain primarily IgG, there are trace amounts of other Igs—IgA and IgM—as well as widely different stabilizing agents, which may affect tolerability. The differences in salt, sugar, and overall osmolarity of these products are particularly important when patients have various comorbidities, such as renal dysfunction, diabetes mellitus, vascular disease, or heart failure. Differences between lyophilized and liquid products may result in changes in product concentration and infusion rate, as well as tolerability.

The tables may be helpful in providing optimal care for patients receiving Ig products. They should be used as a general guide to help determine the product that is best suited for a particular patient population. Because there is variation from batch to batch, the exact numbers represent averages of selected batches; any one batch of any Ig product may have ranges outside these average numbers. When comparing administration rates, clinicians need to keep in mind that each patient has a maximum tolerated rate. This rate is based on patient tolerability and may be different for each product. It is imperative that Ig be administered slowly initially and titrated as tolerated. The rate should be adjusted based on comorbidities as well. The infusion should be slowed or stopped if adverse events become evident during the infusion. (See the full prescribing information for each agent for more information about adverse reactions.)

P H A R M AC Y P R AC T I C E N E WS • JA N UA RY 2 0 1 2

1

Table 1. Therapeutic Considerations

Producta

Manufacturer

FDA-Approved Indications

IgA Content

pH (After Reconstitution)

IgG Subclass,c % Plasma Source

Halflife, db

Viral Inactivation/ Removal

IgG1

I

Intravenous Immune Globulin Carimune NF

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

ITP, PID

1,0002,000 mcg/mL (6%)

6.4-6.8

Plasmapheresis, US donors (>16,000)

23

pH 4.0/pepsin, nanofiltration, TSE removal

60.5

3

Flebogamma 5% DIF, 10% DIF

Instituto Grifols SA Barcelona, Spain Customer service: (888) GRIFOLS www.grifols.com

PID

2.9±0.1 mcg/mL (5%)d <6 mcg/mL (10%)d

5.6±0.1 (5%)d 5.5±0.1 (10%)d

US source IQPP-certified plasma from FDA-registered sites

4-week dosing: 32±5 (5%), 37±13 (10%)

66.6 Pasteurization (60°C, 10 h), SD, dual nanofiltration (35+20 nm), fraction I and II+III precipitation, 4% PEG precipitation, pH 4.0 treatment, TSE removal

2 ( 2 (

Gammagard Liquid 10%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

PID

37 mcg/mL

4.6-5.1

Plasma from FDA-registered sites

35

SD, low pH, nanofiltration

60.9

3

Gammagard S/D 5%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

CLL, ITP, KS, PID

<2.2 6.4-7.2 mcg/mL, <1 mcg/mLe

Plasmapheresis, 10,000 donors

37.7±15

SD

67

2

Gammaplex 5%

Bio Products Laboratory (distributed by FFF Enterprises) Customer service: (800) 843-7477 www.fffenterprises.com

PID

<10 mcg/mL

Plasma from FDA-registered sites

41±14

SD, nanofiltration, terminal low pH incubation

64

3

Gamunex-C 10%

Talecris Biotherapeutics Medical info: (800) 520-2807 www.gamunex-c.com

CIDP, ITP, 46 mcg/mL 4.0-4.5 PID

Plasmapheresis

35

pH 4.2, caprylate chromatography purified, TSE removal

65±4

2

Octagam 5%f

Octapharma Pharmazeutika Octapharma USA Customer service: (866) 766-4860 www.octapharma.com

PID

≤200 mcg/mL

US source and recovered plasma

41

SD, pH 4.0

65

3

Privigen 10%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com; www.privigen.com

ITP, PID

≤25 mcg/mL 4.6-5.0

Plasmapheresis, US donors (≥60,000)

36.6

pH 4.0 incubation, 20 nm virus filtration, depth filtration, TSE removal

67.8

2

Plasma from FDA-registered sites

35

SD, low pH, nanofiltration

60.9

3

4.8-5.1

5.1-6.0

Subcutaneous Immune Globulin Gammagard Liquid 10%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

PID

37 mcg/mL

Gamunex-C 10%

Talecris Biotherapeutics Medical info: (800) 520-2807 www.gamunex.com

PIDg

46 mcg/mL 4.0-4.5

Plasmapheresis

35

pH 4.2, caprylate chromatography purified, TSE removal

65±4

2

Hizentra 20%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com www.hizentra.com

PID

≤50 mcg/mL

4.6-5.2

Plasmapheresis, US donors

NA

pH 4.0 incubation, nanofiltration, depth filtration, virus filtration, TSE reduction

68.7

2

Footnotes on page 7; Key on page 8.

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

4.6-5.1

Bacteria/ Toxin

%

IgG2

IgG3

IgG4

30.2

6.6

2.8

28.5 (5%), 27.9 (10%)

2.7 (5%), 3.0 (10%)

32.1

Diphtheria Toxin

Streptococcus pneumoniae

Haemophilus Influenzae Type B

Streptolysin O

CMV

HAV

HBV (Surface Antibody)

Herpes Simplex Type 1

Polio Type 2

1:64 (RIA)

1:128 (CF)

1:64 (NT)

48±27 IU/g Ig (5%), 42±13 IU/g Ig (10%)

NA

NA

Type 1

Type 3

3.6 IU/mL (NT)

313 (EIA)

180 (EIA)

1:60 (CF)

300 IU/mL (HAI)

1:512 (IFA); 1:348 (RIA) 1:2,560 (EIA)

2.2 (5%), 2.5 (10%)

5.7±0.9 IU/mL (5%), 14.0±1.0 IU/mL (10%)

NA

NA

15±1 mg/L (5%)

NA

30±6 PEI units/mL (5%), 69±16 U/mL (10%)

5

2.1

4.0 units/mL (NT)

NA

21.2 mcg/mL (EIA)

1:2,320 (EIA)

NA

16.4 IU/mL 68 PEI units/mL (RIA) (EIA)

25

5

3

2-5 IU/mL (NT); J5 lipid A 1:273

17.5 mcgAbN/ mL (EIA)

8.5 mcg/mL (EIA)

11 mcg/mL (EIA)

1,150 IU (HH)

37 PEI mcg/mL (EIA), 1:2,480 (NT)

1:267 (RIA)

820 mIU/mL (RIA)

1:1,000 (EIA)

1:305 (NT)

30

5

1

2.2 IU/mL

2.3 mcg/mL

NA

791 mcg/mL

185 IU/mL

431 U/mL

20 IU/mL

4.7 IU/mL

5,129 AU/mL

NA

26±2

5.6± 0.6

2.6± 0.2

≥2 AU/mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 1:139 PEI units/mL

1:944

NA

1:22±0.35

30

3

2

5-30 IU/mL

NA

NA

NA

600-800 IU/mL

33-40 IU/mL 21-25 IU/mL 51 IU/g

1:8,192

1:160-1:320 (NT)

28.7

2.3

1.2

4.9 (3.8-7.3) IU/mL

NA

NA

1,746 36.1 (26.4-45.0) (1,310-2,010) IU/mL IU/mL

76.4 (51.2-116.8) IU/mL

NA

NA

32.1

5

2.1

4.0 units/mL (NT)

NA

21.2 mcg/mL (EIA)

1:2,320 (EIA)

NA

16.4 IU/mL 68 PEI units/mL (RIA) (EIA)

≥0.20 VZV: 32 IU/mL (EIA) units/mL (NT)

Type 1: 1:190 mIU/ mL (NT)

26±2

5.6± 0.6

2.6± 0.2

≥2 AU/mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 1:139 PEI units/mL

1:944

NA

1:22±0.35

26.6

2.7

2

≥2.5 IU/mL

NA

NA

NA

≥1,000 IU/mL

NA

≥0.4 IU/mL

NA

NA

21±4 IU/mL (5%)

NA

NA

≥0.20 VZV: 32 IU/mL (EIA) units/mL (NT)

5.3 (3.0-10.1) IU/mL

Type 1: 1:190 mIU/ mL (NT)

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

3

Table 2. Pharmaceutical Considerations Producta

Method of Preparation

Form

Gamma Globulin, %

Monomers, %

Intravenous Immune Globulin Carimune NF

Kistler-Nitschmanni; pH 4.0 + trace pepsin; nanofiltration

Lyophilized

≥96

92

Flebogamma 5% DIF, 10% DIF

Cohn-Oncleyi; ion-exchange chromatography; acid pH treatment; PEG precipitation; pasteurization; SD; dual nanofiltration (35+20 nm)

Liquid

99.6±0.2 (5%),d 99.4±0.1 (10%)d

>99.8 monomers + dimers (5%),d >99.9 monomers +dimers (10%)d

Gammagard Liquid 10%

Cohn-Oncleyi; SD treatment; anion-exchange chromatography; nanofiltration; ultrafiltration; low pH incubation

Liquid

≥98

≥95 monomers + dimers

Gammagard S/D 5%

Cohn-Oncleyi; ultrafiltration; anion-exchange chromatography; SD treatment

Lyophilized

≥90

96.4

Gammaplex 5%

Cold ethanol fractionation; ion-exchange chromatography; SD treatment; nanofiltration (20 nm); ultrafiltration; terminal low pH incubation

Liquid

>99

≥99 monomers + dimers

Gamunex-C 10%

Cold ethanol fractionation; anion-exchange chromatography; caprylate chromatography purified; low pH incubation

Liquid

≥98

100 monomers + dimers

Octagam 5%f

Kistler-Nitschmanni; ultrafiltration; anion-exchange chromatography; SD treatment

Liquid

≥96

>99 monomers + dimers

Privigen 10%

Cold ethanol fractionation; octanoic acid fractionation; anion-exchange chromatography; pH 4.0 incubation; depth filtration, nanofiltration (20 nm)

Liquid

≥98

≥98 monomers + dimers

Subcutaneous Immune Globulin Gammagard Liquid 10%

Cohn-Oncleyi; SD treatment; anion-exchange chromatography; nanofiltration; ultrafiltration; low pH incubation

Liquid

≥98

≥95 monomers + dimers

Gamunex-C 10%

Cold ethanol fractionation; anion-exchange chromatography; caprylate chromatography purified; low pH incubation

Liquid

≥98

100 monomers + dimers

Hizentra 20%

Cold ethanol fractionation; octanoic acid fractionation; anion-exchange chromatography; pH 4.0 incubation; depth filtration, nanofiltration (20 nm)

Liquid

≥98

≥90 monomers + dimers

Footnotes on page 7; Key on page 8.

4

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

Sodium Content (5% Concentration)

Stabilizer

Osmolality/Osmolarity

Shelf Lifeh

Reconstitution Time

0% water, 0.9% saline

5% sucrose

In sterile water: 3%, 192 mOsm/kg; 6%, 384 mOsm/kg; 12%, 768 mOsm/kg In NS: 3%, 498 mOsm/kg; 6%, 690 mOsm/kg; 12%, 1,074 mOsm/kg

24 mo

Several minutes

Not detectable

Trace

5% sorbitol (polyol)

240-370 mOsm/kg

24 mo RT

Not applicable (liquid solution)

NA

Not detectable

Not detectable

Glycine

240-300 mOsm/kg

36 mo refrigerated; 12 mo RT

Not applicable (liquid solution)

Trace

<3 mg/mL

<2 mg/mL

0.85%

2% glucose

636 mOsm/L (5%), 1,250 mOsm/L (10%)j

24 mo

<5 min at RT; >20 min if cold

<0.02 mcg/mLk

0k

0k

30-50 mmol/L

Sorbitol, glycine

480 mOsm/kg

24 mo

Not applicable (liquid solution)

Trace

<20 mcg/mL

0

Trace

Glycine

258 mOsm/kg

36 mo refrigerated; 6 mo RT

Not applicable (liquid solution)

≤0.1 mg/mL

0

0

0

10% maltosel

310-380 mOsm/kg

24 mo

Not applicable (liquid solution)

3 mg/L

Trace

0

Trace

Proline

240-440 mOsm/kg

36 mo RT

Not applicable (liquid solution)

Trace

NA

Not detectable

Not detectable

Glycine

240-300 mOsm/kg

36 mo refrigerated; 12 mo RT

Not applicable (liquid solution)

Trace

<20 mcg/mL

0

Trace

Glycine

258 mOsm/kg

36 mo refrigerated; 6 mo RT

Not applicable (liquid solution)

Trace

≤2%

NA

≤10 mmol/L

Proline

380 mOsm/kg

30 mo RT

Not applicable (liquid solution)

IgM Content

Albumin

PEG

Trace

0

0

<2 mcg/mL (5%), <6 mcg/mL (10%)

<2 mcg/mL (5%), <5 mcg/mL (10%)

Trace

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

5

Table 3. Cost Consideration Criteria Producta

Supply

Storage

Distribution

Return Policy Warranty

Packaging or Labeling Enhancements

Intravenous Immune Globulin Carimune NF

3, 6, 12 g

≤30°C

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal, RSS bar code, peel-off label with lot number, expiration date

Flebogamma 5% DIF, 10% DIF

2.5, 5, 10, 20 g (5%), 5, 10, 20 g (10%)

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct from Grifols USA (888) GRIFOLS

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal with hologram, prior handling recognition, integral suspension band, laser-etched vials with UIN, bar-code, peel-off labels with product, lot number

Gammagard Liquid 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 12 mo

Direct from Baxter

No

Tamper-evident cap, RSS bar code, peel-off label with lot number, expiration date

Gammagard S/D 5%

2.5, 5, 10 g

≤25°C; do not freeze

Direct from Baxter

No

Tamper-evident cap, peel-off label with lot number, expiration date

Gammaplex 5%

5, 10 g

2°C-25°C, 24 mo; do not freeze

Wholesaler

Shipping error; defective or damaged product; no out-of-date products

Latex-free, single-use vial, tamper-evident cap, peel-off label with lot number, expiration date

Gamunex-C 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Limited

Tamper-evident packaging, peel-off label with lot number, expiration date

Octagam 5%f

1, 2.5, 5, 10, 25 g

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident, latex-free packaging, peel-off label with lot number, expiration date

Privigen 10%

5, 10, 20 g

≤25°C, 36 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Latex-free, single-use vial, tamper-evident seal, RSS bar code, peel-off label with lot number, expiration date

Subcutaneous Immune Globulin Gammagard Liquid 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 12 mo

Direct from Baxter

No

Tamper-evident cap, RSS bar code, peel-off label with lot number, expiration date

Gamunex-C 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Limited

Tamper-evident packaging, peel-off label with lot number, expiration date

Hizentra 20%

5, 10, 20 mL

≤25°C, 30 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Latex-free packaging, singleuse tamper-evident vials, peel-off label with lot number, expiration date

Key on page 8.

