September 2010 digital edition of Pharmacy Practice News by McMahon Group

S Bl po oo tli Se d gh e t pa Fa ge ct 24 or

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The Pharmacist’s News Source

pharmacypracticenews.com

Volume 377 • Number 9 • September 2010

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$17 billion cost to Medicare eyed

Project BOOST Cuts Hospital Readmissions Tampa, Fla.—In a year of sustained predischarge patient education and postdischarge telephone follow-up calls, a multidisciplinary team at the Hospital of the University of Pennsylvania reduced the 30-day readmission rate on a high-turnover, 30-bed general medicine unit by almost three points, from an average of 13.6% to 10.8% (Figure 1, page 8). The achievement occurred as part of Project BOOST (Better Outcomes for Older Adults through Safe Transitions), a multihospital initiative launched by the Society of Hospital Medicine (SHM) in October 2008 with the goal of “improving the care of patients as they transition from hospital to home.” “There is a significant amount of national data to show that unplanned readmissions within 30 days of discharge [are] a significant issue at many hospitals,” said Richard F. Demers, RPh, MS, FASHP, director of pharmacy services at the Hospital of the University of

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see READMISSIONS, page 8

Simple Device Tames Surgical Site Infections Las Vegas—The simple act of probing a surgical wound with a sterile cotton tip soaked in a disinfectant can significantly reduce the rate of surgical site infections, according to a new study. The results, presented at the 2010 annual meeting of the Surgical Infection Society (SIS), impressed at least one veteran infectious disease pharmacist, who called for more study to confirm the potentially practice-changing results. “Having spent a great deal of my pharmacy career with the Department of Surgery at the University of Kentucky Medical Center [in Lexington] and observing many patients following clean-contaminated abdominal surgical procedures, the described technique of probing the wound to remove potential pockets of fluid—which I assume would also allow room air into the incision area—is fascinating,” said Robert P. Rapp, PharmD, professor emeritus of pharmacy and surgery at the university. “While this is a small study, the results are encouraging enough to pursue larger controlled clinical trials.”

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see SURGICAL SITE, page 34

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McMahon Publishing

in this issue Up Front

In Brief Fatal nimodipine reactions, fracture risk from PPIs, liver injuries from RA drug, and more.

Innovative Programs Bring Pharmacy to the Workplace Cost-effective care coordination enhances outcomes and productivityy

Policy

Going Green Should your hospital be recycling anesthetic gases?

Finance Maximizing savings from 340B Prime Vendor Program.

Operations & Mgmt

Leadership in Action Teamwork, collaboration and trust: marks of an effective leader.

Clinical

Hem/Onc Pharmacy Controlling the skyrocketing cost of oncology care: U.S. versus England

Osteoporosis Online tool helps guide drug therapy.

Practice Pearl Low-dose escitalopram helps hospital with ventilator weaning.

s pharmacy services evolve and employers grapple with the cost of maintaining a healthy althy workforce, innovative prorograms that partner pharmaacists with patients through h the patients’ employers are proving to be costeffective ways of improving outcomes and managing chronic diseases such as diabetes. The result of these efforts is a beneficial tri-fecta: workers are healthier er and more productive, employloyers save money and pharmacists acists are reimbursed for providing ding services directly to patients in line with their clinical training. Two programs highlight the advantages of offering pharmacy services through the workplace, the University of Maryland School of Pharmacy’s Patients Pharmacists Partnerships (P3) Program, recipient of the 2010 American Pharmacists Association Foundation’s Pinnacle Award for Group Practices, Health-Systems, and Health Care Corporations, and the Blanchard Valley Health System Center for Medication Management’s (CMM’s) program in

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Technology

Practice Pearl High-tech tools aid antibiotic stewardship efforts.

Educational Review

Compatibility of Commonly Used Intravenous Drugs Insert after page

see WORKER HEALTH, page 13

Drug Combination Improves Survival in Pancreatic Cancer Chicago— The first pancreatic cancer drug regimen in many years to significantly improve overall survival (OS) is already having an impact on hematology/oncology pharmacy practice. The regimen, first-line therapy with FOLFIRINOX, a combination of older chemotherapeutic agents, improved OS by four months (11.1 vs. 6.8 months) in patients with metastatic disease, according to data presented at the

American Society of Clinical Oncology (ASCO) annual meeting. Dina Patel, PharmD, BCOP, a clinical pharmacy specialist at The University of Texas M.D. Anderson Cancer Center, in Houston, said she has written for the regimen “about five times since our physicians came back from ASCO asking that we help them translate this advance into clinical practice.”

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see PANCREATIC, page 20

New Product American Health Packaging adds three new products to its unit-dose line. See page

Pharmacy’s Most Dispensed Name… now appearing on our tablets and capsules

We know you trust our products. On average, pharmacists fill 1 out of every 6 prescriptions with a Teva product*. We want patients to share your trust and confidence in Teva. That’s why, over the next few months, you’ll begin to see tablets and capsules imprinted with the Teva name. In some cases, this new Teva imprint will replace the company identifier code. Ultimately, all our capsules and most of our tablets will proudly bear the Teva name. Patients will come to know us better, making your job a little easier every time you confidently dispense quality Teva products.

*data on file, Teva Pharmaceuticals

888 TEVA USA • www.tevausa.com

8618

Up Front 3

Pharmacy Practice News • September 2010

Capsules

Glucosamine Takes a Hit in Back Pain

surf

SEPTEMBER 2010

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. 2. 3. 4. 5.

Making Smart Pump Drug Libraries Smarter ‘Meaningful Use’ Provision Deemed a Game-Changer The Mark of an Emotionally Intelligent Leader Pharmacist Hire Boosts Reimbursement Dollars Antimicrobial Efficacy [Web-exclusive Educational Review]

Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘There are data to support more

first

proactive intermediate dosing of factor VIII or factor IX for hemophilia a and hemophilia b patients to avoid potential hospitalization.’ —Scott W. Savage, PharmD

See article, page 24

MCMAHONMEDICALBOOKS.COM

The Book Page

Quality & Safety in Pharmacy Practice Terri L. Warholak, David P. Nau See page

randomized, double-blind, placebo-controlled trial of 250 patients with chronic low back pain and degenerative lumbar osteoarthritis (OA) has revealed that six months of treatment is no more effective than placebo in reducing pain in this patient population (JAMA 2010;304:45-52). The results contrast with priorr research showing the popular supplement, believed to restore cartilage and reduce inflammation, leads to mild improvements in pain and physiologic measures in patients with hip and knee OA. Despite the overall strength of the study’s design, one expert said the results are not conclusive and more studies are needed to determine the utility of glucosamine in lumbar OA-related low back pain. “I didn’t find it surprising that there was no evidence of pain improvements, as inclusion criteria allowed for multiple potential pain generators,” said Nirmala R. Abraham, MD, a pain expert at the University of California Los Angeles, Santa Monica. “Given the presence of multiple sources of pain, it would be difficult to observe reduced pain and pain-related disability as a result of improvements specifically in the lumbar facet joints.” Indeed, design weakness is a running theme in glucosamine research, with the generalizability of prior findings limited by their open-label nature and their small sample sizes (Arthritis Rheum 2007;56:555-567). In an attempt to improve the quality of data on this supplement, investigators from Oslo University, in Norway, evaluated 250 outpatients with radiologically proven spinal degeneration and chronic pain. Half the patients received oral glucosamine 1,500 mg; the other half received placebo, both for six months. At study outset and six and 12 months after treatment initiation, the researchers administered two different patient questionnaires to assess response—the Roland Morris Disability Questionnaire (RMDQ) and the EuroQol-5 Dimensions (EQ-5D) questionnaire. The latter test includes a patient-reported daily functioning component as well as a visual analog scale. Results of the RMDQ questionnaire were indicative of their findings: mean RMDQ scores among glucosamine and placebo patients dropped to 5 and 4.8 at six months, respectively, and 4.8 and 5.5 at 12 months, respectively, based on a 24-point scale. The differences were not statistically significant. In their publication, the researchers said, “it seems unwise to recommend glucosamine to all patients with chronic [low back pain] and degenerative OA.” However, like Dr. Abraham, they did not rule out the possibility that other patient populations may benefit from the supplement. —David Wild

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Volume 37 • Number 9 • September 2010 • pharmacypracticenews.com

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4 Up Front

Pharmacy Practice News • September 2010

In Brief

FDA Links IV Nimodipine to Four Deaths

iting at least four patient deaths and several cases of near-lethal injury, the FDA is warning anesthesiologists and other hospital clinicians to avoid administering nimodipine intravenously. Nimodipine (Nimotop, Baxter) is an oral medication used in critically ill patients for the treatment of subarachnoid hemorrhage. Although the drug is available only in capsule form—and since 2006 has a boxed warning on its label cautioning against IV administration—some clinicians resort to injecting the substance in patients who are unable to swallow. According to a recent safety alert from the FDA, the agency received 25 reports of medication errors involving