6

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

Table 4. Log Reduction Factor Comparisonsm Enveloped Viruses HIV Producta

Models for HCV

Model for Large DNA

SBV

BVDV

PRV

Nonenveloped Virus

TSE (Prion)

Intravenous Immune Globulin Carimune NF

≥26

≥19

≥9

≥25

≥19 (BEV)

NA

Flebogamma 5% DIF, 10% DIF

≥20.30

≥6.49

≥16.61

≥23.15

≥15.04 (PPV), ≥13.33 (EMCV)

≥11.64

Gammagard Liquid 10%

≥14.8

NA

≥16.8

≥16.9

≥5.7 (HAV), ≥7.7 (EMCV), ≥5.1 (MMV)

NA

Gammagard S/D 5%

≥18.3 (HIV-1), ≥5.7 (HIV-2)

≥5.1

≥6.2

≥12.3

≥8 (HAV)

NA

Gammaplex 5%

>12.9

>20.2

>11.7

NA

>5.9 (HAV), >7.5 (EMCV)

NA

Gamunex-C 10%

≥14

NA

≥16.3

≥12.2

≥5.0 (HAV)

≥6.6

Octagam 5%f

≥14.6

≥16.7

NA

≥21.1

≥6.2 (MEV), ≥9.2 (PPV)

≥6.7n

Privigen 10%

≥16.0

NA

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Gammagard Liquid 10%

≥14.8

NA

≥16.8

≥16.9

≥5.7 (HAV), ≥7.7 (EMCV), ≥5.1 (MMV)

NA

Gamunex-C 10%

≥14

NA

≥16.3

≥12.2

≥5.0 (HAV)

≥6.6

Hizentra 20%

≥16.0

NA

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Subcutaneous Immune Globulin

FOOTNOTES a

All agents are contraindicated for IgA deficiency with antibodies to IgA.

b

Varies with disease state, immune status, and age of the patient.

c

Average of sample lots; variable range in all IgG classes.

d

Average of sample lots.

j

e

For patients with known reactions to IgA or IgA defi ciency with antibodies; special request only.

Limit infusion rate to <3.3 mg IgG/kg per minute (2 mL/kg/h) for 10% solutions.

k

Data on fi le at Bio Products Laboratory.

l

Maltose may cause false elevations in blood glucose testing with glucose dehydrogenasepyrroloquinolone quinone enzyme test strips; may cause problems with patients allergic to corn. See package insert for complete details.

f

g

Octagam was voluntarily withdrawn from the US market in September 2010, pending investigation into the cause of increased thrombotic events associated with the product. As of November 23, 2011, the product is available again.

DO NOT USE Gamunex-C subcutaneously for ITP.

h

Under appropriate storage conditions.

n

Data on fi le at Octapharma.

i

Cohn-Oncley is the original method of cold ethanol fractionation; Kistler-Nitschmann is the specifi c cold ethanol fraction ation method used by the manu facturer (CSL Behring).

o

Some infusion rates were converted from those listed in the prescribing information for consistency and reader convenience.

p

Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

q

Unless specifi c compatibility information is available, do not mix with other drugs or solutions.

r

Patients at high risk for thromboembolic events include patients who are elderly, overweight, or immobilized; patients with a history of hypertension, cardiovascular disease, thrombotic disorders, or who are >65 or dehydrated also are at increased risk.

m

Log reduction factor values obtained through prescribing information; most are available on respective Web sites.

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

7

Table 5. IVIG Administration Rateso IVIGa

Initial Infusion Rate

Maintenance Infusion Rate

Maximum Infusion Ratep

Carimune NF 6%

0.48 mL/kg/h

1-2 mL/kg/h

3 mL/kg/h

No filter required; compatible with NaCl, D5W; increased risk for renal and thrombotic adverse effectsr

Flebogamma 5% DIF, 10% DIF

0.6 mL/kg/h

Increase gradually as tolerated to: 6 mL/kg/h (5%), 4.8 mL/kg/h (10%)

6 mL/kg/h (5%), 4.8 mL/kg/h (10%)

15- to 20-micron in-line filter recommended (5%); no filter required (10%); for patients >65 and those at risk for renal failure or thrombotic events, administer at the minimum infusion rate practicalr

Gammagard Liquid 10%

0.5 mL/kg/h for 30 min

4 mL/kg/h; increase gradually as tolerated

5 mL/kg/h

No filter required; compatible with D5W but not NaCl; patients at risk for renal dysfunction or thrombotic events should be gradually titrated up to a more conservative maximum rate <2 mL/kg/hr

Gammagard SD 5%

0.5 mL/kg/h for 30 min

1-2 mL/kg/h; increase rate every 15 min as tolerated

4 mL/kg/h (5%), 8 mL/kg/h (10%)

15-micron filter required and supplied with administration set; compatible with sterile water

Gammaplex 5%

0.6 mL/kg/h

Increase gradually as tolerated every 15 min to: 4.8 mL/kg/h

4.8 mL/kg/h

15- to 20-micron in-line filter recommended; for patients at risk for renal dysfunction or thrombotic events, administer at minimum infusion rate practicalr

Gamunex-C 10%

0.6 mL/kg/h, 1.2 mL/kg/h (CIDP)

4.8 mL/kg/h

4.8 mL/kg/h

No filter required; avoid NaCl even in evacuated containers; for patients >65 or at risk for renal or thrombotic events, administer at minimum infusion rate practicalr

Octagam 5%f

0.6 mL/kg/h for 30 min

1.2 mL/kg/h for 30 min, then 2.4 mL/kg/h

<4 mL/kg/h

No filter required or supplied; if an in-line filter is used, the pore size should be 0.2-200 microns; for patients at risk for renal dysfunction or thrombotic events, administer at the minimum infusion rate practical, not to exceed 0.07 mL/kg/minr

Privigen 10%

0.3 mL/kg/h

As tolerated, up to maximum recommended rate

2.4 mL/kg/h (ITP), 4.8 mL/kg/h (PID)

No filter required; for patients at risk for renal dysfunction or thrombotic events, administer at minimum infusion rate practicalr

Commentsq

Footnotes on page 7.

KEY HCV

hepatitis C virus

NS

normal saline

BVDV bovine viral diarrhea virus

HH

inhibition of hemolysis

NT

neutralization test

CF

complement fixation

HIV

human immunodeficiency virus

PEG

polyethylene glycol

CIDP

chronic inflammatory demyelinating polyneuropathy

IFA

immunofluorescence assay

PEI

IgA

immune globulin A

Paul Ehrlich Institute International Units

CLL

chronic lymphocytic leukemia

IgG

immune globulin G

PEV

CMV

cytomegalovirus

IgM

immune globulin M

porcine enterovirus (model for HAV)

CPV

canine parvovirus (model for parvovirus B19)

IHA

indirect hemagglutination assay

PID

primary immunodeficiency

IQPP

International Quality Plasma Program

PPV

porcine parvovirus

PRV

pseudorabies virus

ITP

idiopathic thrombocytopenic purpura

RIA

radioimmunoassay

RSS

reduced space symbology

IU

international units

RT

room temperature

IVIG

intravenous immune globulin

SBV

Sindbis virus

KS

Kawasaki syndrome

SD

solvent detergent

LPS

lipopolysaccharide

SQ

subcutaneous

MEV

mouse encephalomyelitis virus

TSE

MMV

mice minute virus (model for non-lipid DNA virus)

transmissible spongiform encephalopathy

UIN

unique identifier number

information not available

VZV

varicella zoster virus

BEV

bovine enterovirus (RNA model)

D5W

dextrose 5% in water

EIA

enzyme immunoassay (formerly ELISA)

EMCV encephalomyocarditis virus (RNA model) FDA

Food and Drug Administration

GPA

guinea pig assay

HA

headache

HAI

hemagglutination inhibition assay

HAV

hepatitis A virus

HBV

hepatitis B virus

8

NA

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

Pharmacy Practice News • January 2012

Clinical 29

Journal Scan

Pharmacists Key To Optimizing Outpatient IV Antimicrobial Therapy From Annals of Pharmacotherapy

B

y involving pharmacists in the clinical oversight of outpatient parenteral antimicrobial therapy (OPAT), the University of California, Davis Health System was able to cost-effectively improve patient safety, according to an observational study (Heintz B et al. Ann Pharmacother 2011;45:1329-1337).

Over one year, the researchers analyzed the impact of the OPAT team, which included an infectious disease (ID) pharmacist, an ID physician and a case manager. The researchers evaluated medication safety, efficacy and complexity and calculated the economic benefits the service provided by

preventing hospital discharge delays, central venous catheter (CVC) placement or the need for OPAT. During the study period, 569 of 644 referrals to the OPAT team resulted in 494 courses of OPAT. At discharge, the ID pharmacist made interventions for safety (56%), regimen complexity

(41%) and efficacy (29%).

Discharge delays were avoided for 35 referrals, for a total of 228 days saved at a cost of $1,605 per day, or approximately $366,000 in hospital bed cost savings for the year of the study. Use of OPAT was avoided in 75 cases (13.2%) and CVC placement was avoided in 48

referrals (8.4%), resulting in $58,080 in additional savings.

The ID pharmacist spent an average of 27 minutes on each of the initial 644 referrals, for a total of 290 hours of service and $24,360 in salary-related expenses. All told, there was a net savings of $620.70 per OPAT referral.

COMMENTARY Elizabeth Dodds Ashley, PharmD, MHS, BCPS Associate Director of Clinical Pharmacy Service Adjunct Associate Professor of Pharmacy Practice PGY-1 and PGY-2, Infectious Disease University of Rochester Rochester, New York

This paper confirms that a multidisciplinary team that pulls together experts in medication is what is best for patients.

So often, when we prepare to discharge patients, we get caught up in just getting it done. But having a team of clinicians overseeing OPAT at discharge brings a pause to the process, during which the team considers whether the patient even needs IV antibiotics. Although

these medications are safe, the OPAT team optimizes outpatient therapy and can prevent the use of IV antibiotics in some patients who may have alternatives, as this study has shown.

In today’s economy, it is difficult to justify additional positions in a department unless there is a return on investment. This paper demonstrates a significant return on investment in a

pharmacist’s time. Given the current health care climate, I would say the authors did a good job of showing how pharmacist involvement is in line with the current mission of decreasing length of stay and readmissions.

All too often, when hospital pharmacy administrators approach their leadership for staffing, the response is, “That’s nice, but where is the real money?” Another common criticism in other studies is that they extrapolate out to inpatients. Instead, this paper looked at real hospital savings and offers solid numbers that hospital pharmacy administrators can take to their leadership and say, “Look at how they improved care while saving money.”

CPOE Alert Fatigue Can Influence Responses to Warfarin Interactions From Journal of the American Medical Information Association

A

lert fatigue may contribute to higher rates of inappropriate alert overrides in computerized prescriber order entry (CPOE) systems, according to a study by researchers at the University of California, San Francisco and the San Francisco Veterans Affairs (VA) Medical Center.

The researchers conducted a retrospective review of 137 admissions (133 unique patients) that occurred between January 2007 and June 2008 and lasted at least 72 hours (Miller A et al. J Am Med Inform Assoc. doi: 10.1136/amiajnl-2011-000262 [Epub ahead of print]).

All patients had at least one warfarin critical drug–drug interaction (cDDI).

Provider and pharmacist responses when overriding the cDDI were categorized as clinically appropriate, inappropriate or absent. Providers were not allowed to have an “absent” (no) response, although pharmacists were allowed. Pharmacist responses were considered appropriate when they indicated that the pharmacist had contacted the provider to adjust the warfarin dose, adjust the interacting medication or monitor the international normalized ratio (INR). Adverse drug

events (ADEs) were defined as an INR outside the goal range, administration of fresh frozen plasma or vitamin K not related to surgery, a bleeding event or a clotting event.