Pain Drug Trials Halted Due to Adverse Events

or the second time in as many months, the FDA has asked Pfizer to stop clinical trials of its investigational pain drug tanezumab. The clinical hold, initially placed on the drug’s osteoarthritis (OA) pain trials, now also will apply to its trials involving low back pain (LBP) and diabetic peripheral neuropathic pain (DPNP). Pfizer must refrain from enrolling new patients and suspend dosing of existing patients in current LBP and DPNP trials. The company reported that the FDA is allowing it to continue tanezumab trials in “areas of unmet need,” such as cancer pain. Tanezumab is a recombinant, humanized monoclonal antibody that targets nerve growth factor (NGF), which has been shown to play a significant role in the development of pain (Pain 2007;133:183-196). Previous pharmacokinetic research has found that the antibody displays “the general advantages of this class of products, including good specificity and favorable pharmacokinetics,” adding that it “appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system” (Curr Opin Mol Ther 2010;12:94-106). On June 23, Pfizer was asked by the FDA to suspend its OA tanezumab trials, because of reports of worsening symptoms in some subjects, requiring joint replacement in some cases. The FDA allowed Pfizer to continue its OA and LBP clinical trials of tanezumab, but requested that the company assess “potential implications” of the adverse events seen in the OA trials on the rest of the drug’s clinical trials program, according to a Pfizer statement posted on its

the injection of nimodipine between 1989 and 2009 (out of 31 total reports linked to the drug). Of those, four resulted in the death of the patient and five resulted in near-fatal harm. In one case, the patient was left with permanent injuries. The agency said that despite the label warning, clinicians might be administering nimodipine by IV for two reasons. The drug frequently is used in patients with feeding tubes who cannot swallow the capsule. For these patients, Baxter advises that clinicians pierce the capsule with a needle to withdraw the liquid inside, then inject the drug into the feeding tube. “Because a standard needle will not fit on an oral syringe, the needle must be attached to an

Web site at the time. “The FDA’s request follows further consideration of reports of adverse events in osteoarthritis patients taking tanezumab, and the agency’s concerns regarding the potential for such events in other patient populations in which the compound is being studied,” wrote Pfizer in a second statement on its Web site following the suspension of the LBP and DPNP trials. Despite the clinical hold on the lion’s share of its clinical trials program for the investigational pain drug, Pfizer acknowledged in a statement that it hopes to “continue to work with the FDA to reach a common understanding about the appropriate scope of continued clinical investigation of tanezumab.”

High-Dose, Long-term PPI Use Tied to Fractures

n late May, the FDA warned consumers and health care professionals about a possible increased risk for fractures of the hip, wrist and spine from high doses or long-term use of proton pump inhibitors (PPIs). The prescription and over-the-counter (OTC) labels for these drugs have been revised to include new safety information about this possible increased risk. The new safety information is based on the FDA’s review of several epidemiological studies that found those at greatest risk for these fractures received high doses of PPIs or used them for one year or more. The majority of the studies evaluated individuals aged 50 years and older, and the increased risk for fracture primarily was observed in this age group. The greatest increased risk for fractures in these studies involved people who had been taking prescription PPIs, specifically. However, as a precaution, the “Drug Facts” label on OTC PPIs (indicated for 14 days of continuous use) also is being revised to include information about this risk. Prescription PPIs, which are used to treat conditions such as gastroesophageal reflux disease, stomach and small intestine ulcers, and inflammation of the esophagus, include esomeprazole

intravenous syringe,” the FDA said. “The use of intravenous syringes to deliver nimodipine increases the chance that the medication will be given intravenously instead of by mouth or nasogastric tube.” In addition, the FDA said, patients who receive nimodipine tend to be in hospital intensive care units and already are receiving IV medications.

(Nexium, AstraZeneca), dexlansoprazole (Dexilant, Takeda), omeprazole (Prilosec, Proctor & Gamble; Zegerid, Santarus), lansoprazole (Prevacid, Novartis), pantoprazole (Protonix, Wyeth), and rabeprazole (Aciphex, Esai). OTC versions, used for the treatment of frequent heartburn, include omeprazole (Prilosec OTC, Zegerid OTC) and lansoprazole (Prevacid 24HR). The FDA recommends that health care professionals, when prescribing PPIs, should consider whether a lower dose or shorter duration of therapy would adequately treat the patient’s condition. Any side effects or other problems with PPIs should be reported to FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling (800) 332-1088.

Warning of Liver Injury Added to Rheumatoid Arthritis Drug Label

he FDA has added information on severe liver injury to the boxed warning for Arava (leflunomide, Sanofi-aventis)—a drug used to treat rheumatoid arthritis—to highlight the risk for severe liver injury in patients using this drug and how this risk might be reduced. The FDA previously required a boxed warning stating that leflunomide was contraindicated in pregnant women or women of childbearing potential who were not using reliable contraception. Although a bolded warning statement on severe liver injury was added to the leflunomide drug label in 2003, the FDA determined that information on severe liver injury should be included in the boxed warning to highlight the importance of appropriate patient selection before starting treatment, and monitoring once treatment has begun.

Liposomal Vincristine Formulation Improves Leukemia Outcomes

HICAGO—A

liposomal formulation of vincristine (Marqibo, Hana Biosciences) is active in adult patients with refractory or relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL), according to a Phase II trial presented at the recent American Society of Clinical Oncology meeting (abstract 6507). Twenty percent of patients in the study achieved complete remission (CR) or CR with incomplete blood count recovery (CRi). Another 9% had a partial remission and 6% had bone marrow that normalized but without full recovery of blood counts. “We have a significant response rate of 35% in a very heavily pretreated population of patients with ALL—poor performance status in 23%, almost 50% receiving four lines or greater of therapy, and all of whom had prior vincristine,” said Susan O’Brien, MD, professor, Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, in Houston. “The CR/CRi rate of 20% compares favorably to historical experience of 4% CR with single agents. There were no unexpected toxicities.” Patients were included in the openlabel trial if they were in their second relapse or had progressed after two or more prior lines of treatment. Data were available for 56 patients who received liposomal vincristine sulfate injection at 2.25 mg/m2 with no dose cap, IV weekly over one hour. The most common related adverse events of grade 3 or higher were neuropathy (22%), febrile neutropenia (32%), constipation (2%) and diarrhea (5%). Dr. O’Brien said the liposomal formulation allows higher doses of vincristine to be delivered and prolongs the type of exposure. Additional trials are planned.

The decision to add information on severe liver injury to the boxed warning was based on the FDA’s 2010 review of adverse event reports that identified 49 cases of severe liver injury, including 14 cases of fatal liver failure, between August 2002 and May 2009. In this review, the greatest risk for liver injury was seen in patients taking other drugs known to cause liver injury and patients with pre-existing liver disease.

Correction:

n the July issue, in the article entitled “Post-Pump Recall, Industry Responds” and its accompanying sidebar, Gale White was misidentified. His correct title and affiliation are Mr. Gale White, vice president, B. Braun, Infusion Systems Division.

The PROOF is everywhere you look GAmunex is the IGIV therapy supported by robust clinical trials n Proven efficacy in more FDA-approved

indications (CIDP, PI, and ITP)* than any other liquid IGIV1

Important Safety Information for GAmunex Gamunex, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is indicated for the treatment of primary humoral immunodeficiency disease (PI), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Gamunex does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. Gamunex is contraindicated in individuals with acute severe hypersensitivity reactions to Immune Globulin (Human). It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity. There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Lung Injury (TRALI)], hemolytic anemia, and aseptic meningitis in patients administered with IGIV. Thrombotic events have been reported in association with IGIV. Patients at risk for thrombotic events may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy. Gamunex is made from human plasma. Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. In clinical studies, the most common adverse reactions with Gamunex were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection site reaction, nausea, pharyngitis, and urticaria (in PI); and headache, vomiting, fever, nausea, back pain, and rash (in ITP). The most serious adverse reactions 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. Reference: 1. Data on file. Talecris Biotherapeutics, Inc. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see adjacent page for brief summary of GAmunex full Prescribing Information.

Evidence based. Patient proven. To get GAMUNEX call 1-888-MY-GAMUNEX (694-2686) USA Customer Service 1-800-243-4153 Clinical Communications 1-800-520-2807 Reimbursement Help line 1-877-827-3462 ÂŠ2010 Talecris Biotherapeutics, Inc.