Providers overrode an average of 21 warfarin-related cDDI alerts per patient hospitalization, and an average of six interactions with warfarin at each medication-ordering session. Provider and

pharmacist responses to alert overrides were appropriate in 19.7% and 9.5% of admissions, respectively. There were 50 ADEs with warfarin, 80% of which were considered to have no clinical effect or a mild clinical effect. Alerts that resulted in inappropriate responses occurred simultaneously with an average of four noncritical alerts, whereas alerts resulting in appropriate responses occurred

simultaneously with an average of 2.4 noncritical alerts. Multivariate analysis showed that the number of simultaneous noncritical alerts was the only factor associated with an inappropriate provider response (P=0.01).

The investigators concluded that the results suggest that alert fatigue may contribute “to the high prevalence of inappropriate alert override text responses.”

COMMENTARY Brian Pinto, PharmD Clinical Specialist, Drug Information Johns Hopkins Hospital Baltimore, Maryland

The study notes an average of 21 alerts to warfarin. I’m not sure what the VA policy is, but many hospitals require warfarin to be ordered every day, to force clinicians to be actively involved in monitoring. If that is the case at the VA, and the patients are on amiodarone or other drugs, there is going to be at least one cDDI

every day. That raises the question of whether providers need to see the alert every time, or if those repeated alerts are banging them over the head needlessly.

It seems that a system designed to provide a method for prescribers to communicate their rationale for overriding cDDI alerts was not being used as expected. If a provider overrides an alert but provides no reason, that doesn’t help the pharmacist and would cause me to rethink the system and how it was designed, which is what the authors have done.

The absence of pharmacist response to the majority of alerts might be explained by the nature of warfarin,

for which the effects of potential interactions are not known until later. The pharmacists may have been thinking, “If I get an alert today, I’ll be on watch and make adjustments if necessary.” It’s possible that the most appropriate response is no response.

However, this is a retrospective study and the pharmacists weren’t documenting their thought processes.

The only way to capture their thought processes is through a prospective, observational study, which would be extremely tedious, if not impossible. Overall, I think the authors did a nice job in trying to answer a question that would be particularly difficult to address in a retrospective manner.

For more Journal Scan, see page 33.

30 Clinical

Pharmacy Practice News • January 2012

Critical Care

Bar-Code Scanning Can Fix ‘Black Hole’ of OR Drug Safety Error rates slashed; anesthesiologists embrace technology New Orleans—When an anesthesiologist calls the operating room (OR) a “black hole of medication safety,” hospitals might want to pay attention. The description came from Ludwik Fedorko, MD, PhD, FRCPC, staff anesthesiologist at the University Health Network’s (UHN) Toronto General Hospital in Canada, during a session on OR drug safety at the 2011 American Society of Health-System Pharmacists Midyear Clinical Meeting.

Dr. Fedorko noted that anesthesiologists are the only health care professionals in the hospital setting who dispense, premix, repackage, relabel and administer medications without independent verification. Given that most drugs administered perioperatively are high risk, the potential threat to patients is obvious. If that’s not enough to make hospital administrators uneasy, other figures presented by Dr. Fedorko are equally disconcerting: The OR and the postanesthesia care unit disproportionately accounted for 81% of all medication error reports, which exceeds by fivefold the error rates reported in the rest of the hospital (MEDMARX Data Report: A Chartbook of 1998-2004 Findings from the Perioperative Setting; 2006). Additionally, more than 60% of medication errors committed by anesthesiologists are related to the removal of incorrect ampoules or vials from anesthesia drug trays, incorrect labeling of syringes after admixing and syringe swaps during surgery (Can J Anaesth 2001;48:139-146).

On average, anesthesiologists administer 10,000 drug doses a year, with estimated error rates ranging from 0.1% to 0.85%, Dr. Fedorko noted. At best then, one error is committed for every 1,000 drug-dose administrations, or 10 errors annually.

But even that calculus may underes-

timate the true extent of the trouble because a vast majority of the errors—many of which pose a significant risk for harm—are reversible. “We can almost always dig ourselves out of a

hole,” Dr. Fedorko said. “The event is charted, but it doesn’t always show up as an error.”

Errors are often system-driven, Dr. Fedorko continued—a result of the fast pace of the OR workflow combined with a lack of redundant checks and balances. One possible solution, a satellite pharmacy for the OR, is exceedingly expensive and still would not address emergency doses. “We’re very good clinicians, but we’re not machines,” he said. “Throughout the hospital, there are safety steps in place to prevent medication errors, but not in the OR.”

The Power of Collaboration That is until now. Under the leadership of Esther Fung, RPh, BScPhm, MScPhm, director of pharmacy operations at UHN, a pharmacy–anesthesia collaboration was established to explore the potential of a point-of-care, computer-aided syringe labeling, bar-coding and verification process. The system was designed and developed at the UHN, with funding from the Canadian Patient Safety Institute and drug-industry sponsors.

In January 2010, the system was implemented in all 20 ORs at Toronto General, a 762-bed tertiary academic health system. Use by anesthesiologists was completely voluntary. The process requires the anesthesiologist to scan every drug ampoule and syringe label for accuracy verification throughout drug dispensing, premixing, administration and documentation. Dr. Fedorko explained that it enables real-time documentation of medication, fluids, infusions, and urine and blood loss through an interface similar to a touch-pad screen. Electronic anesthesia data capture produces a complete intraoperative record that funnels directly to the UHN electronic medical record, which means that anesthesiologists do not have to document their actions after the procedure, as they had to do previously.

Within two weeks of implementation, all staff anesthesiologists had adopted the new process. Five months out, the bar-coding system had been used for more than 60,000 doses in more than 4,000 surgeries. All anesthesiologists who had used the system were surveyed about medication errors that were intercepted by barcode scanning and to grade their satisfaction level with the system within that five-month window. The survey also asked if the anesthesiologists preferred the new system over the traditional one.

Surveys were submitted anonymously.

Twenty-one of the 41 survey respondents (52%) reported 29 medication

errors, all of which were intercepted by bar-code scanning. Opinions about the system were overwhelmingly positive: More than 97% of the responding anesthesiologists favored it.

Now, after 23 months and more than 300,000 doses administered in more than 20,000 surgical cases, no medication error incidents related to mistaken drug identity have been reported when barcode scanning was used. A single critical drug error did occur when an anesthesiologist bypassed the bar-code scanning process. The results were so compelling that the system has become the standard of care at Toronto General and will soon extend throughout the UHN system to Princess Margaret Hospital and Toronto Western Hospital, both in Toronto.

Embracing Change At first, Dr. Fedorko feared that his colleagues would resist the change, in part because they would need to scan every ampoule pulled from the dispensing cabinet. So he was surprised at how quickly and enthusiastically the staff anesthesiologists embraced the process. “In fact, there was unanimous acceptance and they were very keen to use it,” he said.

“They understood that it would not only prevent them from making drug errors, but also that it improved and automated workflow in terms of easier charting and documentation because they would no longer have to do it manually.”

Another key that led to systemwide adoption is the relatively low implementation and operational costs. “The process is orders-of-magnitude cheaper than alternatives, such as a satellite pharmacy, and it also puts us fully in compliance with the Joint Commission for injectable medication labeling in the OR,” Dr. Fedorko said.

He emphasized that the real driver of the project was the pharmacy, which took the lead in the system’s development and rollout. “I’d advise others who want to introduce this technology to coordinate closely with leadership in the pharmacy and anesthesia departments right from the start, and to make sure that the end users—the anesthesiologists—are involved in the development process,” he said.

“Anesthesia on its own had no knowledge of, or appetite for, implementing a medication safety system. It was only the continuous education and support from pharmacy leaders that made it happen.”

“This a fascinating study, especially coming from a practicing anesthesiologist who sees these problems every day and did something to address them,” said Roy Guharoy, PharmD, FASHP, chief pharmacy officer and profes-

sor of medicine with the University of Massachusetts Memorial Health Care in Worcester. “What they did was unique, because they didn’t mandate use of the system. But once it could be shown that it helped anesthesiologists save time, the anesthesiologists were won over, and now they have 100% compliance.”

Dr. Guharoy concurs with Dr. Fedorko’s characterization of the OR as a “black hole” of drug safety. “They’re often in a rush; they get these drugs very fast and it’s easy to mix up the wrong dose. It happens. All around the country there are major initiatives, and a lot of federal money, to implement electronic medical records. But the OR is one area that has not been adequately addressed in terms of safety, and there’s lots of room for improvement.”

In fact, shortly after hearing Dr. Fedorko’s presentation, Dr. Guharoy said he spoke to his facility’s medication safety pharmacist, and his hospital has begun looking into implementing a similar system. “This is an area we really need to address. Not nearly enough has been done.”

Does Initiative Go Far Enough?

In 1999, the American Society of Health-System Pharmacists issued Guidelines on Surgery and Anesthesiology Pharmaceutical Services, which called for ongoing and direct pharmacy involvement in numerous aspects of surgical care. Matt Grissinger, BS, RPh, director of error reporting programs at the Institute for Safe Medication Practices, said the bar-coding initiative at Toronto General Hospital is an important first step in meeting that goal. But more work remains. He noted, for example, that the hospital is not yet using the pharmacy to manage the formulary and evaluate the actual use of drugs in the OR. Still, he said he was impressed that the project was led by the pharmacy, that project leaders involved the anesthesiologists in the development process, and that they solicited end-user opinions after the system had been up and running for a while.

“They made sure it was going to be used correctly and what feelings the anesthesiologists had about it,” he said. “That’s not a small task. A lot of people implement technology but don’t prepare for it, but this group did.”

—Steve Frandzel Dr. Fedorko disclosed that he is a consultant and stockholder with Thornhill Research Inc., a spin-off of the University Health Network, which developed the technology described in the article.

Dr. Guharoy and Ms. Fung disclosed no relevant conflicts of interest.

Switch to Privigen

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3-step virus inactivation/removal process, including nanofiltration to approximately 20 nanometers, reduces the risk of pathogen transmission. The risk of virus transmission cannot be completely eliminated

Important Safety Information Privigen is indicated as replacement therapy for patients with primary immunodeficiency (PI) associated with defects in humoral immunity, including but not limited to common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, WiskottAldrich syndrome, and severe combined immunodeficiencies. Privigen is also indicated to raise platelet counts in patients with chronic immune thrombocytopenic purpura (ITP).

WARNING: Use of Immune Globulin Intravenous (IVIg) products, particularly those containing sucrose, have been associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death. Privigen does not contain sucrose. Administer Privigen at minimum rate practicable in patients at risk of renal dysfunction or acute renal failure. At-risk patients include those with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia; over 65 years of age; or receiving known nephrotoxic drugs.

See full prescribing information for complete boxed warning.

Privigen is contraindicated in patients with history of anaphylactic or severe systemic reaction to human immune globulin, in patients with hyperprolinemia, and in IgA-deficient patients with antibodies to IgA and history of hypersensitivity.

treatment. In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Also monitor patients with risk factors for thrombotic events; consider baseline assessment of blood viscosity for those at risk of hyperviscosity.

Patients could experience increased serum viscosity, hyperproteinemia or hyponatremia; infrequently, aseptic meningitis syndrome (AMS) may occur (most often with high doses and/or rapid IVIg infusion). There have been reports of IVIg-related hemolysis, hemolytic anemia, and pulmonary adverse events, including transfusion-related acute lung injury (TRALI). Avoid highdose regimen where fluid volume is of concern.

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

In clinical studies of patients being treated with Privigen for PI, the most serious adverse reaction was hypersensitivity (one subject). Adverse reactions observed in >5% of subjects with PI were headache, pain, nausea, fatigue, chills, vomiting, joint swelling/effusion, pyrexia, and urticaria.

Monitor patient vital signs throughout infusion of Privigen. In cases of severe hypersensitivity or anaphylactic reactions, discontinue administration and institute appropriate medical

In clinical studies of patients being treated with Privigen for chronic ITP, the most serious adverse reactions were AMS (one subject) and hemolysis (eight subjects). Adverse reactions seen in >5% of subjects with chronic ITP were headache, pyrexia/hyperthermia, positive DAT, anemia, vomiting, nausea, increases in conjugated and unconjugated bilirubin, hyperbilirubinemia, and increased blood lactate dehydrogenase.

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

Treatment with Privigen might interfere with a patient’s response to live virus vaccines and could lead to misinterpretation of serologic testing.

©2011 CSL Behring LLC 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901 USA www.CSLBehring-us.com www.Privigen.com PVG10-11-0014 10/2011

Please see brief summary of full prescribing information on following pages.

32 New Products

Pharmacy Practice News • January 2012

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5.6

Hemolysis

in

vivo

WARNING: ACUTE RENAL DYSFUNCTION/FAILURE

10

containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose.

Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]).

4

see Adverse Reactions [6]

5.7

Transfusion-Related Acute Lung Injury (TRALI) 11

CONTRAINDICATIONS

see Description [11] 5 5.1

see Warnings and Precautions [5.1] WARNINGS AND PRECAUTIONS Hypersensitivity see Contraindications [4]

5.9

see Dosage and Administration [2.2] Transmissible Infectious Agents

5.10

.

Interference with Laboratory Tests

see Description [11]).

5.2

Renal Dysfunction/Failure

1

Boxed Warning Dosage and Administration [2.3]

see 6.1 Clinical Trials Experience Because different clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

2

5.4

Administration [2.3] 5.5 Aseptic Meningitis Syndrome (AMS) [6]

see Clinical Studies [14.1]

Thrombotic Events

see Dosage and see Adverse Reactions irrespective of causality

Pharmacy Practice News • January 2012

Clinical 33

Journal Scan

IV Infusion Concentrations Still Not Consistently Standardized From AJHP

M

any institutions do not use standard IV infusion concentrations of commonly used high-risk medications, according to the results of a 2008 survey by the U.S. Pharmacopeia (USP) Safe Medication Use Expert Committee (SMU EC) (Philips M. Am J Health Syst Pharm 2011; 68:2176-2182).