www.gamunex.com

July 2010

GX104-0610

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to � Hyperproteinemia, increased serum viscosity and hyponatremia use GAMUNEX®, Immune Globulin Intravenous (Human), 10% occur in patients receiving IGIV therapy. Caprylate/Chromatography Purified, safely and effectively. See � Thrombotic events have occurred in patients receiving IGIV therapy. full prescribing information for GAMUNEX. Monitor patients with known risk factors for thrombotic events; GAMUNEX (Immune Globulin Intravenous [Human], 10% Caprylate/ consider baseline assessment of blood viscosity for those at risk of Chromatography Purified) 10% Liquid Preparation hyperviscosity. Initial U.S. Approval: 2003 � Aseptic Meningitis Syndrome has been reported with GAMUNEX and other IGIV treatments, especially with high doses or rapid infusion. WARNING: ACUTE RENAL DYSFUNCTION and FAILURE � Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. See full prescribing information for complete boxed warning. � IGIV recipients should be monitored for pulmonary adverse reactions � Renal dysfunction, acute renal failure, osmotic (TRALI). nephrosis, and death may be associated with Immune Globulin Intravenous (Human) (IGIV) products � The product is made from human plasma and may contain in predisposed patients. infectious agents, e.g., viruses and, theoretically, the CreutzfeldtJakob disease agent. � Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing ADVERSE REACTIONS sucrose. GAMUNEX does not contain sucrose. � Administer IGIV products at the minimum concentration � PI – Most common drug related adverse reactions during clinical available and the minimum infusion rate practicable. trials were headache and cough. � ITP – Most common drug related adverse reactions during clinical INDICATIONS AND USAGE trials were headache, vomiting, fever, and nausea. GAMUNEX is an immune globulin intravenous (human), 10% liquid � CIDP – Most common drug related adverse reactions during clinical indicated for treatment of: trials were headache and fever. � Primary Humoral Immunodeficiency (PI) To report SUSPECTED ADVERSE REACTIONS, contact Talecris � Idiopathic Thrombocytopenic Purpura (ITP) Biotherapeutics, Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 � Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or www.fda.gov/medwatch. CONTRAINDICATIONS DRUG INTERACTIONS � Anaphylactic or severe systemic reactions to human immunoglobulin � IgA deficient patients with antibodies against IgA and a history of � The passive transfer of antibodies may interfere with the response to live viral vaccines. hypersensitivity � The passive transfer of antibodies may confound the results of WARNINGS AND PRECAUTIONS serological testing. IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. USE IN SPECIFIC POPULATIONS Epinephrine should be available immediately to treat any acute � In patients over age 65 or in any patient at risk of developing renal severe hypersensitivity reactions. insufficiency, do not exceed the recommended dose, and infuse � Monitor renal function, including blood urea nitrogen, serum GAMUNEX at the minimum infusion rate practicable. creatinine, and urine output in patients at risk of developing acute renal failure. � Pregnancy: no human or animal data. Use only if clearly needed. �

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

08939392/08939393-BS Revised: October 2008

Policy 5

Pharmacy Practice News â&#x20AC;˘ September 2010

Going Green

OR Gases Pose Ecologic Risk, Economic Reward Growing awareness of climate impact from volatile anesthetics may make recycling technologies more appealing

f recycling technology developed by two companies in the United States and Canada takes off, patients will not be the only ones in recovery after surgeryâ&#x20AC;&#x201D;so will the anesthetic gases used during the procedures. The firms are hoping that more hospitals will use their systems to recapture, recycle and ultimately resell the gases used in operating rooms. According to the competing companiesâ&#x20AC;&#x2122; founders, hospitals have both an environmental and economic incentive to convert. Volatile anesthetics â&#x20AC;&#x153;are very potent greenhouse gases,â&#x20AC;? said Dusanka Filipovic, founder of the Canadian firm Blue-Zone Technologies Ltd, of Concord, Ontario. â&#x20AC;&#x153;Based on a 20-year global warming impact, these gases are 3,766 times more intense than carbon dioxide (Figure). One average-sized hospital, having 20 operating rooms, annually releases emissions equivalent to about 400 cars.â&#x20AC;? The 2007 Intergovernmental Panel on Climate Change report includes isoflurane and desflurane (Suprane, Baxter) as potential contributors to global warming. But the document did not discuss other inhaled anesthetics. The carbon dioxide (CO2) equivalent of about 4.5 million metric tons of anesthetic gases is released into the atmosphere yearly in the United States, according to James M. Berry, MD, professor of anesthesiology at Vanderbilt University School of Medicine, in Nashville, Tenn., and founder of Anesthetic Gas Reclamation LLC. That figure is less than 1% of the greenhouse gases released by automobiles. â&#x20AC;&#x153;We are nothing compared to car exhaust, but it is low-hanging fruit,â&#x20AC;? said Dr. Berry, whose company has developed

a prototype recycling system that Vanderbilt is using. â&#x20AC;&#x153;We have gotten a [regulatory] pass on it because we are medical, but there are cost-effective methods to eliminating that emission tomorrow. You can recapture anesthetics for less cost than it takes to make them from scratch. You donâ&#x20AC;&#x2122;t have to throw an anesthetic away after using it once.â&#x20AC;?

Recognizing the Benefits

Before recycling becomes common, â&#x20AC;&#x153;it will take increased awareness of the large eco-footprint produced by anesthesia practice, and it will take economic feasibility [studies] before gas capturing will become a priority,â&#x20AC;? said Susan Ryan, PhD, MD, clinical professor of anesthesia at the University of California, San Francisco School of Medicine. Dr. Ryan co-wrote an article in the July issue of Anesthesia & Analgesia (2010;111:92-98) looking at the possible impact on global warming of desflurane, isoflurane and sevoflurane. The study found that desflurane had the greatest potential impact on the climateâ&#x20AC;&#x201D; based on the gasâ&#x20AC;&#x2122;s propensity to absorb infrared radiationâ&#x20AC;&#x201D;followed by isoflurane and sevoflurane. After years of trying, the companies each have come up with slightly different methods of recycling the gases safely and efficiently. But reselling them has been an obstacle because of FDA regulations, Dr. Berry said. â&#x20AC;&#x153;The FDA wants the history of every molecule of where it comes from,â&#x20AC;? he said. That pedigree is next to impossible to produce for recycled drugs. According to the FDA, companies that fill medical gases must document that a volatile anesthetic purchased from a vendor is medical grade. Unlike containers used for other drugs, those used to hold medical gases are reused. Federal regula1R`SYb_N[R # tions require manufacturers of medical gases to ensure that their containers are clean, non-reactive and do not interfere with the safety, strength, quality or purity of the agent inside. These steps include venting any residual gas

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Figure. Estimated global warming potential (GWP) of anesthetic gases over 20 years, compared to GWP of carbon dioxide (defined as 1). Source: Anesthesia & Analgesia (2010;111:92-98).

from a previous filling, the agency said. Because a returned cylinder has been out of the manufacturerâ&#x20AC;&#x2122;s control, the company cannot guarantee that any residual gas is free of contamination or still meets USP or other applicable standards. Patients metabolize only about 5% of the anesthetic gases they receive during surgery; the remainder is vented through a dedicated air vent system in the hospital. â&#x20AC;&#x153;The 95% loss is a loss forever, and the hospital has to go into the marketplace and replace it,â&#x20AC;? Ms. Filipovic said. For an industry that spends $1 billion a year on anesthetic gasesâ&#x20AC;&#x201D;and $2,500 per gallon for sevofluraneâ&#x20AC;&#x201D;â&#x20AC;&#x153;thatâ&#x20AC;&#x2122;s pretty expensive stuff to be throwing out,â&#x20AC;? Dr. Berry said. Dr. Berryâ&#x20AC;&#x2122;s system, which is linked to several operating rooms, condenses the gases by supercooling them, he explained. Blue-Zone Technologies, on the other hand, collects and filters the gases through a stainless-steel canister in the operating room. Blue-Zone distills the gases and delivers recycled gases, Ms. Filipovic said. Dr. Berry said that Blue-Zoneâ&#x20AC;&#x2122;s technology was a step or two ahead of his. â&#x20AC;&#x153;We have slightly different approaches, but were trying to save a little money and save a little environment,â&#x20AC;? he said. Dr. Ryan said both methods were feasible, noting that Blue-Zoneâ&#x20AC;&#x2122;s technology has been used clinically in several hospitals in Canada. â&#x20AC;&#x153;There is no reason it couldnâ&#x20AC;&#x2122;t work in the U.S. as well.â&#x20AC;? â&#x20AC;&#x153;Recovered drugs can be distilled and made particularly pure so they can be suitable for resale,â&#x20AC;? said D. John Doyle, MD, PhD, a staff anesthesiologist at the Cleveland Clinic Foundation, in Ohio, and an unpaid adviser to Blue-Zone.

Laying the Groundwork Dr. Ryan said that some places are already preparing for the service. â&#x20AC;&#x153;Hospital architects and engineers are considering designing and installing separate gas waste lines in operating rooms to allow for inhaled anesthetic gas capturing in the future,â&#x20AC;? she said. Once recycled, the drugs could be sold at a fraction of their original cost, making them affordable to veterinarians and doctors in the developing world, Dr. Berry said. The idea of keeping the drugs out of the atmosphere and receiving carbon emission credits is worth the cost, but if the FDA clears the recycled drugs for sale, then â&#x20AC;&#x153;it pays for itself,â&#x20AC;? he said. Dr. Ryan offered a caveat to selling recycled desflurane, which has a higher impact on the environment. If doctors in developing countries use it instead of a lower-impact anesthetic, then the use of these gases â&#x20AC;&#x153;is being expanded and really just makes the greenhouse gas problem

worse,â&#x20AC;? she said. Selling reclaimed sevoflurane would be advantageous, she added, because of its gentler impact on the environment than desflurane. â&#x20AC;&#x153;The most immediate answer to reducing greenhouse effect from inhaled anesthetics is thoughtful use of these gases in practice,â&#x20AC;? Dr. Ryan continued. â&#x20AC;&#x153;Avoid high fresh gas flows during the maintenance portion of the caseâ&#x20AC;&#x201D;particularly with desflurane; avoid reflexive use of nitrous oxide as a way to reduce use of inhaled anesthetics; and consider which inhaled anesthetic can be usedâ&#x20AC;? on the basis of individual patients. Erin Gardiner, a spokeswoman for Baxter Healthcare Corp., a leading maker of anesthesia drugs, said the company would not comment on the recycling movement.