The survey—sent out electronically to approximately 3,500 U.S. hospital and health-system pharmacy directors by the American Society of HealthSystem Pharmacists—sought to obtain an overview of currently used IV concentrations and identify opportunities for improvement. Of the more than 350 responses, those from 229 organizations met inclusion criteria. Lists of standard IV concentrations from

Table 2: PI Pivotal Study – Adverse Events Occurring in >5% of Subjects During a Privigen Infusion or Within 72 Hours After the End of an Infusion, Irrespective of Causality Number (Rate) of Number (%) of Subjects Adverse Event Infusions with Adverse (Excluding Infections) [n=80] Event [n=1038]

these organizations were included in the data analysis.

According to the report, many of the standard concentrations reported by the survey respondents failed to meet recommendations laid out by the SMU EC with respect to standardization.

The total numbers of unique medication concentrations were 118, 80 and 53 for adult, pediatric and neonatal patients, respectively. For adult IV infusion medications, 32% to 79% of institutions that had a standard concentration policy adhered to one standard concentration per medication.

Table 6: Chronic ITP Study – Adverse Events Occurring in >5% of Subjects During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle, Irrespective of Causality (Two consecutive daily infusions) Number (%) of Subjects [n=57]

Adverse Event

Number (Rate) of Infusions With Adverse Event [n=114]

COMMENTARY Matthew P. Fricker Jr., MS, RPh, FASHP Program Director Institute for Safe Medication Practices Horsham, Pennsylvania

Table 3: PI Pivotal Study – Adverse Reactions Occurring in >5% of Subjects, Irrespective of Time of Occurrence Adverse Reaction

*

Number (%) of Subjects [n=80]

Table 7: Chronic ITP Study – Adverse Reactions Occurring in >5% of Subjects, Irrespective of Time of Occurrence

Number (Rate) of Infusions with Adverse Reaction [n=1038]

Adverse Reaction

Number (%) of Subjects [n=57]

Number (Rate) of Infusions With Adverse Reaction [n=114]

†

6.2

Postmarketing Experience

12

see Dosing and Administration [2.3]

irrespective of causality

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

[14.2]

see Clinical Studies

CSL Behring AG

CSL Behring LLC

Although the paper discusses the drugs, it does not break out the number of concentrations reported. If 10 hospitals used 10 different concentrations of a drug but only one concentration each, that is not standardized nationally, but it is standard for each hospital.

Although you really cannot tell from the results exactly how bad the situation is, it is easy to see that we are not where we should be with standardization. For example, one of the tables indicates that only 50% of the respondents used a single standard concentration of lidocaine. That jumps out at me.

When you standardize, you take the variation out of medication management, and when you take the variation out, you make it safer. This comes into play when you program different concentrations of a drug into a smart pump library. If there are five or 10 concentrations, how easy is it for the nurse to pick the wrong dose for administration?

Or you may have a standard concentration, but then some of the prescribers write for milliliters per hour, others write in units per hour and others write in units per kilogram per hour. It is one drug in the library, but you can administer it three different ways.

The bottom line is that when you administer drugs, you don’t want people having to do math all the time.

The more options you have, the more opportunities there are for error.

None of the commentators had any relevant disclosures.

34 Clinical

Pharmacy Practice News • January 2012

Medication Safety

HYDROMORPHONE continued from page 1

Mr. Fricker described results of the regional initiative during a Dec. 14, 2011, webinar hosted by ISMP. “We wanted to determine, if hospitals developed specific risk-reduction strategies, would we see a positive impact,” he said. Overall, staff physicians, nurses and pharmacists demonstrated a 15% to 19% improvement in their knowledge of hydromorphone equianalgesic potency, but their understanding of comorbidities did not meaningfully improve, and misinformation persisted about the effects of obesity, respiratory disease, opioid tolerance and sleep apnea. “More work must be done in these areas,” Mr. Fricker noted.

Still, there was a 51% reduction in

DRUG MISHAPS continued from page 7

additional monitoring between regular physician visits. But they acknowledged that limited resources, including time, manpower and money, often rules out this extended role.

At the University of Arizona Medi­ cal Center in Yuma, Daniel Hays, PharmD, BCPS, clinical pharmacist in the Departments of Pharmacy and Emergency Medicine, said he sees elderly patients with ADEs arrive daily at his ED. “One of the great things that we as pharmacists can do in the ED is identify these adverse drug events,” Dr. Hays said. “Physicians are great at diagnosing, but they may not have a full awareness of all the medications, side effects, interactions and so forth. Our real input can be in education—discussions with physicians here as well as with the patient’s primary care physician, or prescribing physician in the case of a specialist.”

Once patients are discharged from the ED, he said, they “should definitely follow up with their primary or specialty physician.” A visit to an ambulatory care pharmacist specialist for a full pharmaceutical workup would also be beneficial, he added.

Dr. Acquisto also stressed the need for constant communications between pharmacists and physicians. “It is important,” she said, “for clinical pharmacists to [collaborate] with prescribers in both ambulatory settings and at discharge following hospitalization to perform an adequate review of all medications, to determine the appropriate dose for the specific patient, and to provide adequate medication counseling in an effort to reduce hospitalizations due to adverse medication events.”

—Bruce Buckley

the number of patients who required a rescue agent or rapid response call, indicating that improvements can in fact be made as a result of these types of safe medication use initiatives, Mr. Fricker stressed.

A Continuing Drug Safety Issue Hydromorphone (Dilaudid), the morphine derivative commonly used to manage moderate to severe pain, continues to be implicated in medication errors and patient harm despite efforts to educate pharmacists and cli-

nicians about its safe use. According to the Pennsylvania Patient Safety Authority, nearly 1,700 hydromorphone errors were reported between January 2008 and October 2009, with almost 70% of them reaching the patient. A 2006 Canadian study reported 251 deaths in the previous decade due to oral and IV overdoses with hydromorphone (J Anal Toxicol 2006;30:202-209).

“Hydromorphone continues to be associated with patient harm in many hospitals and health systems,” said Matthew Grissinger, RPh, director of

ISMP’s Error Reporting Programs.

“Some organizations have begun to recognize this risk but may not have developed effective strategies for reducing the potential for patient harm. Others may not be aware of the number of hydromorphone-related events occurring in their institutions because they are not visible through the usual medication event reporting system.”

Why the gap in awareness? “For the most part, bad events that happen with hydromorphone are not being reported as medication errors through the ‘tra-

Pharmacy Practice News • January 2012

Clinical 35

Medication Safety ditional’ error reporting process,” Mr. Grissinger said. “For example, I’ve seen far too many events that were reported as ‘unpreventable’ adverse drug reactions when, in fact, they were more than likely preventable. We’ve seen patients get hydromorphone 2 mg and higher doses (which is more than likely inappropriately too much), the patient has a bad response to the drug (e.g., their respirations decrease dramatically) and the doctor/nurse gives the patient a reversal agent/antidote like naloxone. From my vantage point, it almost comes across

like ‘this type of stuff happens all the time, so we just give naloxone and everything is better.’ But hospitals don’t realize that this is NOT okay practice and those types of events are not thought of or reported as medication errors.”

Another problem is that hydromorphone is approximately seven times more potent than morphine IV, but both drugs come in the same dosage forms and in similar packaging. “There are still a number of practitioners who believe [hydromorphone and morphine] are one and the same drugs, or that hydromor-

phone is a generic name for morphine,” Mr. Fricker said. “It’s complicated by the fact that both of these drugs have been available in exactly the same dosage forms. It’s easy to mix them up,” he said, adding that the use of “tall man” lettering for the painkiller (i.e., HYDROmorphone) can help reduce errors due to name confusion.

Establishing the Baseline Participating hospitals in the demonstration project—done in conjunction with the Health Care Improvement

Foundation—included Abington Memorial Hospital, Doylestown Hospital, Hahnemann University Hospital, Holy Redeemer Hospital, LifeCare Hospitals of Chester County, Nazareth Hospital, Riddle Hospital, the Chester County Hospital and Thomas Jefferson University Hospital. The process began with hospitals surveying their physicians, nurses and pharmacists to determine their baseline knowledge about proper hydromorphone dosing and administration. The hospitals also analyzed their

•

see HYDROMORPHONE, page 36

36 Clinical

Pharmacy Practice News • January 2012

Medication Safety

HYDROMORPHONE continued from page 35

internal databases to determine the numbers of pharmacist interventions, medication errors, ADRs and patients requiring naloxone rescue.

They found that the vast majority of ADRs occurred among acutely ill patients in medical-surgical units (76%), followed by the emergency department (11%). The lowest incidence rate (1%) was found in critical care units, but Mr. Fricker cautioned about under-reporting, especially

‘Overwhelmingly, it’s the pharmacists who catch ADRs at our institutions, and that’s pretty much the case elsewhere.’

—Dean Bennett, RPh among patients who are not well or who are not expected to improve. “That’s a common error reporting problem in critical care units,” he said.

In addition to general confusion about differences between the two drugs,

the practitioner surveys and databases revealed other factors that contributed to ADRs. These involved believing that a patient was opioid-naive when he or she was not (46%), inadequate patient monitoring (34%), believing that obese

patients require higher doses (30%) and failure to recognize concomitant use of potentiating drugs (19%). Still other contributing factors involved the patient’s age, presence of respiratory disease, orders being placed for excessive doses and too-short intervals between doses.

The hospitals then developed and conducted a range of educational efforts for their staff and implemented a number of other changes. These included removing higher doses of hydromorphone (2 and 4 mg forms) from patient care units, revising paper and computerized physician order entry (CPOE) order sets to list lower doses and warnings about comparative doses, removing the ability to override hydromorphone doses, reducing initial doses and eliminating the administration of frequent doses (two to three times per hour). Other interventions included requiring an independent double-check of the dose and dosage form if an override of the automatic dispensing cabinet is entered and requiring a consultation with pain management or pharmacy intervention for higher doses.

“Confusing hydromorphone with morphine, and gaps in knowledge about the potency and efficacy of hydromorphone, have frequently contributed to preventable adverse drug events described in the patient safety literature,” said Dave Ehlert, PharmD, vice president, Pharmacy Practice Resources, McKesson Pharmacy Optimization.

“Therefore, it is important for hospitals and other health care settings to develop and implement effective strategies that address these issues and minimize the incidence and severity of hydromorphone-related adverse drug events,” noted Dr. Ehlert, who was not a webinar participant but who was asked to comment on the ISMP pilot project.

Christiana Care Update “Overwhelmingly, it’s the pharmacists who catch ADRs at our institutions, and that’s pretty much the case elsewhere,” said Dean Bennett, RPh, medication safety specialist at Christiana Care Health System in Wilmington, Del. During the webinar, Mr. Bennett presented updated data from an ongoing project to improve injectable hydromorphone safety at 913-bed Christiana Hospital in Newark, and at 241-bed Wilmington Hospital, both in Delaware.

The project received a Cheers Award from the ISMP in 2010 (see Pharmacy Practice News, January 2011).

When the project began in 2004, Christiana Care did not have a CPOE system and ADE data showed that hydromorphone was a contributing or causative factor in a number of moderately severe and severe events, and use of the drug was increasing. “This was very troubling for us because we knew a preference was developing for hydromorphone

Pharmacy Practice News • January 2012

Clinical 37

Medication Safety versus morphine,” Mr. Bennett said.

“Our prescribers told us, ‘It’s just a much better drug for treating pain.’”

Christiana assembled a multidisciplinary task force to focus on the safe use of injectable hydromorphone. As at other facilities, the task force found the most concerning and risky behavior revolved around an under-appreciation of the drug’s potency. This was exacerbated by the fact that the 1 mg dose was the smallest available, equivalent in potency to about 7 mg of morphine. Despite a variety of educational efforts from 2006 to 2009, including newsletter articles, distribution of pocket cards and use of preprinted order forms to which prescribing statements had been added, the number of ADEs related to IV hydromorphone continued to fluctuate. “There was no sustained improvement,” Mr. Bennett said.

When Christiana installed a CPOE system in 2009, one of the pharmacy’s first priorities involved hydromorphone. The system was populated only with doses that fell within the hospital’s recommended ranges for opioid-naive patients (<65 years, 0.5-1.0 mg IV every four to six hours; ≥65 years, 0.2-0.3 mg IV every four to six hours). Any other dose required an active alteration. Additionally, an “acute pain module” was designed and placed within all electronic order sets needing pain management orders. The pain module included baselines and acceptable dosages for all agents. Finally, a custom alert system was embedded in the clinical decision support system to notify prescribers when orders fell outside the recommended range.

The effort bore results: The percentage of 1 mg initial doses fell from a baseline of 46% in 2005 to 34% post-education to 18% post-CPOE. During the 21-month period after CPOE was installed, the hospitals experienced only one hydromorphone-related ADR, and that was in an area that wasn’t connected to the CPOE. “CPOE allows us to hammer home recommended prescriber doses. It’s right there in their faces,” Mr. Bennett said.

In the future, Mr. Bennett said that Christiana plans to modify the order entry format to require a data entry about whether a patient is opioid-naive or tolerant. Also in the works are clinical documentation modifications to include such risk factors as sleep apnea and high body mass index. Ultimately, the system will be programmed to issue alerts based on specific risk factors and recommendations for each patient, he said.

In June 2011, in response to ongoing medication errors, the FDA approved some revisions to the prescribing information, container labels and carton labels for 1, 2, 4 and 10 mg hydromorphone products. The dosing information and warnings now appear at the front of the prescribing information. Additionally, the IV starting dose has been reduced

to 0.2 to 1 mg from a previous 1 to 2 mg.

Finally, container and carton information now display the generic name using tall man lettering to better distinguish it from morphine.

Concerning all of these efforts, “no one of these strategies by [itself ] is going to make a huge difference,” Mr. Fricker said. “But as with any medication error reduction effort, when you start stacking them and getting additive effects, the result is greater than the sum of the parts.”

—Ted Agres

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38 Clinical

Pharmacy Practice News • January 2012

Infectious Disease

Survey: Injection Habits of Anesthesiologists ‘Discouraging’ A Table 1. Reported Barriers To Using a New Vial of

new survey paints an at times alarming picture of injection practices among anesthesiologists in New York state.

Nearly half (49%) said they sometimes used the same vials of medication for more than one patient—a strict no-no for many kinds of drugs, including propofol. (Indeed, 31% of clinicians who reported using propofol said they had used the same vial on multiple patients.) Roughly one-fourth said they did not always use a new needle FILE SLUG and syringe when drawing medication CMEzone qtrpg.indd 1ST PROOF the LAYOUT APPROVED from a vial. And about same proINITIALS AND DATE portion reported using an open vial of MAX sign-off they had not medication even though directly observed someone else openSenior Editor ing the container.

Copy Editor Perhaps most concerning, the survey R2 Sales anesthesia resialso found that four dents in the state (8%) January 10, 2012 1:29 PM Production said they had reused syringes on different patients, Creative although the researchers who conCOMMENTS: Half Vertical ducted the survey expressed doubt that everyone who said they did so under4C stood the question. Attending physicians were much less likely to admit to reusing syringes—2%, the survey found,

which is in line with previous reports.

“I was discouraged to see the number of respondents who were not using appropriate safe injection practices,” said Elliott Greene, MD, professor of anesthesiology at Albany Medical College, in Albany, N.Y., and a co-author of a report on the survey. “That was a reminder that we have a lot of work to do to educate not only the trainees—the residents were showing some differences from the attending physicians—but the overall responses show some very serious infection control lapses.”

PROOF 1 12/10 FINAL OK Physicians blamed drug shortages, DATE REV 1 12/17with prosuch asINITIALS theAND ongoing problems REV 2 pofol, and efforts to reduce waste as the REV 3 biggest obstacles to using a new vial of REV 4 medication for each patient REV 5 (Table 1).

“I’m not using that as an REV 6 excuse; I’m REV 7 just saying that’s something that we REV 8 need to work on,” said Richard Beers, 9 the SyraMD, an anesthesiologistREVat cuse VA Medical Center and the State University of New York Upstate Medical University, in Syracuse, who helped lead the survey.

Dr. Beers said he was not sure every physician who reported reusing a

Medication for Every Patient Total

Shortage of medication Lack of storage High cost STATUS AND HISTORY Inconvenience PICKED UP FROM: Reduce APPLIED TO:

waste

Save time Personal preference None

Practice Setting

n (%)

Any Outpatient (n=431) n (%)

No Outpatient (n=85) n (%)

231 (44)

192 (45)

38 (45)

25 (5)

20 (5)

5 (6)

143 (27)

125 (29)

18 (21)

48 (9)

42 (10)

6 (7)

229 (44)

203 (47)

26 (31)

7 (1)

7 (2)

0 (0)

23 (4)

21 (5)

2 (2)

174 (33)

137 (32)

33 (39)

Table 2. Questions From the NYSSA/NYCDOH Survey on Injection Practices Total n

%

Resident

Attending

n

n

%

%

Medication Vial Use How often did you use the same medication vial for more than one patient?

www.CMEZone.com Your premier source for practical, relevant and timely continuing medical and pharmacy education

Always/Most of the time/Sometimes

269

Total

545

49%

27

51%

53

180

49%

365

Did you leave a needle, cannula or spike device inserted into a medication vial’s rubber stopper for reuse?

Always/Most of the time/Sometimes

81

Total

543

15%

10

19%

52

59

16%

364

How often did you combine leftover contents of medication vials for use on a new patient?

Here are FREE educational activities available now on CMEZone.com

Applying Recent Evidence in Hereditary Angioedema: Optimizing Individual Care

Always/Most of the time/Sometimes

58

Total

528

11%

5

10%

50

39

11%

355

How often did you use an open medication vial where you did not directly observe someone else opening it?

Never/Sometimes/Most of the time

126

Total

540

23%

10

20%

51

88

24%

363

Needle/Syringe Use

MN1111

Expires October 1, 2012

Did you keep used syringes and needles (or cannulae) separate from clean, unused needles and syringes while providing anesthesia?

Never/Sometimes/Most of the time

73

Total

538

14%

8

15%

52

41

11%

362

How often did you use a new needle and syringe each time [you] accessed a medication vial?

Tailoring Therapy in Metastatic Breast Cancer: Novel Clinical Approaches Expires October 1, 2012

MN113

Never/Sometimes/Most of the time

144

Total

523

28%

28

55%

51

83

24%

350

How often did you use a new needle and syringe when administering medications for each new patient?

Never/Sometimes/Most of the time

16

Total

522

3%

4 51

8%

7

2%

250

NYCDOH, New York City Department of Health; NYSSA, New York State Society of Anesthesiologists

Pharmacy Practice News • January 2012

Clinical 39

Infectious Disease gist at the New York City Department of Health and Mental Hygiene, who worked on the report, said the results call for a “multifaceted” approach.

Education of providers about safe injection practices still is necessary, Dr. Gounder said, but so, too, are efforts to change what he called systemic problems—such as the continued availability of multidose vials of propofol. “We’d like to work with the CDC and the FDA to potentially change how medication vials are labeled. We think all medication vials should be labeled syringe understood the question. However, he added, even if only one doctor did so knowingly, “that would be horrendous practice if it were true. I hope sincerely it’s not true.”

Training Widespread— But Is It Effective?

The news was not all bad, however. The survey, conducted by the New York State Society of Anesthesiologists (NYSSA) and the New York City Department of Health, found that 98% of attendings who participated said they’d taken a sanctioned infection control course in the past year. Meanwhile, 84% of all respondents said they were aware of outbreaks linked to poor injection practices.

The survey, which had a response rate of 26%, included 595 residents and attending anesthesiologists practicing in New York (Table 2). Of those, 82% said they worked at least part time in an outpatient facility.

More than 125,000 patients in the United States have potentially been exposed to hepatitis B and C, and HIV, since 1999, according to the Centers for Disease Control and Prevention (CDC). Although the agency said “many of these lapses” involve reused syringes, it did not provide a more precise figure.

These cases spurred the development of the One & Only Campaign, a collaboration of the CDC and the Safe Injection Practices Coalition, to reduce the incidence of unsafe injections. The campaign is focused on New York, New Jersey and Nevada. In New York and Nevada, several high-profile cases of unsafe injection practices have surfaced in recent years.

The most dramatic of these involved an outbreak of hepatitis C linked to a chain of endoscopy clinics in Las Vegas.

Health officials notified nearly 63,000 patients in the area of their potential risk for exposure to hepatitis C virus and other bloodborne pathogens—although eventually only five cases of hepatitis C were definitively linked to medical procedures performed at the facilities.

Prabhu Gounder, MD, an epidemiolo-

as single-use vials only.”

In addition, Dr. Gounder said, the government must do more to address drug shortages. The Obama administration recently issued new rules regarding shortages, but whether these will ease the problem remains to be seen.

“Shortage is going to be an ongoing issue,” Dr. Gounder said. “Anesthesiologists may have to make alternative arrangements. In inpatient settings, pharmacists can split vials in a sterile environment, or propose alternative medicines.”

For Dr. Greene, who with Dr. Beers helped create a training module for the NYSSA on safe injections, the message is simple enough: “Don’t enter a vial with a used syringe or needle. Always use a clean syringe and needle, and all vials, including multidose vials, are single-patient use; throw them out at the end of the case. Don’t administer medications from the same syringe to more than one patient. That way, there’s no potential for transmitting something inadvertently.”

—Adam Marcus

40 Clinical

Pharmacy Practice News • January 2012

Pain Medicine

‘Medical Marijuana’ Fizzles in PONV Trial Side effects of injected THC halt study early, but expert sees reason for optimism Chicago—Intravenous tetrahydrocannabinol (THC), the active ingredient in marijuana, does not prevent postoperative nausea and vomiting (PONV) in high-risk patients undergoing elective surgery under general anesthesia, researchers have found. To the contrary, patients in the study group experienced more sedation, confusion and

anxiety than did controls, which led to the trial being stopped after 40 patients participated.

“Despite advances in medical re­­ search, we still see a lot of postoperative nausea and vomiting,” said Maren Kleine-Brueggeney, MD, senior fellow at the University of Washington, in Seattle, who led the research. “Oral THC has

been shown to prevent nausea and vomiting in cancer patients who receive chemotherapy, and anecdotal evidence suggests that oral THC may prevent PONV. So we decided to perform our double-blind, randomized controlled trial with intravenous THC.” The investigators planned on enroll-

ing 320 patients into the study; only 40 (39 women) participated before the trial was stopped. After accounting for smoking status and history of PONV, the patients were randomly assigned to receive either placebo or one dose of IV THC (0.125 mg/kg) 15 minutes before the end of surgery.

The incidence of postoperative nausea was similar for the study and control groups (Table). Moreover, no differences were found with respect to vomiting in the first two hours (26% of patients receiving THC vs. 26% receiving placebo), between two and six hours after surgery (0% for THC vs. 5% for placebo; P=0.35) or between six and 24 hours after surgery (13% for THC vs. 6% for placebo; P=0.44). Retching in the first two hours after surgery proved to be significantly more common in patients who received THC than in those who received placebo (53% vs. 21%; P=0.04).

The time to extubation after surgery was longer for patients given THC than for controls (20±16 vs. 12±6 minutes; P=0.04). Patients in the THC group also had higher scores for confusion (P<0.01), anxiety (P=0.03), change of perception (P<0.01) and sedation (P<0.01) at admission to the postoperative care unit (PACU). These scores then were equal at all time points between 30 minutes and 24 hours after admission to the PACU. Patients who received THC also consumed significantly less fentanyl in the first two hours after surgery than those in the placebo group (P=0.03).

One patient given THC experienced extensive mood swings during the first 24 hours after surgery. No significant cardiovascular or respiratory side effects were observed, according to the researchers, who presented their findings at the 2011 annual meeting of the American Society of Anesthesiologists (abstract 834).

Despite the disappointing results, Dr. Kleine-Brueggeney said she is not ready to give up on the possibility that THC may prove to be an effective postoperative antiemetic. “We were really positive about the effects of THC prior to the study because of the knowledge we had from chemotherapy patients, but it really seems to be different in this patient population. So perhaps in a different setting with a different dosage or a different form of administration it might work, but there is certainly not enough evidence to recommend THC for the prevention of PONV.”

Pharmacy Practice News • January 2012

Pain Medicine

Table. Incidence of Nausea Daniel I. Sessler, MD, chair of the Department of Outcomes Research at Cleveland Clinic, in Ohio, said the study was stopped too soon. “PONV studies need hundreds of patients,” said Dr. Sessler. “The reported results are perfectly consistent with the 25% relative risk reduction provided by ondansetron, dexamethasone and droperidol.

The investigators can’t rule out the expected effect. This is not a negative trial; it’s underpowered.”

In a related study (abstract 815), Dr. Kleine-Brueggeney’s group and col-

leagues from the University of Miami Miller School of Medicine found evidence of a genetic effect on the metabolism of THC. “There is some evidence that certain polymorphisms of the cytochrome P450 enzyme might have an effect on the pharmacodynamics and pharmacokinetics of THC,” she said.

“So we studied healthy volunteers [n=40] to evaluate the effects of those polymorphisms on the metabolism of THC.” The healthy, nonsmoking participants were screened for CYP2C9 polymorphisms on chromosomal location 10q24; interim data are available for 16 patients to date. The researchers found that a person’s CYP2C9*3 status significantly affected how much of the COOHTHC metabolite they produced, leading them to conclude that there is a slow metabolizer phenotype for CYP2C9*3.

In other words, genetic variation determines the pharmacokinetics of THC and may impact vital signs and psychotropic side effects, thereby influencing clinical anesthesiology and potentially explaining the varied results noted in the Seattle group’s study.

“We observed very different effects between individual patients,” Dr. Kleine-Brueggeney added. “We had some patients who had had PONV

THC (n=19)

Placebo (n=21)

P value

Overall nausea

11/19 (58%)

14/21 (67%)

0.57

Early nausea (first 2 hours postoperative)

9/19 (47%)

10/21 (48%)

0.99

Nausea (2-6 hours postoperative)

4/19 (21%)

6/21 (29%)

0.58

Late nausea (6-24 hours postoperative)

1/18a (6%)

3/21 (14%)

0.37

Highest nausea score (VAS)-10

3.7±3.5

4.1±3.2

0.65

THC, tetrahydrocannabinol; VAS, visual analog scale a

Clinical 41

previously, received THC and did not experience PONV thereafter. We had patients who were very sedated and confused. And we also had patients who described it as an extremely positive experience. So even though there was a trend for an antiemetic effect of THC in our PONV trial, the psychotropic side effects were too pronounced and common to make the drug a suitable adjunct in the setting we chose for the study.”