Pharmacy Directorâ&#x20AC;&#x2122;s View Tricia Meyer, PharmD, MS, director of pharmacy, Scott and White Healthcare, and assistant professor of anesthesiology, Texas A&M College of Medicine, in Temple, agreed that there are both economic and environmental incentives to recycle OR gases. â&#x20AC;&#x153;It would be a win-win solution to help the environment and at the same time pay for the recycling technology,â&#x20AC;? Dr. Meyer said. â&#x20AC;&#x153;If the technology truly has this capability, without the need to allocate major resources such as personnel time and logistical oversight, then I cannot see a downside. Of course, the device would need to meet the approval of the FDA and other regulatory agencies and not have opposition from professional organizations based on safety concerns, etc.â&#x20AC;? Dr. Meyer added that the potential environmental impact of anesthetic gases is not a new concern. â&#x20AC;&#x153;Depleting the atmospheric ozone layer by volatile anesthetics causing ultraviolet radiation to reach the earth has been an ongoing discussion for several years,â&#x20AC;? she said. â&#x20AC;&#x153;There still, however, remains a debate on the overall impact of these medicinal gases on the environment compared to other agents. The evidence on this topic is gaining strength and it seems reasonable to take precautions to diminish the impact.â&#x20AC;? Should such precautions fall to pharmacists for implementation? â&#x20AC;&#x153;As hospital pharmacists, we recognize that most hospitals charge the pharmacy as the responsible department not only for the purchase of drugs, but also for the return and/or destruction of drugs. The inhalation anesthetics are purchased by pharmacy, so it would seem appropriate for pharmacy, in collaboration with anesthesia, to be involved in decisions to recapture and recycle the OR gases.â&#x20AC;? â&#x20AC;&#x201D;John Dillon, with additional reporting by David Bronstein

6 Policy

Pharmacy Practice News â&#x20AC;˘ September 2010

Finance

Maximizing Savings From the 340B Prime Vendor Program Director of Marketing Apexus/340B Prime Vendor Program Irving, Texas

ince 1992, the 340B Drug Pricing Program and its affiliated Prime Vendor Program (PVP) have delivered outpatient medication cost savings to more than 10,000 eligible hospitals and other health care facilities across the country. Now, as part of the Patient Protection and Affordable Care Act of 2010, the advantages of 340B and the PVP have been extended to thousands of additional health care entities, including certain childrenâ&#x20AC;&#x2122;s hospitals, freestanding cancer hospitals, critical access hospitals, rural referral centers and sole community hospitals. With as many as 20,000 facilities qualified to participate, it is worth recapping the programâ&#x20AC;&#x2122;s key benefits, with a focus on the Prime Vendorâ&#x20AC;&#x2122;s role in securing discounts below 340B ceiling prices. The PVP is voluntary and free to all covered entities that register with the Health Resources and Services Administrationâ&#x20AC;&#x2122;s (HRSA) Office of Pharmacy Affairs (OPA). Apexus, the wholly owned, not-for-profit subsidiary of Provista, has been awarded through a competitive bidding process the status of Prime Vendor for a second five-year term. Under Apexus, the PVP has grown to include both medications and other value-added products and services. By leveraging volume purchases of the entire 340B community, the Apexus team can negotiate discounts beyond the reach of any individual facility. Savings range from 11% on common generic drugs to over 30% on many branded products. The level of additional savings is directly related to the use of PVP-contracted items and the extent to which the program is incorporated into the eligible facility. For example, family planning facilities operating under Title X of the 1970 Public Health Service Act experience the greatest proportional discounts due to the limited nature of their formulariesâ&#x20AC;&#x201D;approximately 30% below the 340B pricing ceiling on Apexus-contracted items (Figure). In contrast, disproportionate share hospitals enjoy 15% in additional savings. The less steep discounts are attributed to the type and quantity of products selected and the contracts available.

$32 Million in Savings Apexus, as HRSAâ&#x20AC;&#x2122;s 340B Prime Vendor, works collaboratively with the OPA and Pharmacy Services Support Center (PSSC) in promoting the 340B Drug Pricing Program and improving access

is an online tool that enables them to securely view all contracted pricing and validate purchase orders. Periodic review of the PVP Web site and catalog can help maximize the savings value of the program. Value-added reports are housed within the secured side of the Web site. These reports contain the best buys by therapeutic class, chemical compound and over-the-counter medications. The reports are updated following the release of the quarterly 340B price files.

Danielle Mathers Senior Manager, Program Development Health Resources and Services Administration - Pharmacy Services Support Center Washington, D.C.

to affordable medications for covered entities and the patients they serve. In 2009, the collaborative impact yielded a savings of over $32 million on 340B purchases through the PVP. Each year, the goal to improve services and offer greater savings provides a challenge for the PVP team. Thoughtful consideration of contracts, services and new opportunities are guided by PVP Advisory Panels. These panels are composed of 10 to 15 representatives from each subset of the PVP participant base. As a voice for PVP participants, the panels help to guide new product selection and provide feedback on established solutions. Registration with the PVP affords participants access to a secure Web site, www.340bpvp.com, containing contracts and pricing in addition to educational information, archived issues of the Pharmacy Flash newsletter, the Institute for Safe Medication Practices (ISMP) newsletter and a tutorial on navigating the 340B program. Particularly valuable to participants

keep participants abreast of issues affecting the 340B community. Educational opportunities are listed on the PVP Web site under the Education tab. Also listed is information on other programs offered by HRSAâ&#x20AC;&#x2122;s OPA, such as Safety Net Hospitals for Pharmaceutical Access (SNHPA), National Association of Community Health Centers (NACHC) and Title X. While the PVP negotiates discounts below the ceiling price, the PSSC, an APhA-contracted arm of the OPA, provides 340B policy analysis, networking and free pharmacy technical assistance including help in adhering to program guidelines. Pharmacy technical assistance (PharmTA) consultants are available to support participants in a variety of areas including development of pharmacy models, formularies, patient safety initiatives and staffing requirements. The programâ&#x20AC;&#x2122;s value-added component falls within two distinct categories: pharmacy software and value-added products and services. The latter include vaccines and diabetes meters and strips. These items fall outside normal 340B coverage, but PVP advisory boards have strongly recommended including them in the PVP contract catalog. GlaxoSmithKline and Novartis have contracts with the PVP for vaccines, while Home Diagnostics Inc. (HDI), Bayer and Abbott provide

Transparency a Valued Trait Transparency is a cornerstone for the PVP. Each quarter, PVP staff confirms 340B and PVP pricing and posts the information for all participants to review. Wholesale distributors are contacted in the event of a discrepancy. The validation helps to streamline the process for both the participants and wholesale distributors, thus avoiding overpayment and eliminating the backlog of tedious rebilling months after the overcharge. Guidelines published by the OPA can help participants understand the programâ&#x20AC;&#x2122;s parameters. The HRSA Web site www.hrsa.gov/opa, provides detailed information on how to fully implement the program. To maximize the utilization of available discounts, a periodic review of the PVP catalog, the Flash newsletter and the PVP tutorial will

â&#x20AC;˘

see 340B SAVINGS, page 15

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Mary Ellen England, MS, MBA

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Figure. 2009 Prime vendor program savings by entity type. BL, black lung clinic; CH, community health center; DSH, disproportionate share hospital; FP, Title X family planning clinic; FQHC638, tribal contract/ compact with Indian Health Service (PL638); FQHCLA, federally qualified health center look alike; HM, hemophilia clinic; HV, Ryan White HIV clinic; NH, native Hawaiian clinic; RWI, II and IID, Ryan White clinics; STD, sexually transmitted disease clinic; TB, tuberculosis clinic; UI, urban Indian 638 grantee Tribal Contract/Compact with IHS (P.L. 93-638)

8 Operations & Management

Pharmacy Practice News • September 2010

Finance

READMISSIONS

Pennsylvania (UPenn), in Philadelphia. “Some authors have estimated that the percentage of [patient rehospitalizations] can be upward of 20% and the range can double that when you get to a 90-day period after [discharge]. These readmissions are estimated to cost Medicare in one year a total of around $17 billion. “So obviously,” he said, “there is a huge opportunity for all of us in acute care to try to reduce these outcomes and improve the care of patients.” Mr. Demers, who was referring to a 2009 report in The New England Journal of Medicine (360:1418-1428), was part of a UPenn hospital pharmacy team that presented the results of the BOOST program at the American Society of HealthSystem Pharmacists’ Summer Meeting. Other studies also have shown that improving discharge instructions to patients and following up afterward can pay off in fewer trips to the emergency department and rehospitalizations. Janelle Ocampo, PharmD, BCPS, pharmacy practice specialist at the UPenn hospital, cited a 2009 Boston Medical Center effort that resulted in 30% fewer readmissions and emergency room visits among patients who received detailed predischarge instructions from a nurse and medication follow-up calls from a pharmacist, compared with a group that did not receive similar services. Additionally, average per-patient costs were $412 lower for the intervention group (Ann Intern Med 2009;150:178-187). At the UPenn medical unit, pharmacists played an integral role in BOOST as drug therapy advisers to patients as well as to medical and nursing staffs. With limited time to perform medication reconciliation and counseling for all discharges, Dr. Ocampo said, pharmacists used BOOST’s “7P” screening tool to zero in on patients at higher risk because of the severity of their conditions and drugs being taken. The screening tool lists seven highrisk factors including problem medications (anticoagulants, antiplatelets, digoxin, insulin and narcotics), polypharmacy and principal diagnoses of stroke, chronic obstructive pulmonary disease, diabetes, heart failure or cancer. Patients with depression or poor health literacy and lack of home support also are considered at high risk. Dr. Ocampo said pharmacists added antibiotics to the problem medications. Although BOOST guidelines do not include a specific role for pharmacists, the UPenn pharmacy group used its specialized knowledge and skills to support the multidisciplinary initiative. As Dr. Ocampo described it: “Our pharmacists attend daily medical rounds in