Data missing for one patient.

—Michael Vlessides

42 Clinical

Pharmacy Practice News • January 2012

Pain Medicine

Opioid Overdose Report Points Finger at Prescribers Atlanta—Centers for Disease Control and Prevention (CDC) experts say clinicians need to review their opioid prescribing practices and take greater responsibility for their role in the rising incidence of prescription opioid abuse and overdose.

In a report issued by the CDC, investigators found a fourfold increase in both nationwide opioid sales and opioidrelated deaths between 1999 and 2008

and suggested that the two variables may be linked (MMWR Morb Mortal Wkly Rep Nov. 1, Vol. 60). The supposed correlation also was mimicked on a state-by-state basis, with variations in overdose death rates between states coinciding with similar variations in opioid sales.

“It’s clear from this report that the substantial amount of drugs prescribed and distributed has been contributing

In 2010, enough opioids were sold to medicate each American adult at a dose of 5 mg of hydrocodone every four hours for one month. to the problem of overdose,” said the study’s lead author, Leonard Paulozzi, MD, from the Division of Unintentional

Injury Prevention at the National Center for Injury Prevention and Control, CDC. “The responsibility is there for prescribers to be much more judicious and cautious in prescribing opioids.”

Dr. Paulozzi and several colleagues evaluated several data sources in their assessment: International Classification of Diseases (ICD)-10–coded drug overdose deaths registered in the National Vital Statistics System (NVSS), rates of unprescribed or recreational opioid use reported through the Substance Abuse and Mental Health Services Administration’s (samhSa) 20082009 National Surveys on Drug Use and Health (NSDUH), and annual drug sales between 1999 and 2010 recorded in the Drug Enforcement Administration’s Automation of Reports and Consolidated Orders System.

Out of a national total of 36,450 overdose-related deaths reported to the NVSS in 2008, 20,044 were related to prescription medications and 14,800 (73.8%) of these involved opioids. Dr. Paulozzi noted that approximately 9,000 of the 36,450 death certificates did not specify the cause of overdose, which means there could be as many as 25% more opioid-related deaths.

A regional analysis of the data revealed that 21 of the 27 states with drug overdose death rates above the national average also had opioid sales and nonmedical opioid use that was above the national average. In contrast, only five states with overall mortality rates at or below the national average had rates of opioid sales above the national average (P<0.001; Figure 1).

Although data on opioid-related mortalities were available only through 2008, Dr. Paulozzi said increases in overdoserelated emergency department visits, opioid abuse treatment admissions and opioid sales since 2008 suggest that opioid-related deaths also have continued to increase in the past few years (Figure 2). In fact, in 2010, enough opioids were sold to medicate each American adult at a dose of 5 mg of hydrocodone every four hours for one month, he noted.

These findings also strongly implicate physicians as significant contributors to the “epidemic” of opioid overdoses.

“There has been a dramatic increase in opioid sales overall and we also know the wide variation in deaths by state coincides with the presence of high-volume

Pharmacy Practice News • January 2012

Clinical 43

Pain Medicine Dr. Chou agreed with the report’s recommendations that physicians and insurers should make better use of prescription drug monitoring programs and pharmacy oversight programs, that clinicians closely adhere to evidence-based guidelines and that substance abuse treatment be made more accessible. He cautioned, however, that “although prescription drug overdoses are a serious problem, we also don’t want to go back to the days where people weren’t treated appropriately for pain. In addition to seeing how these policies and initiatives affect prescription drug overdoses, it’s also important to see how they affect pain management. There are a lot of patients being appropriately treated with opioids and not having any issues with the drugs and that’s an important thing to remember.”

Kg of OPR sold per 10,000 8.5-12.6 7.3-8.4 6.0-7.2 3.7-5.9

—David Wild

Figure 1. Rate of opioid pain relievers sold in the United States, 2010.

Drs. Paulozzi, Chou and Twillman had no conflicts of interest to disclose.

OPR, opioid pain reliever

‘The responsibility is there for prescribers to be much more judicious and cautious in prescribing opioids.’

—Leonard Paulozzi, MD Robert Twillman, PhD, director of policy and advocacy for the American Academy of Pain Management, argued that finding concurrent increases in sales and deaths does not translate to a causal relationship between the two variables. In an interview with Pharmacy Practice News, he scolded the CDC for publishing poor science.

“The quality of the data analysis supporting potentially wide-ranging policy recommendations is shockingly poor,” Dr. Twillman argued. “This report does not contain any solid statistical analysis of the relationship between prescribing and deaths. Concluding that prescribing patterns are causally related to the number of deaths threatens to lead to sweep-

ing policy recommendations that will limit appropriate prescribing, which can impact the treatment of chronic pain.”

He cited research from samhSa’s 2010 NSDUH, which showed that 83% of opioid drug abuse cases involved an intervening supply source and 66% of opioid abusers obtained their drugs from friends or family (www.samhsa. gov). Although he said physicians play a role in the problem of opioid overdose, these figures also point to the need for public health officials to address other sources of drug diversion.

“Why aren’t we focusing on the bulk of the source of inappropriately used drugs?” Dr. Twillman asked.

Dr. Paulozzi countered that although many abusers do obtain opioids from friends and relatives, “if you go back a few steps, the physician is always at the source of the drug pipeline.”

The researcher said clinicians can help limit the circulation of opioids by thoroughly screening their patients for a history of substance abuse and mental illness.

Roger Chou, MD, associate professor of medicine at Oregon Health & Science University in Portland, and director of clinical guidelines development for the American Pain Society, agreed.

“We need to do a much better job of assessing a patient’s risk before starting opioids; we need to make better decisions about who should or should not be started on a trial of opioids; and we need to do a better job of monitoring patients on opioids and stopping medications in patients who are not benefitting or who are having problems such as dose selfescalation or concomitant use of illicit drugs,” said Dr. Chou.

‘This report does not contain any solid statistical analysis of the relationship between prescribing and deaths.’

—Robert Twillman, PhD

8 OPR deaths/100,000 Treatment admissions/10,000

7

OPR sales kg/10,000

6

5

Rate

prescribers in those states who provide large amounts of opioids to large volumes of patients without adequate evaluation or follow-up,” Dr. Paulozzi said. According to a California study, 3% of physicians prescribed 62% of opioids from 2005 to 2009, suggesting that attention needs to be focused on these high-volume prescribers, he added (Swedlow A et al., “Prescribing Patterns of Schedule II Opioids in California Workers’ Compensation.” California Workers’ Compensation Institute Research Update; March 2011).

4

3

2

1

0 1999

2001

2003

2005

2007

2009

Figure 2. Opioid pain reliever death rates, sales and substance abuse treatment admission rates, 1999-2009.a a Age-adjusted rates per 100,000 population of OPR deaths, crude rates per 10,000 population for OPR abuse treatment admissions and crude rates per 10,000 population for kilograms of OPR sold

OPR, opioid pain reliever

PREMIXED AMIODARONE. Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication.

Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

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

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

s

Cardiogenic shock

s

Marked sinus bradycardia

s

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

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

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

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

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

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

s Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. s Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information.

1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular ďŹ brillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information].

Use NEXTERONE for acute treatment until the patientâ&#x20AC;&#x2122;s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: s +NOWN HYPERSENSITIVITY TO ANY OF THE COMPONENTS OF .%84%2/.% 0REMIXED )NJECTION INCLUDING iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage BLEEDING FEVER ARTHRALGIAS JOINT PAINS EOSINOPHILIA ABNORMAL BLOOD COUNTS URTICARIA HIVES

thrombotic thrombocytopenic purpura, or severe periarteritis (inďŹ&#x201A;ammation around blood vessels). s #ARDIOGENIC SHOCK s -ARKED SINUS BRADYCARDIA s 3ECOND OR THIRD DEGREE ATRIO VENTRICULAR !6 BLOCK UNLESS A FUNCTIONING PACEMAKER IS AVAILABLE 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and beneďŹ ts of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically signiďŹ cant hypotension during infusions was seen most often in the ďŹ rst several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients.

Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information].

In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information].

5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difďŹ cult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical deďŹ brillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically signiďŹ cant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.

Acute, centrolobular conďŹ&#x201A;uent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. )N PATIENTS WITH LIFE THREATENING ARRHYTHMIAS THE POTENTIAL RISK OF HEPATIC INJURY SHOULD BE WEIGHED against the potential beneďŹ t of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE FOR EVIDENCE OF PROGRESSIVE HEPATIC INJURY )N SUCH CASES CONSIDER REDUCING THE RATE OF ADMINISTRATION or withdrawing NEXTERONE.

5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when ďŹ&#x201A;uoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information].

Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias.

5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity 4HERE HAVE BEEN POSTMARKETING REPORTS OF ACUTE ONSET DAYS TO WEEKS PULMONARY INJURY IN PATIENTS treated with intravenous amiodarone. Findings have included pulmonary inďŹ ltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death.

ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy.

Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary ďŹ brosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone).

5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone.

5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information].

Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3.

Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone.

Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

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

Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

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

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

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

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

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

5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone.

5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole Fever

Body as a whole 24 (2.9%)

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia

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

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

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

Digestive System Liver function tests normal Nausea

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

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever Cardiovascular: hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri Pancreatic: pancreatitis

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

Renal: renal impairment, renal insufficiency, acute renal failure

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

Vascular: vasculitis

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

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

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

48 Technology

Pharmacy Practice News • January 2012

Guest Editorial

Tips for Casting a Wider BCMA Net Karla Miller, PharmD Assistant Vice President of Pharmacy Services and Clinical Therapeutics Clinical Services Group, Hospital Corporation of Americaa

A

lthough bar code medication administration (BCMA) has been demonstrated to improve quality and safety, according to a recent presentation at the unSUMMIT for Bedside Barcoding educational conference, only about 30% of hospitals in the United States have adopted the technology.

Hospital Corporation of America (HCA) supported implementation of BCMA scanning more than 10 years ago because we felt it was an important safety tool. Then, a few years ago, we encouraged expansion of BCMA to other areas of hospital care. Locations like catheterization labs or the emergency department (ED) generally do not have the benefit of prospective pharmacy review. We believed that if the hospitals implemented bar-code scanning in these areas, there would be additional safety checks—at minimum, the ability to check for allergies. In 2008, BCMA was made available to HCA hospital EDs, catheterization labs, endoscopy suites and radiology departments.

It has required a strong multidisciplinary approach and HCA hospitals have continued to improve the bar-code point-of-care process. The results have been great. In 2005, the HCA system administered 113 million doses of medications. By the time of HCA’s expansion in 2008, it was up to 150 million doses. In 2011, with continuous quality improvement, we’re at 160 million doses. To demonstrate just how well it has worked, there have been more than 3 million system-generated warnings, 1.6 million of which turned out to be clinically significant in helping avert errors.

There also has been a 58.5% reduction in malpractice claims related to medication errors over the past 10 years.

If you are looking to do something similar, keep these practice areas in mind: • Radiology. Most radiopharmaceuticals are not bar coded. We divided medications into radiopharmaceuticals and contrast agents, then worked with the contrast manufacturers to get a readable bar code; we’re almost at the same place with radiopharmaceuticals. Also, contrast agents are given in both inpatient and outpatient areas; for some procedures, the patient takes the medication at home. The hospitals wanted a consistent approach, so a process was developed to allow staff to fully document the medi-

cation administration and put in “selfadministration” as the reason code.

• Emergency Department. A key concern in the ED was defining what is an emergent or urgent medication versus those that are less pressing. The question continues to crop up. Although some HCA hospitals had learned how to incorporate BCMA technology in the workflow, many had not. There’s also a question of trauma: What level of trauma is excluded and considered a code? What about stroke patients? It took a lot of discussion and partnering with ED directors to arrive at definitions of what is an urgent situation in which bar-code verification can be bypassed and what is not.

Another issue HCA hospitals faced— and I’m sure that a lot of other hospitals are in the same situation—is that EDs often use a different health information technology system than other areas of the hospital. HCA hospitals wanted Meditech and BCMA to be the “source of truth” for medication administration, even when a niche system is used in a particular clinical area. Toggling between two systems was challenging, as was defining what needed to be documented in each system. All medication-related information is documented in Meditech. Information on allergies is the only area that must be in both systems. The result is one com-

prehensive patient medication administration record. Bar-code scanning also helped because the ED did not normally have pharmacist verification. BCMA provides an opportunity to check allergies and interactions, as well as offering displays related to lab values for review and verification before medication admin- Nurses play an integral role in HCA’s recent efforts to istration. Also, about 95% expand its BCMA system. of medications in HCAaffiliated EDs are maintained in auto- success in the catheterization lab is the mated dispensing cabinets (ADCs). multidisciplinary approach: Make sure BCMA helped verify the medication that even though pharmacy is not proadministered with the medication pro- spectively reviewing medication orders, pharmacy is making sure that everything cured from the ADC. • Cardiac Catheterization Laboratory. has a readable bar code and that everyBCMA in the operating room (OR) thing is working appropriately on the proved challenging because patients are scanning side. You don’t want staff to draped for procedures, limiting access to interrupt the procedure. armbands. Patients should be scanned • ORs. HCA hospitals have not yet before being draped and each dose veri- implemented BCMA in the main ORs. fied against previously profiled order A pilot program is underway in some sets. HCA hospitals discovered that ORs in which there is an anesthesia sometimes the layout and workflow of group that is very passionate about the room had to be changed to assure the medication safety and open to reconscanner was readily available yet not in sidering its entire workflow. Some the way of the procedure. There’s a fine facilities enjoyed success, but are still line in finding what works. The key to working with the technology to make it more user-friendly for an OR setting.

One issue has been how the anesthesiologists administer their medication, ‘If I had to sum up the No. 1 benefit of expanding BCMA, it’s the so we’ve recommended that the anescontinuity of care for a patient’s entire hospital stay.’ thesiologists, not the nurses, procure the medication and then scan it before administration. Another issue is the sterile environment in which patients’ arms could be covered by drapes. HCA hospitals are working on a process by ant to expand bar code medication administration in your hospital? which the patient’s armband can be The costs aren’t as prohibitive as you may think, according to scanned as they come into the room but Tom Van Hassel, BSPharm, MPA, director of pharmacy at Yuma Regional before they’re draped, and then scan Medical Center, in Yuma, Ariz. the medications later.

“Once you’ve taken care of the initial costs of obtaining the servers, If I had to sum up the No. 1 benefit of equipment and training, the additional cost per unit is not that expensive,” expanding BCMA, it’s the continuity of he said. The biggest expense lies in training additional staff members. care for a patient’s entire hospital stay.

Mr. Van Hassel offered the following tips for a successful expansion: You get a patient’s entire medication • Get everyone on board, and once you expand, make scanning mandatory. record; you see exactly when an antibiotic Many hospitals are about 80% to 85% compliant, so there’s still a likelihood was administered in the ED or preoperaof making errors. tively, or what was administered in the • Make sure all bar codes for medications to scan actually work. This avoids catheterization lab and you see how that staffers trying to work around bar coding. And be sure that the bar codes may impact stay in the step-down unit. scanned bring up the correct medications.

Those data are hard to get to otherwise.

• Take time to prep your products. A lot of medications are already bar Don’t be afraid to forge ahead and coded, but others are not. Getting all of them synched requires a fair amount do this in your own facility. It is a large of effort, especially in areas like the operating rooms and intensive care task to implement, but a team approach units, where the doses are the least standardized. Make sure your system accommodates a variety of doses and delivery systems. among hospital division directors can help make it happen.

• Establish consistent training procedures. Instruct the staff to make sure to

BCMA Rollouts on a Budget

W

scan bar codes every time they administer medications.

• Don’t forget to use your common sense. Some systems beep every time a medication is scanned, whether it’s the correct one or not. Always read the label to double-check.

—Karen Blum

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50 Technology

Pharmacy Practice News • January 2012

Medication Safety

When Technology Falters, Who Is To Blame?

‘Rather than human errors, these may be system flaws and deficiencies that lead people down the wrong path.’

88

80 60 40

—Stuart Levine, PharmD

20 0

12

Human Errors

Figure 1. Sources of medication errors.

‘Because [younger physicians are] new to the hospital, there may be bit of a learning curve in adapting to our particular system.’

—Jennifer Phillips, PharmD, BCPS to programming flaws or system breakdowns. All others were counted as human errors. “We were not surprised to find that most were human errors and not technology system errors,” said Jennifer Phillips, PharmD, BCPS, assistant professor of pharmacy practice at Midwestern University Chicago College of Pharmacy and lead author.

That just meant, she said, that a technology was working as programmed but was being used incorrectly or builtin safety nets were being bypassed.

“It could be a training issue,” Dr. Phillips said, “or maybe there are too many alerts and we need to reduce the number of nuisance alerts to prevent alert fatigue.”

The study’s main objective, however, was not to determine a human ver-

100

Technology Errors

sus technology error ratio but to see if one type of technology was more prone to errors than others. The researchers found that the answer was yes. Errors associated with computerized prescriber order entry (CPOE) led all others with 30% of 303 reported technologyassociated errors. The pharmacy information system (PIS) ranked second, with 20% of reported errors (Figure 2).

Residents May Be the Culprits Dr. Phillips said one factor in the higher proportion of CPOE errors might be the large number of resident physicians at the 654-bed teaching hospital. “Younger physicians, in general, are better at using technology than some of the older physicians,” she said, “but because they’re new to the

80

Incidence, %

100

Incidence, %

Pittsburgh—Human errors rather than technology system flaws were the cause of most technology-associated medication errors reported last year at a large Midwestern hospital, according to a study presented at the American College of Clinical Pharmacy (ACCP) annual meeting.

In a retrospective analysis of 703 reported medication errors at Chicago’s Advocate Lutheran General Hospital in 2010, pharmacist-researchers found that 88% of the errors associated with technology were human errors, whereas 12% were the result of system malfunctions (no P value obtained) (Figure 1). The researchers defined technology-related errors as those due

60 40

30 20

20 0

CPOE

PIS

Figure 2. Causes of technology-related medication errors.

CPOE, computerized prescriber order entry; PIS, pharmacy information system

hospital, there may be bit of a learning curve in adapting to our particular system. They also may be more likely to make medication errors than a more experienced physician because it’s still early in their training.” When a resident makes a technology-related error, she added, it’s difficult to determine which of these possibilities applies.

A second study goal was to determine where in the medication-use process various types of errors were mostly likely to occur. The results showed that a lot depended on whether or not errors were technology-associated. If

they were, they were more apt to happen during prescribing (35% of reported technology-related errors vs. 16% of non-technology errors; P<0.0001).

In contrast, the highest proportion of non-technology errors took place during administration (34% of non-technology errors vs. 13% of technologyrelated errors; P<0.001).

Additionally, the research showed that technology-related errors were more likely than non-technology errors to be near misses (59% vs. 51%; P<0.05), whereas non-technology errors were more apt to reach patients than technology-related errors (45% vs. 35%; P=0.014), though these errors did not result in harm. To Dr. Phillips, that made sense because the largest percentage of technology-related errors took place during prescribing, where they were most likely to be caught in downstream safety nets. Conversely, the large proportion of non-technology errors occurring in the final stage meant less likelihood of detection before reaching the patient. The number of harm-producing errors was too small to draw any conclusions, she said.

The next phase of the investigation, Dr. Phillips said, will be to look at the top two or three technology-related errors and see what can be done to fix them and also improve performance.

ISMP’s Take Commenting on the study, Stuart Levine, PharmD, informatics specialist at the Institute for Safe Medication Practices (ISMP), noted that “just because you have technology doesn’t mean it’s safer. Certainly there are unintended consequences of all the new technologies that we have to try to address.”

But overall, he added, technology has been “very beneficial” to pharmacy.

“Certainly having common databases has been a big plus,” he said, and so have “clinical decision support systems that provide information to pharmacists as to when they should contact the physician when doses are out of range.”

However, Dr. Levine took issue with the focus on human activity as the source of a high proportion of the medication errors reported in the study. “Rather than human errors,” he said, “these may be system flaws and deficiencies that lead people down the wrong path.”

Dr. Phillips agreed with Dr. Levine on technology’s potential patient safety benefits. “Our main point,” she said, “was that technology does offer advantages in preventing medication errors, but those advantages can only be achieved if you use the system appropriately.”

—Karen Blum

Pharmacy Practice News • January 2012

Technology 51

Informatics

Appetite for Health Care Apps Fuels Growth W

ith the increasing popularity of tablets and smartphones, mobile medical applications or “apps” are on the rise. There are thousands of mobile apps available for download, some free and many at varying prices.

In 2009, health care applications comprised about 1.5% of the total mobile application market, and by 2015, it’s estimated that there will be 500 million smartphone users with health care applications, according to the FDA. In September 2011, the agency held a public workshop to draft guidance on its oversight for certain mobile medical applications that may impact the performance or functionality of currently regulated medical devices. Public comments were accepted until mid-October.

The apps are part of a natural progression of technology, explained Kevin Clauson, PharmD, director of the Center for Consumer Health Informatics Research at Nova Southeastern University in Fort Lauderdale, Fla. He gave a lecture on helpful apps for pharmacists in October at the Florida Society of Health-System Pharmacists meeting.

Those interested in mobile technology used to use personal digital assistants like the Palm products, “but since cell phones are ubiquitous, there’s been a massive amount of interest and effort to make this available for smartphones,” he said. “We are still in the early days [of apps], where

we will see a lot more use.”

Already there are a plethora of apps that could be helpful to pharmacists (box), including medication reference tools, medical calculators, medical journals and literature libraries and dictation tools. A current trend is creating mobile versions of electronic health records that can be accessed via smartphones or iPads, Dr. Clauson said. Some hospitals already have rolled these out

Dr. Clauson recommends the following resources for more information:

Bridging the gap between the hospital and post-discharge care

In This Issue Technology Watch Patient telemonitoring helps hospitals maintain seamless post-discharge care.

10

12

• itunes.com/healthcare professionalsiphone apps: Catalogue to purchase mobile apps.

TPN Regimens In Hospital Causing Problems at Home

For Aralast, Limiting Distribution Helps Boost Drug Safety

Overfeeding triggers risky electrolyte imbalances post-discharge

Registries, monitoring plan help ensure optimal outcomes

O

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

Fight or switch?

One health-system’s strategy for becoming a specialty pharmacy contractor.

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•

see APPS, page 52

•

13

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

Educational Review Compatibility of Commonly Used Intravenous Drugs

see ARALAST, page 1

Coding Consult POLICY WATCH

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Clinical Controversies

14

• Happtique.com: Mobile application store allowing hospitals and other health care enterprises the ability to create individually branded substores supporting employee and patient mobile technology use.

•

Volume 1 • Number 1 • November 2011

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Q&A

Business Case Study

• iMedicalApps.com: Web site providing reviews and commentary on mobile medical technology and applications submitted by physicians and other members of the medical community.

The surge of apps also puts pharmacists in a greater position to engage with patients, Dr. Clauson said. There

COMING SOON

6

More Apps on Tap

but the coming years should see a bigger spike in adoption, he noted. And as hospitals decentralize, pharmacists working on patient floors have the potential to check orders on the go. Although security/privacy issues are still being worked out at many facilities, there is an enterprise configuration of the iPhone that enables HIPAA-compliant FaceTime calls and secure transmission of patient information.

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•

see COMMISSION, page 1

Top 10 Coding Mistakes—And How To Fix Them

G

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

New Products Ipilimumab (Yervoy, BMS) approved for metastatic or unresectable melanoma.

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Scriptpro announces new enhancements to its remote telepharmacy system.

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Bridging the gap between the hospital and post-discharge care

52 Technology

Pharmacy Practice News • January 2012

Informatics

Tablet Computers Shed Pounds, Gain Ground Washington—Physicians and other health care professionals have been trying to find an effective portable patient record for years, and the invention of tablet computers such as the iPad has made it happen, according to experts at Beth Israel Deaconess Medical Center in Boston.

Until recently, tablet computers were too heavy, had too short a battery life, were too expensive or had too poor a user interface to serve as an effective tool, said Henry Feldman, MD, chief information architect for Harvard Medical Faculty Physicians, speaking at the American Medical Informatics Association meeting as part of a panel on the use of tablets in health care. Laptop computers on rolling carts used by some hospitals were unwieldy to wheel through Beth Israel’s emergency department or two-patient hospital rooms.

Today’s tablets are relatively inexpensive, lightweight, have a 10-hour battery life and a screen large enough for many prescriber order entry programs. Tablets can be made waterproof by covering them with a water-resistant protective “skin” by Frog Skin or other companies, and can be made sterile by wiping the skin with antibacterial wipes like Steris wipes or hand sanitizers like Cal Stat. The skin has a reusable sticker that covers a small opening by the device’s dock connector; the sticker can be removed to charge the device and then replaced 10 to 15 times before needing a new skin. The device even can be made sterile for an operating room setting either by placing it in a sterile bag or by covering it with a Frog Skin and running it through an ethylene oxide sterilizer.

Some 600 professionals at Beth Israel are using iPads in their prac-

APPS continued from page 51

are apps available to help patients manage their medication lists and set digital reminders to take their medicines.

Other apps can help patients manage weight loss, diabetes and other chronic medical conditions.

Verizon and Medco Partnership In April, Verizon Wireless and Medco Health Solutions, Inc., launched an app to help guide patients and their physicians to the lowest-cost prescription drug to meet their health needs and help them identify potentially harmful drug interactions. The app, available on Verizon Wireless Android handsets and BlackBerry devices, provides informa-

tice; the majority were self-purchased, according to Dr. Feldman, adding that he and 20 other hospitalists purchased their own iPads, which are supported by the hospital’s information technology department. In addition to using his iPad to access patients’ electronic health records, he uses it to show patients results from x-rays, magnetic resonance imaging, other imaging tests, lab tests, as well as textbook images or other information related to a patient’s condition.

Getting the Patient Involved The technology enables a hospitalized patient to be as involved as an office-based patient. “I’ve found that I can pretty much do everything, including engaging the patient with this device, at the bedside,” he said.

“This has really changed the way I practice,” he added. “Now, when I do medication reconciliation, I actually write the orders, hand them to the patient and say, ‘I want to go over your medications before I sign.’” The process not only helps catch mistakes but also allows patients to take ownership of their orders, he said.