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ciliation and we provide discharge medication counseling for high-risk patients.” One discharge tool they use is a walletsized patient MedAction Plan (Figure 2) that outlines specific medications, dosing

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schedules and indications in an easyto-read format, along with small color photos of brand drug pills. Dr. Ocampo said pharmacists create the take-home cards using a HIPAA-compliant, Internet-based program into which they enter all patient information including their medication regimens. As part of their involvement in BOOST, Dr. Ocampo said, pharmacists conducted a discharge medication reconciliation pilot project for high-risk patients from October 2008 to August 2009. “We looked at 354 patients at discharge,” she said, “and found that 37% of them had unintended medication errors, [a rate of ] 1.5 errors per patient.” About half of the 49 medication error interventions involved adding a missing medication (Figure 3). Changing an incorrect dose was the second most common intervention, occurring in 36% of the total, followed by changing instructions (25%), stopping an unnecessary medication (24%) and changing a medication (16%).

•

see READMISSIONS, page 10

10 Operations & Management

Pharmacy Practice News • September 2010

Finance

READMISSIONS continued from page 8

Pharmacists also calculated the severity of errors based on a 2005 paper published in the Archives of Internal Medicine (2005;165:424-429). The ratings ranged from class 1 (no potential for patient discomfort or clinical deterioration) to class 3 (potential for severe patient discomfort or clinical deterioration). They found that 61% of the errors had the potential to cause moderate to severe discomfort or clinical deterioration. Additionally, about one-fourth of

‘We serve as a drug information resource for everyone on the floor, including patients, nurses and physicians. We perform discharge medication reconciliation and we provide discharge medication counseling for high-risk patients.’ —Janelle Ocampo, PharmD the 201 pharmacist interventions (49) were made on targeted medications, with insulin being the most common, followed by antibiotics and opioids. As for future pharmacist initiatives, Gene Gibson, PharmD, associate director of clinical affairs and pharmacoeco-

nomics at UPenn, suggested a greater emphasis on communications among health-system pharmacists, community pharmacies and primary care providers and “maybe even working on a process in-hospital to get medications filled for the patient prior to leaving.” He noted

Immune Globulin Intravenous (Human) Flebogamma® 5% DIF For intravenous use only Rx only

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Flebogamma® 5% DIF is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders. DOSAGE AND ADMINISTRATION The usual dose of Flebogamma® 5% DIF for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks. An in-line filter with a pore size of 15 to 20 microns is recommended for the infusion. Antibacterial filters (0.2 micron) may also be used. Discard unused contents and administration devices after use. The infusion of Flebogamma® 5% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (0.5 mg/kg/minute). If, during the first 30 minutes, the patient does not experience any discomfort, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute). For patients judged to be at risk for developing renal dysfunction or considered to be at increased risk of thombotic/thromboembolic events, it may be prudent to limit the infusion rate to a maximum rate less than 0.06 mL/kg body weight/minute (3 mg/ kg/minute). Reduction in dose, concentration, and/or rate of infusion in patients at risk of acute renal failure, which includes patients over 65, has been proposed in the literature in order to reduce the risk of acute renal failure. CONTRAINDICATIONS Flebogamma® 5% DIF should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using Flebogamma® 5% DIF even though it contains low amounts of IgA (typically < 50 μg/mL). Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions. If patients are known to be intolerant to any component of Flebogamma® 5% DIF, such as sorbitol (i.e., intolerance to fructose), they should not receive the product. WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Flebogamma® 5% DIF does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. Flebogamma® 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 888-GRIFOLS (888-474-3657). All patients, but especially individuals receiving Flebogamma® 5% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations may reduce the risk of these types of events. Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.

that the latter might also provide a welcome revenue stream. Dr. Gibson noted that three patients had to be readmitted recently at the UPenn hospital because they had not filled their prescriptions. One was a patient with Clostridium difficile infection who failed

PRECAUTIONS General: Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative. Do not use if turbid. Solution that has been frozen should not be used. Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV. Renal Function: Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma® 5% DIF at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute. Aseptic Meningitis Syndrome: An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., > 1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis: Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests]. Thrombotic Events: Thrombotic events have been reported in association with IGIV (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests]. Transfusion-Related Acute Lung Injury (TRALI): There have been reports of non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests]. Information For Patients: Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians. It is recommended that the lot number of the vials used be recorded when Flebogamma® 5% DIF is administered. Laboratory Tests: Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.

Operations & Management 11

Pharmacy Practice News • September 2010

Finance to get a vancomycin prescription filled because insurance didn’t cover it. “Sure enough,” he said, “the patient was back in the hospital in seven days with significant diarrhea. We should give the medications to the patients so they don’t come back.”

Another BOOST at Methodist Julie Williams, PharmD, BCPS, clinical manager, ambulatory pharmacy services, Methodist Hospital, Clarian Health, Indianapolis, is familiar with the Project BOOST initiative. She is part of a multidisciplinary team that is about two

months into a new effort to reduce readmission rates, and they are using some of the core strategies that BOOST employs. The Methodist effort began with a gap analysis in the renal/metabolic unit, because that area of care had one of the facility’s higher 30-day readmission rates. “We never found any one ‘smoking gun,’” Dr. Williams said. “The causes were multifactorial; there were at least 20 aspects of care we identified that could be improved.” Still, a few care gaps stood out, she stressed. Ensuring that discharged patients not only had an appointment

Following infusion of Flebogamma® 5% DIF, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum. Pregnancy Category C: Animal reproduction studies have not been performed with Flebogamma® 5% DIF. It is also not known whether Flebogamma® 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 5% DIF should be given to a pregnant woman only if clearly needed. Drug Interactions: Antibodies in Flebogamma® 5% DIF may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. Pediatric Use: The above mentioned clinical trial with Flebogamma® 5% DIF enrolled only a very limited number of children (0) and adolescents (3) with primary humoral immune deficiency, a number insufficient to fully characterize and establish the efficacy and safety in pediatric patients. Geriatric Use: Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma® 5% DIF should be limited to < 0.06 mL/kg/min (3 mg/kg/min). Adverse Reactions Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis. Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms. Post-Marketing: The following adverse reactions have been identified and reported during the postapproval use of IGIV products. Respiratory

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

Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiac arrest, thromboembolism, vascular collapse, hypotension Coma, loss of consciousness, seizures, tremor Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, bullous dermatitis Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Pyrexia, rigors Back pain Hepatic dysfunction, abdominal pain

Because post-marketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently. Adverse events were reported in a study of 46 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-three (94%) subjects experienced at least 1 adverse event

with their next care provider, but actually kept the appointment, proved to be a challenge. Something as seemingly simple as transportation often led to missed appointments, Dr. Williams noted. More serious issues emerged during inpatient care—for example, ensuring the right medication regimens for tricky disease states such as heart failure, diabetes and post-myocardial infarction. The solution they came up with was a two-page checklist that caregivers could use as a reminder to focus on areas of care that could impact readmission rates. And the checklist wasn’t just for one

irrespective of the relationship with the product, and these subjects reported a total of 595 adverse events. None of the 46 subjects who participated in this study discontinued the study prematurely due to an adverse experience related to the study drug. One subject had treatment-emergent bronchiectasis, mild, ongoing, after infusion #10; and one subject had recurrent moderate leukopenia after the 7th and 12th infusions. No adverse events occurred with an incidence of > 2% on a per infusion basis. Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event

Number of AEs

Combined Bronchitis Cough and productive cough Diarrhea NOSa Headache NOS and sinus headache Nasal congestion Injection site reaction NOS Pyrexia Arthralgia Sinusitis NOS Pharyngitis Upper respiratory tract infection Wheezing and asthma aggravated

19 10 14 46 11 13 27 11 38 9 24 24

Number of Subjects with AEs 14 10 9 16 7 7 17 7 20 8 15 10

Percent of Subjects with AEs 30 22 20 35 15 15 37 15 44 17 33 22

a. NOS = not otherwise specified The total number of AEs (regardless of attribution) reported whose onset was within 72 hours after the end of an infusion of Flebogamma® 5% DIF was 216. There were a total of 709 infusions, resulting in a rate of 0.305 (95% confidence interval 0.225 to 0.412) temporally associated AEs per infusion. There were 144 infusions (20.1%, 1-sided 95% upper bound confidence interval = 24.4%) associated with 1 or more AEs that began within 72 hours after the completion of an infusion. Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe

No. Infusions 58 25 1

Adjusted % a with AE 7.9 3.6 0.1

Confidence Intervalb 10.4 4.9 0.3

a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic. The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3. Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT

Assessment Criteria Above 3x the ULNa Above 3x the ULN

n 3 1

% 6.5 2.2

a. ULN = upper limit of normal. None of these subjects had a concomitant treatment-emergent rise in total bilirubin. Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion. Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented. Manufactured by INSTITUTO GRIFOLS, S.A. Barcelona - Spain U.S. License No. 1181 Distributed by GRIFOLS BIOLOGICALS INC. Los Angeles - CA 90032 Phone: 888-GRIFOLS (888-474-3657)

group of specialists: it was developed by a multidisciplinary team of physicians, pharmacists, clinical nurse specialists and social workers, among others. One goal in developing the checklist was to get clinicians focused on readmissions far earlier in the spectrum of care. “The checklist helped us start the discharge planning process at the time of admission, so that we were working on identifying potential trouble spots throughout the patient’s hospital course,” Dr. Williams said. “You could review the list and see that, OK, my partner in care management is working on one issue, and my partner in social work is working on another. That’s a huge help.” Clinical issues are often the most demanding—and the ones most amenable to improvement via a checklist approach. In the case of a patient with heart failure, “there are boxes that remind us to check off whether the patient has been given an ACE inhibitor, a diuretic, an aspirin, a statin, etc.,” she said. “If we see something that is missing or hasn’t been documented appropriately, we refer that issue back to the physician.” Another issue arose during the Methodist hospital gap analysis: the sometimes “atrocious” quality of hand-written discharge instructions for patients. The instructions were often made by multiple providers, in nearly illegible writing, and used abbreviations for dosages “that can even confuse clinicians, let alone patients,” Dr. Williams said. The answer was to implement a new tool developed by Clarian’s information systems team, working in conjunction with clinicians—an electronic discharge form that has been in use in the renal/ metabolic pilot floor for about six weeks. “It’s a great facilitator for medication reconciliation,” Dr. Williams said. “You have all of the medications displayed on the screen, you select what you want with radio buttons, and those selections go on the patient’s home meds list, with detailed instructions on dosing, all in patient-friendly language, whether it’s something we prescribed or an existing home medication.” “The format is great,” she added. “The patients get a beautiful, clean copy of all their meds, as well as details on followup appointments, in an easy-to-read font. It’s much more professional and userfriendly than our handwritten forms.” It’s too soon to measure the impact these various efforts are having on hospital readmissions, Dr. Williams said. But if the electronic discharge form is any indication, Methodist is on the right track. “The physicians and nurses love it, patients certainly love it, and as pharmacists, it’s a huge step forward for us. It’s really starting to pay off.” —Bruce and Joan Buckley, with additional reporting by David Bronstein

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Compatibility of

Commonly Used Intravenous Drugs LISA CAYO, PHARMD Clinical Pharmacy Coordinator Garden City Hospital Garden City, Michigan

he number of available IV medications continues to expand. Many institutions have observed an

increase in patient acuity and a rise in the number of medications administered to each patient. This increases the likelihood that multiple IV medications will need to be administered concurrently.

These factors contribute to the escalating complexity of IV drug administration and have resulted in an everincreasing number of possible incompatibilities. The potential for serious and life-threatening adverse drug events exist when incompatible medications are infused together. Therefore, it is important to verify drug compatibility prior to coadministration. A clear and concise compatibility chart can be a useful tool in helping to deliver safe, high-quality IV therapy to patients. A chance of incompatibility exists whenever any

medication is combined or added to an IV fluid. It is important to recognize that compatibility is not just a function of the drugs themselves, but also can be dependent on a variety of factors including the concentration, temperature, storage vehicle, infusion solution, order of mixing, and administration technique. Compatibility differences even have been reported for different brands of the same drug. Three types of incompatibilities are commonly discussed: physical, chemical, and therapeutic. Physical Text continues on page 1.

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

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

Amiodarone

Ampicillin

Ampicillin-sulbactam

Anidulafungin

Argatroban

Azithromycin

Aztreonam

Bivalirudin

Bumetanide

Calcium gluconate

Caspofungin

Cefazolin

Cefepime

Cefotaxime

Cefoxitin

Ceftazidime

Ceftizoxime

Ceftriaxone

Ciprofloxacin

Clindamycin

Dexamethasone

Dextrose 5% in water

Diazepam

Diltiazem

Diphenhydramine

Dobutamine

Dolasetron

Dopamine

Doripenem

Doxycycline

Enalaprilat

Epinephrine

Eptifibatide

Esmolol

Esomeprazole

Famotidine

Fentanyl

Fluconazole

Furosemide

Gentamicin

Acyclovir

(continued)

Amikacin

Acyclovir

Table. Compatibility of Selected IV Drugs

Amikacin

Amiodarone

Ampicillin

Ampicillin-sulbactam

Anidulafungin

Argatroban

Azithromycin

Aztreonam

Bivalirudin

Bumetanide

Calcium gluconate

Caspofungin

Cefazolin

Cefepime

Cefotaxime

Cefoxitin

Ceftazidime

Ceftizoxime

Ceftriaxone

Ciprofloxacin

Clindamycin

Dexamethasone

D5W

Diazepam

Diltiazem

Diphenhydramine

Dobutamine

Dolasetron

Dopamine

Doripenem

Doxycycline

Enalaprilat

Epinephrine

Eptifibatide

Esmolol

Esomeprazole

Famotidine

Fentanyl

Testing was performed with ethylenediaminetetra-acetic acid (EDTA)-free formulation.

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

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

C C

Granisetron

Heparin

Hydrocortisone Sod. Succ.

Hydromorphone

Imipenem-cilastatin

Insulin, regular

Labetalol

Levofloxacin

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meropenem

Methylprednisolone sod. Succ.

Metoclopramide

Metronidazole

Micafungin

Midazolam

Morphine sulfate

Nafcillin

Nitroglycerin

Nitroprusside

Norepinephrine

Ondansetron

Pantoprazolea

Penicillin G Potassium

Phenylephrine

Phenytoin

Piperacillin-tazobactam

Potassium chloride

Prochlorperazine

Propofol

Ringerâ&#x20AC;&#x2122;s, lactated

Sodium bicarbonate

Sodium chloride 0.9%

Ticarcillin-clavulanate

Tigecycline

Tobramycin

TMP-SMX

Vancomycin

Vasopressin

Voriconazole

Acyclovir

Amikacin

Amiodarone

Ampicillin

Ampicillin-sulbactam

Anidulafungin

Argatroban

Azithromycin

Aztreonam

Bivalirudin

Bumetanide

Calcium gluconate

Caspofungin

Cefazolin

Cefepime

Cefotaxime

Cefoxitin

Ceftazidime

Ceftizoxime

Ceftriaxone

Ciprofloxacin

Clindamycin

Dexamethasone

D5W

Diazepam

Diltiazem

Diphenhydramine

Dobutamine

Dolasetron

Dopamine

Doripenem

Doxycycline

Enalaprilat

Epinephrine

Eptifibatide

Esmolol

Esomeprazole

Famotidine

Fentanyl

Table continues on page 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

Ampicillin-sulbactam

Anidulafungin

Argatroban

Azithromycin

Aztreonam

Bivalirudin

Bumetanide

Calcium gluconate

Caspofungin

Cefazolin

Cefepime

Cefotaxime

Cefoxitin

Ceftazidime

Ceftizoxime

Ceftriaxone

Ciprofloxacin

Clindamycin

Dexamethasone

Dextrose 5% in water

Diazepam

Diltiazem

Diphenhydramine

Dobutamine

Dolasetron

Dopamine

Doripenem

Doxycycline

Enalaprilat

Epinephrine

Eptifibatide

Esmolol

Esomeprazole

Famotidine

Fentanyl

Furosemide

Gentamicin

Granisetron

Heparin

Hydrocortisone

Hydromorphone

Imipenem-cilastatin

Insulin, regular

Labetalol

Levofloxacin

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meropenem

Methylprednisolone

Metoclopramide

Metronidazole

Micafungin

Midazolam

Morphine sulfate

Nafcillin

Nitroglycerin

Nitroprusside

Norepinephrine

Ondansetron

Pantoprazolea

Penicillin G

Phenylephrine

Phenytoin

Piperacillan-tazobactam I

Gentamicin

Ampicillin

Furosemide

Amiodarone

Fluconazole

Amikacin

(continued)

Acyclovir

Table. Compatibility of Selected IV Drugs

C N

Potassium chloride

Prochlorperazine

Propofol

Ringerâ&#x20AC;&#x2122;s, lactated

Sodium bicarbonate

Sodium chloride 0.9%

Ticarcillin-clavulanate

Tigecycline

Tobramycin

TMP-SMX

Vancomycin

Vasopressin

Voriconazole

Testing was performed with ethylenediaminetetra-acetic acid (EDTA)-free formulation.

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

Fluconazole

Furosemide

Gentamicin

Granisetron

Heparin

Hydrocortisone

Hydromorphone

Imipenem-cilastatin

Insulin, regular

Labetalol

Levofloxacin

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meropenem

Methylprednisolone

Metoclopramide

C C

Voriconazole

Vasopressin

Vancomycin

TMP-SMX

Tobramycin

Tigecycline

Ticarcillin-clavulanate

Sodium chloride 0.9%

Sodium bicarbonate

Ringerâ&#x20AC;&#x2122;s, lactated

Propofol

Prochlorperazine

Potassium chloride

Piperacillin-tazobactam

Phenytoin

Phenylephrine

Penicillin G Potassium

Pantoprazolea

Ondansetron

Norepinephrine

Nitroprusside

Nitroglycerin

Nafcillin

Morphine sulfate

Midazolam

Micafungin

Metronidazole

Levofloxacin

Metoclopramide

Labetalol

Methylprednisolone sod. Succ.