In the emergency department (ED), panelist Larry Nathanson, MD, director of emergency medicine informatics, said he can check his iPad to see an updated list of ED patients, their chief complaints, who is taking care of them, and can use a drop-down computerized prescriber order-entry (CPOE) menu to order additional tests. He also brings the iPad to patient rooms to go over lab work, review electrocardiograms and pull related information to share. The department purchased four iPads that are shared among other staff. He said the iPad is convenient for typing a line or two of notes but if he needs to write

tion about out-of-pocket costs for any prescription drug and lower-cost options specific to a patient’s prescription drug plan, and drug interaction alerts based on the patient’s prescription history—even if the patient has been treated by several doctors or has filled prescriptions at multiple pharmacies. The app also allows patients to view their medications and set reminders for themselves or family members to take or refill medications.

Nearly 40,000 Medco members have downloaded the app, according to Amy Foley, chief Web officer for Medco. “The feedback from our clients and members has been positive, and members who are active mobile users are looking forward to additional enhancements coming by year end, including refills and pharmacy care alerts,” she said.

more information he uses one of the ED’s desktop computers.

Approximately seven pharmacists at the hospital also are making use of the devices. Pharmacy resident Jason Mordino, PharmD, told Pharmacy Practice News he employs his iPad on a daily basis, using the device for functions such as accessing patient medication lists, approving orders and getting access to lab results. “It saves me a good hour or two of work a day,” Dr. Mordino said in a telephone interview. “I can put in interventions during rounds and answer questions for the team on the spot.”

Dr. Mordino said he generally doesn’t bring the device in to patient rooms unless he’s conducting an education session, but if he needs it he can wipe down its hard case with a sterile wipe.

Panelists said security is an ongoing issue. Tablets potentially are more secure than desktop computers because they’re more limited: Electronic health records at the hospital are accessible through a secure network only, so no personal health information is stored locally, and the devices don’t run Flash, which is prone to viruses. John Halamka, MD, Beth Israel’s chief information officer, said the hospital has two networks: a highly secure medical network that is password-protected for those directly involved in patient care, and a guest network for patients or other employees bringing their personal devices to the campus.

Pharmacy Informaticist: Tablets Just a Start Bill Felkey, BA, MS, professor emeritus of health care informatics and pharmacy care systems at Auburn University in Alabama, said tablets are just

Apps are popular overseas as well.

In Korea, a mobile application providing information about medications and chronic medical conditions and allowing patients to email questions to a pharmacist has proved popular among residents. The iPhone app, called PharmConsult, was created by a team of seven clinicians, pharmacists and information technology experts at Asan Medical Center and the University of Ulsan College of Medicine in Seoul. It features a database of more than 1,300 drugs, including close-up photos and information about the medications’ efficacies, side effects and precautions. The app also offers medical information about some chronic diseases and conditions, including asthma and Parkinson’s disease, through electronic books and links

part of a small array of technology pharmacists are using: “The best device is what people choose to have with them,” be it a tablet, smartphone, laptop or other mobile technology.

The screen on smartphones is too small to see a synopsis of patient information at once, so the user has to scroll through several screens, compared with other devices offering a larger screen.

Mr. Felkey said he has a 37-inch monitor for his desktop, allowing him to manage multiple tasks and patients at once.

Mr. Felkey said pharmacists and other health care professionals should consider the following six factors in choosing the appropriate mobile technology for them: 1. preference for input—touch screen, voice, keyboard, etc.; 2. preference for output—tablets can run videos, smartphones have smaller screens; 3. storage; 4. memory; 5. processor speed; and 6. connectivity—especially in settings that don’t disrupt telemetry.

He noted that 93% of Americans have cell phones or smartphones with them 24/7, so that baseline technology already is established and available for clinicians to use as patient-care aids. In fact, he noted, some applications, running on either smartphones or other devices, have communication features enabling patients to track vital signs and transmit them to the health care team.

—Karen Blum

to videos on YouTube. Patients can use the app to email a hospital pharmacist about medication concerns; queries are answered within one day.

More than 15,000 people have downloaded the free app since its Jan. 10 release date, according to a poster presented recently at the American Medical Informatics Association’s annual meeting in Washington, and pharmacists have responded to 45 counseling questions: 25 about adverse drug events/contraindications; seven each about indications/usual dosage for medications and drug interactions; and three each about potential toxicity related to pregnancy/ lactation and drug purchase/storage/ terms of validity.

—Karen Blum

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1

AHFS 2012 and Handbook on Injectable Drugs 16th Edition Package

Various Authors ASHP, 2011 The go-to book in pharmacies for more than 50 years, AHFS 2012 is your trusted source when you need unbiased answers to critical questions. It offers the highest level of quality and trust that a drug guide can provide, and gives the most expert, authoritative analysis to guide clinical decisions. Handbook on Injectable Drugs is the leading injectable drug guide: trusted, turned to and touted the world over for its intuitive, easy-to-use layout and its accessible organization and presentation of data.

2

Anticoagulation Therapy: A Point-of-Care Guide

William E. Dager; Michael P. Gulseth; Edith A. Nutescu ASHP, February 28, 2011 This book is an excellent resource for any pharmacist who wants to build expertise in caring for inpatients on anticoagulants. It also serves as a resource for the pharmacist who is tasked with teaching other pharmacists the clinical knowledge they need to manage patients on anticoagulants.

3

Basic and Clinical Pharmacology, 12th Edition

Bertram Katzung; Susan Masters; Anthony Trevor McGraw-Hill, December 13, 2011 This book covers the important concepts students need to know about the science of pharmacology and its application to clinical practice.

Selection of the subject matter and order of its presentation are based on the authors’ many years of experience teaching this material to thousands of medical, pharmacy, dental, podiatry, nursing and other health science students.

4

Clinicians Pocket Drug Reference 2012

Leonard G. Gomella; Steven A. Haist; Aimee G. Adams McGraw-Hill, November 17, 2011 Everything you need to know when prescribing and administering 1,000 of the drugs most often used in medical practice.

5

Development of Therapeutic Agents Handbook

Shayne Cox Gad John Wiley, December 6, 2011 Providing both understanding and guidance in characterizing potential drugs and their production and synthesis, this handbook gives professionals a basic tool to facilitate research and development within this challenging process. This comprehensive text brings together, in one resource, a compendium of concepts, approaches, methodologies and limitations that need to be considered in the formulation of therapeutic agents across a range of therapeutic fields.

6

Drug Facts and Comparisons 2012

Facts & Comparisons Lippincott Williams & Wilkins, October 17, 2011 This has been the health care professional’s first choice for comprehensive, authoritative and timely drug information for over 60 years. Drugs are divided into related therapeutic or pharmacologic groups for easy comparison.

7

Mosby’s Pharmacy Review for the NAPLEX®

Mosby Elsevier/Mosby, April 20, 2010 In this guide to the North American Pharmacy Licensure Examination, an outline format lets you review important test topics quickly and efficiently.

Review questions cover areas such as the evaluation of patient conditions, communicating with the patient or health care professional and preparing and dispensing medications safely and effectively. A companion CD lets you practice with two 185-question exams that mirror the NAPLEX.

8

Pediatric Non-Clinical Drug Testing: Principles, Requirements, and Practice

Alan M. Hoberman; Elise M. Lewis John Wiley, February 14, 2012 Covering the full scope of non-clinical testing, regulations, models, practice and relation to clinical trials, this text offers a comprehensive and up-to-date resource.

PPN0112

54 Technology

Pharmacy Practice News • January 2012

Informatics

Investigational Drug Service Excellence Closed-loop med management system helps streamline IDS program Jamie Kelly President Entropy Research San Diego, California

T

he components of a closed-loop medication management system strike a delicate balance: computerized provider order entry (CPOE), a pharmacy information system, automated dispensing technology and an electronic medication administration system are all linked together to facilitate safe and effective medication management. However, numerous challenges have impeded the implementation of closed-loop systems.

In particular, bar code medication administration (BCMA) systems present strategic and tactical issues because they were initially developed to follow the standard episodic medication administration scenario in which a discrete dose is given at a specific time and documented, and many medications do not fit this paradigm. To address these challenges, the Vanderbilt University Medical Center (VUMC), in Nashville, Tenn., has applied its closedloop medication use system to a highly specialized area—its investigational drug service (IDS)—and has achieved significant clinical and financial benefits.

A Team Approach The IDS at VUMC employs a team of specially trained pharmacists and certified pharmacy technicians within the VUMC Department of Pharmaceutical Services, which currently manages drugs for approximately 300 active human research trials. The team manages study protocol dispensing for inpatient and outpatient research on the main campus and at remote clinic sites.

The IDS staff is supported by the central pharmacy or sterile admixture staff on nights, weekends and holidays, which allows for the dispensing of investigational agents around the clock.

Using the components of the McKesson Horizon Medication Management suite, VUMC’s IDS pharmacy staff, led McMahon Publishing mcmahonmed.com Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036.

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by Richard Malone, PharmD, BCPS, MHA, IDS program director, maintains the same standards for research protocol orders as those instituted for “regular” medications administered to bedded patients (inpatient and outpatient) throughout the facility. From CPOE order set creation to dose administration documentation at the point of care, IDS protocols are supported by the existing closed-loop medication management system. But effectively incorporating investigational drug protocols into the institution’s hospital information system backbone requires significant ongoing work to achieve the reward.

The Work For each study, the VUMC IDS team collaborates with the informatics team to build a CPOE order set tailored to each investigational drug protocol, including the drug name, dosage, administration instructions and quantity to be dispensed. Customized support tools such as dosage calculators guide the prescriber to appropriate ordering of the investigational drug, reduce the likelihood of ordering errors and ensure the collection of all information needed to dispense the drug according to study protocol (eg, randomization code or visit number). To prevent other consultants or residents from ordering the FDA-approved version of a drug when a patient is enrolled in a study, the orders are predesignated for authorized prescribers only.

Dr. Malone noted that CPOE users may accidentally select a dose of a study drug instead of its non-study counterpart, “so it’s important that our CPOE system is capable of restricting physicians who are not involved in a study from ordering an investigational drug.”

It can take the VUMC IDS team up to 10 hours to create detailed order sets for each protocol, if not longer. “Additional work is often needed in cases of institutional review board amendments due to protocol changes or changes in study personnel,” said Dr. Malone. “Such changes are inevitable, particularly when working with Phase I and Phase II research at a dynamic teaching facility.”

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The IDS and informatics teams also must build the necessary formulary items for each study within the pharmacy order management system. Formulary items for investigational agents are formatted clearly to indicate to pharmacy staff that the order is for a study drug. Training non-IDS pharmacists who are unfamiliar with the study protocols to dispense study drugs after hours can be challenging, so the IDS constructs explicit, detailed how-to guidance sheets to guide the dispensing pharmacist through proper drug preparation and labeling.

The team has the ability during set-up to enter contraindicated drugs to alert prescribers to possible drug interactions and to therapeutic agents the protocol prohibits. “There are cases in which a protocol might specify that no subject be administered opiates, such as hydrocodone, while enrolled in the study. By entering this information into our system, both the prescribing physician and pharmacy staff can be reminded of this exclusion so prescribers do not accidently violate the protocol,” said Dr. Malone.

Per standard VUMC procedure, all investigational and study drugs are barcode labeled and scanned throughout the dispensing and administration phases of the medication use process. Rather than using the institution’s BCMA system for standard medications and a parallel paper system for documenting study drugs, nurses scan all medications in the same fashion. Although study subjects may be anonymous, labels scanned at the bedside contain the entire patient name to ensure positive patient identification.

Also, the comment fields displayed to the nurse within the BCMA system are used to identify the study protocol and give any special instructions critical to maintaining the integrity of the research related to the dose. Thus, with bar code– enabled electronic documentation, the IDS is able to aid in protocol adherence and provide more accurate data for monitors to review than can be gathered with manual documentation by nurses. Studyspecific documentation is addressed by the appointed study nurse and does not require special action by floor nurses.

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Richard E. Malone, PharmD, BCPS, MHA, program director, Investigational Drug Service at Vanderbilt University Medical Center, presenting at the 2011 unSUMMIT for Bedside Barcoding.

Investigational drug service programs have traditionally been considered in terms of cost and risk to their hosting institutions. Although most institutions charge fees in an attempt to recoup the costs of the IDS pharmacists’ time and supplies, the fees often are insufficient to cover operational costs or sustain a budget-neutral program. However, topperforming IDS pharmacy teams like VUMC’s that have the ability to attract high study volume can generate substantial economic benefit to their institutions beyond fee-based revenue. With volume, the dollars that would have been spent on FDA-approved medications augment the total financial benefit.

By investing time and resources in meticulous adherence to well-defined standard operating procedures supported by the use of closed-loop medication use technology, VUMC IDS has built a program highly attractive to researchers and financially beneficial to the institution. Although incorporating investigational and study drugs within the existing closed-loop medication management system requires significant IDS and informatics staff resources, the VUMC experience suggests that doing so prevents medication errors; promotes adherence to study protocols; decreases the need for clarifications between the pharmacist and authorized prescriber; assists pharmacists in dispensing, preparing and labeling study drugs; and minimizes work for floor nurses while ensuring accurate documentation of study drug administration.

Jamie Kelly is the president of Entropy Research, Inc, a marketing firm serving the life science industry. Ms. Kelly is the cofounder of the annual unSUMMIT for Bedside Barcoding educational conference (www.unsummit.com). She may be contacted at jkelly@entropyresearch.net.

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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