Insulin, regular C

Meropenem

Imipenem-cilastatin N

Mannitol

Hydromorphone C

Magnesium sulfate

Hydrocortisone Sod. Succ. C

Lorazepam

Heparin C

Linezolid

Granisetron C

Metronidazole

Micafungin

Midazolam

Morphine sulfate

Nafcillin

Nitroglycerin

Nitroprusside

Norepinephrine

Ondansetron

Pantoprazolea

Penicillin G

Phenylephrine

Phenytoin

Piperacillin-tazobactam

Potassium chloride

Prochlorperazine

Propofol

Ringerâ&#x20AC;&#x2122;s, lactated

Sodium bicarbonate

Sodium chloride 0.9%

Ticarcillin-clavulanate

Tigecycline

Tobramycin

TMP-SMX

Vancomycin

Vasopressin

Voriconazole

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

incompatibilities are the most easily detected and are evidenced by visible changes, such as particulate formation, haze, precipitation, color change, and gas evolution. Chemical incompatibilities are those that result in decomposition of a drug. Loss of potency of greater than 10% over the defined testing period is considered chemical incompatibility. Most chemical incompatibilities can be detected only with a suitable analytic method. Therapeutic incompatibilities in which a drug combination results in undesirable antagonistic or synergistic pharmacologic activity are beyond the scope of most compatibility references. The purpose of this chart is to provide data in an organized, concise format from which compatibility information can be accessed quickly and conveniently. Although there are differing types of incompatibilities, the type of incompatibility or compatibility is not specified in this chart. A designation of â&#x20AC;&#x153;compatibleâ&#x20AC;? indicates that the combination evaluated appears to be compatible based on the tests performed, whether these tests measured physical, chemical, or both types of compatibility. All conditions that may affect compatibility cannot be included in such a format and it is not possible to predict all incompatibilities that may

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

arise, but it is hoped that the information provided may help clinicians minimize their occurrence. Continuing research adding to the existing body of knowledge on IV compatibilities is vital.

Suggested Readings Bertsche T, Mayer Y, Stahl R, Hoppe-Tichy T, Encke J, Haefeli WE. Prevention of intravenous drug incompatibilities in an intensive care unit. Am J Health-Syst Pharm. 2008;65:1834-1840. Canann D, Tyler LS, Barker B, Condie C. Visual compatibility of IV medications routinely used in bone marrow transplant recipients. Am J Health-Syst Pharm. 2009;66:727-729. Condie CK, Tyler LS, Barker B, Canann DM. Visual compatibility of caspofungin acetate with commonly used drugs during simulated Y-site delivery. Am J Health-Syst Pharm. 2008;65:454-457. Data on File, Sanofi-Aventis. Data on file, Wyeth Pharmaceuticals. DRUGDEXÂŽ System (Internet database). Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion solutions to reduce the risk of incompatibility. Am J Health-Syst Pharm. 2008;65:1648-1654. Trissel LA, ed. Handbook on Injectable Drugs. 15th ed. Bethesda, MD: American Society of Health-System Pharmacists, 2009.

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Operations & Management 13

Pharmacy Practice News • September 2010

Pharmacy Services

WORKER HEALTH continued from page 1

Findlay, Ohio, recipient of a 2009 American Society of Health-System Pharmacists Best Practices Award.

Coaching in Maryland The P3 Program at the University of Maryland centers on diabetes management, with an additional focus on cardiovascular care. Self-insured employers offer the program to their employees as a benefit. Employees sign up through their human resources department and choose a participating pharmacist to serve as a “health coach.” Pharmacists registered with the program undergo training at the University of Maryland’s School of Pharmacy and must qualify to provide education in diabetes management. The P3 Program has two components. First, the participant has a comprehensive visit with the pharmacist during which the pharmacist gathers information about the participant’s health, medications and medical history. The pharmacist advises the participant about his or her medications, including how they work, how to take them and the potential side effects. Together, pharmacist and participant choose short- and longterm therapy goals. After the initial consultation, the participant sees the pharmacist on a regular basis, five to seven times over the first year depending on the participant’s acute needs. After that, visits may become quarterly. Where the visits take place depends on the employer and what kind of health care facilities exist in the participant’s neighborhood, said program director Magaly Rodriguez de Bittner, PharmD, BCPS, CDE, professor and chair of the Department of Pharmacy Practice and Science. “When pharmacists become part of the network, they agree to have a private or semi-private area to see the patient, and the time and equipment to do so,” she said. “We have a nice mix. Some are seen in health systems in outpatient clinics, some are seen at community pharmacies or at retail chains and independent pharmacies. We also have pharmacists who go to the employer’s site.” State involvement is an important part of the program, Dr. Rodriguez de Bittner said. “It’s a coordinated effort. We get financial support from the Department of Health and Hygiene. They understand that we need solutions for managing chronic diseases.” As far as solutions go, the P3 Program appears to be an effective one. A 2008 evaluation of the program revealed that more than half of the participants met their therapeutic goals, and fewer participants were in poor control of their diabetes after one year compared with those in other programs. By measuring the participants’ hemoglobin (Hb) A1c

The Blanchard Valley Health System team (L-R): Angela Marriott, CPhT; Cheryl Bishop, CPhT; Tracey Pierce, RPh, CGP, FASCP; Mark Johannigman, RPh; Michael Leifheit, RPh, PharmD, BCPS; Nick Bellman, RPh, PharmD, BCPS.

‘Too much of our health care is delivered and paid for in silos, and these programs are a great example of [what] we need to be thinking about as we redesign our health care system.’ —William Ellis, RPh, MS levels, low-density lipoproteins (LDL) and blood pressure, as well as whether participants received recommended vaccinations, performed foot exams and had dilated eye exams, the evaluation revealed an overall health care cost savings of $1,000 per participant after one year. Participants reported satisfaction with the pharmacists: In a survey ranking pharmacists on a scale from 1 (low satisfaction) to 5 (high satisfaction), they received a mean ranking of 5.

Flexibility in Ohio The Blanchard Valley Health System’s CMM program contracts directly with an employer’s benefit department and is divided into two components. The first is an initial wellness and medication therapy management session that is broken into three parts and conducted by teams of pharmacists and technicians. First, the participant undergoes a general health assessment onsite at the workplace. This assessment covers basics such as height, weight, blood pressure, body fat percentage, body mass index, lipid profile and blood glucose. Next, the participant completes an online assessment and answers questions about lifestyle and overall health. Finally, the participant sits down with a pharmacist, and together they go through the results of the general and online assessments and discuss the participant’s medications. The pharmacist ensures that the participant understands what each medication is for, how it works and how it should be taken, and ensures that the participant has an action plan that covers any appropriate and necessary screenings (e.g., mammogram, colonoscopy). The entire session takes about 45 minutes. The second component is an ongoing care program. If the initial screening

reveals that a participant is a good candidate for ongoing care, he or she will have the option of continuing to see the pharmacist at the CMM between two and four times over the next 12 months, or until the next screening. The CMM takes a three-pronged approach to providing these services, said Mark J. Johannigman, RPh, director of pharmacy. “We use the information that we take in a HIPAA-compliant way and bring it back to the employer to show the employer three things—what the patients think of the program, the clinical outcomes and the money we can save the employer through those outcomes,” he said. Program participants complete patient satisfaction surveys, and a recent survey revealed an average score of 4.81 (5 is excellent). Among those who took the survey, 99.68% would recommend the service to others and 98.01% felt it was a good use of their time. Patients with diabetes experienced a greater average reduction in LDL (15.6 mg/dL) than the rest of the patients who were screened for lipid levels. In the latter group, LDL reductions averaged 6.3 mg/dL. Among patients with diabetes, 35 had desirable HbA1c values of less than 7% upon their initial visit and 40 patients had achieved that goal by their last visit, an increase of 14.3%. Such outcomes translate into financial savings for the employer, said Mr. Johannigman. “By using different systems as references that are tied to outcomes— hemoglobin A1c, cholesterol levels, LDL and so on—we can tie dollar amounts to pharmacist intervention,” he said. Those dollar amounts can be described as “hard” savings, and in a CMM study of three employers’ first year of participation, such savings averaged $253 per

patient per year, Mr. Johannigman said. But the financial picture brightens further when “soft” savings are included. Soft savings are based on earlier, published data, rather than a direct tie-in to current pharmacist interventions. One example would be savings achieved from reduced rates of complications that have been documented in diabetes patients with improved levels of HbA1c. When those soft savings were accounted for in the CMM study, an average total cost savings of $1,011 per patient per year was achieved, Mr. Johannigman said. The program’s success stems from its approach. “Companies understand that patients have to be involved in their own health care. They incentivize their employees to go through the program by making it a wellness benefit. It’s a team effort to reduce costs and improve health care.” He also stressed the program’s flexibility. “It can be used in any type of pharmacy. We’re a health system, but the model can be used in retail, community or academic settings. It’s portable.”

Closing Gaps in Care Programs that bring pharmacy services and medication management to workers through their employers are the wave of the future, said William Ellis, RPh, MS, chief executive officer of the American Pharmacists Association Foundation. “Too much of our health care is delivered and paid for in silos, and these programs are a great example of [what] we need to be thinking about as we redesign our health care system.” Mr. Ellis added that these programs benefit all involved. “Patients have access to discounted co-pays and a coach to help them live with their disease, pharmacists have an opportunity to use their training and education in a meaningful way and receive compensation for it and employers are supporting a healthier and more productive workforce while saving money by avoiding catastrophic events.” That is not to say that pharmacists are taking the place of physicians, he added. “It’s more that their patients are getting coordinated care,” he said. “When you think about a typical patient–physician interaction, the patient is diagnosed and given a script, and it can be three months before a follow-up visit. That’s a huge gap. Seeing a pharmacist four or six weeks after the physician’s visit closes that gap.” “We’re not taking the place of anyone in the health care team,” Dr. Rodriguez de Bittner said. “Instead, we’re fulfilling the role of the pharmacist as the medication expert. We know that lifestyle is a big deal in managing chronic diseases, but medication also is key. Having a pharmacist accessible to help patients achieve their goals can be a wonderful solution.” —Terri D’Arrigo

14 Operations & Management

Pharmacy Practice News • September 2010

Leadership in Action

Emotional Intelligence: Teamwork and Collaboration “Real knowledge is to know the extent of one’s ignorance.” —Confucius “The only true wisdom is in knowing you know nothing.” —Socrates

he older I get, the more I realize that I don’t know everything. As a manager, I strive to surround myself with people who “fill in” my

“gaps,” complementing my skills and knowledge with their own. Rather than regarding my areas of deficiency as weakness, I believe that my job is to build a strong, diverse team composed of individuals from a variety of disciplines and departments. Building strong interdisciplinary teams requires a high Emotional Intelligence quotient (EQ). As such, this issue’s column focuses on the role of EQ in collaboration and team building.

Developing a functional team takes discipline, planning and commitment. Unfortunately, these abilities do not always come naturally. Reldan Nadler’s book, “Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leadership” (Santa Barbara, CA: Psyccess Press; 2006) identifies 10 ingredients crucial to the mastery of collaboration and teamwork. Below, we examine each of these ingredients and identify the ways in which to apply

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

Ernest R. Anderson Jr., MS, RPh

them in the practice of pharmacy. Create and share a clear vision. The star performer creates a clear vision for the future and effectively communicates it to the department. For example, you might choose to focus on the goal of fostering impeccable attention to detail. For a technician, this vision might manifest in assuring accurate dispensing so the right drug gets to the right patient. For a pharmacist, attention to detail may be in catching potential prescribing errors or renally adjusting the dose of a drug. To build buy-in to your vision, begin by asking team members how they might contribute to it. Build trust. Developing team trust takes time. Don’t expect it to happen overnight. Being humble and open helps to build trust. Additionally, showing others that you trust them engenders their trust in you. Admitting that you need your team’s participation— because you don’t know it all—empowers the group. Establish clear expectations and guidelines. Too often, the manager assumes that the team understands his or her goals and expectations, only to be faced with the fact that poor performance keeps popping up as a result of the manager’s lack of clarity in communication. Practice good communication skills. Communication skills and conflict resolution are part of the mindful manager’s repertoire. Good communication with each individual demonstrates that the leader values each unique contribution to the team. Listening and asking leading questions also are part-andparcel of good communication. Think system-wide. “Systems thinking” is imperative in pharmacy, whether we are completing a root cause analysis or determining how to provide the best patient care. The wise manager thinks from the perspective of each stakeholder in a decision-making process and models this behavior to team members. Don’t make the mistake of thinking that everyone sees an issue the way you do. Instead, make sure you practice “walking a mile” in your stakeholders’ shoes. Be willing to take risks. Personal leadership includes taking risks within the

Operations & Management 15

Pharmacy Practice News • September 2010

Leadership in Action confines of the values that have been established (and encouraging others to do so, as well). Value diversity. Valuing and appreciating the diversity of the team will help you place each team member in the role that most suits them. This requires getting to know the team and familiarizing yourself with the ways members are able to contribute from their unique points of view. In this way, the leader models this behavior, encouraging team members to do this among themselves as well. This facilitates consensus. Establish clear accountability and consequences—both positive and negative. Project plans that include timetables help provide clarity and accountability.

POLICY

Finance

340B SAVINGS continued from page 6

discounts on diabetes meters and strips. The need to carve out the Medicaid population using 340B-priced medications has led to the development of splitbilling software. Maintaining virtual inventories has simplified the need to separate 340B-priced medications from the rest of the inventory. The PVP has contracts with Talyst Inc., eAudit Solutions and ABC Works (AmerisourceBergen Corp.) for discounts on split billing software for facilities in need of inventory assistance.

Sharebacks Add Value For the past three years, Apexus has distributed additional value to participants, in the form of a shareback (the 2009 shareback was $4.5 million). Revenues that exceed operational expenses are divided among participants, and credits are applied to accounts at the wholesale distributor level. This process enables pharmacy departments to achieve the full value of the PVP with savings remaining in the department. Shareback recipients are sent notification prior to administering the credits, which are determined within the first quarter following the close of the previous year’s data. An integral component of the program is the ability to obtain feedback from participating facilities. A satisfaction survey is distributed yearly, and the responses serve as the cornerstone for improving the program. The growth of the program depends on the activity of the participants and their feedback. A customer support service center is available for questions Monday through Friday. Call the Pharmacy Services Support Center at (800) 628-6297 or the Prime Vendor Program at (888) 340-BPVP.

Keep learning. Ongoing learning is a requirement for everyone, at all levels. Managers who model enthusiasm for constant learning help encourage this behavior in their teams. You can also reinforce this principle by publicly acknowledging the individuals who teach you new things. Mentor others. Great leaders are willing to share what they know in an effort to develop their team members. Watching team members grow and flourish as a result of your mentoring is one of the greatest rewards of leadership. Nadler also provides some extra tips

that are very applicable to team-based pharmacy practice. • Focus on greetings and “goodbyes.” Greeting people communicates that you value their presence. • Clearly and frequently update the team on the status of the department, including financial performance, progress toward reaching goals, pharmacy metrics (such as clinical interventions) and other key performance indicators. • Consider holding “red-flag meetings” that bring attention to critical issues, as well as regular team meet-

ings that afford team members the opportunity to share information and ideas. This might include ideas about process improvement, workflow redesign or other issues. This communicates the message that you value your staff. • Catch people “in the act” of doing something well. Recognize these people and their accomplishments in your regular team meetings. • Maintain and project a positive attitude injected with a little humor (where appropriate). This builds camaraderie and diffuses stress.

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Hem/Onc Pharmacy

PPN • September 2010

RECOTHROM Thrombin, topical (Recombinant)

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DOSAGE AND ADMINISTRATION

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Controlling Cancer Care Costs: U.S. Versus England A s leaders argue about how to control the skyrocketing costs of cancer care, some say it is worthwhile to look at how other countries, such as England, cope. Over the past year and a half, England’s National Institute for Health and Clinical Excellence (NICE) has rejected a number of cancer drugs for certain indications, concluding that patients would derive minimal benefits at an excessively high cost. The rejection list includes erlotinib (Tarceva, OSI/Genentech) for maintenance therapy of non-small cell lung cancer, sorafenib (Nexavar, Bayer Healthcare/Onyx Pharmaceuticals) for advanced hepatocellular carcinoma, and lapatinib (Tykerb, GlaxoSmithKline) in combination with capecitabine (Xeloda, Roche Pharmaceuticals) for women with advanced or metastatic HER2-positive breast cancer. In contrast, the FDA has approved these drugs for these indications in the United States. The rejections mean that the U.K.’s National Health Service won’t pay for the costly treatments, or will pay only under narrowly defined circumstances. Patient advocacy and physician groups in England have lambasted NICE as insensitive to severely ill patients. NICE insists that the money would be better spent on treatments with more demonstrable benefits. Nothing comparable to NICE exists in the United States. The FDA evaluates drugs for safety and efficacy compared with placebo; it considers neither cost nor comparative efficacy against other treatments in determining what to approve. NICE considers all four factors in calculating what to cover, after the European Medicines Agency (the European equivalent of the FDA) has approved a drug. NICE is free to negotiate drug prices with suppliers, and whereas physicians in the United States can choose to prescribe drugs for off-label indications, NICE’s guidance is binding. NICE has become increasingly skeptical of drugmakers’ claims about the efficacy and economics of newer antineoplastic agents. The institute’s decision to reject bevacizumab (Avastin, Genentech) for breast cancer characterizes that trend. In early July, NICE estimated that the drug, in combination with a taxane for metastatic breast cancer (MBC), extends life by only seven weeks at a cost per quality-adjusted life-year (QALY) of at least $175,000. This is far above its threshold approval range of $30,000 to $45,000 per QALY. According to NICE, “the cost of bevacizumab is too high for the limited and uncertain benefit it may offer patients.” The FDA approved bevacizumab in combination with paclitaxel

for MBC in 2008 based on a trial showing the drug improved progression-free survival. In July 2010, however, an FDA advisory panel overwhelmingly recommended that this indication be revoked because further trials showed the drug did not improve overall survival. At press time, it was unknown whether the FDA would follow this recommendation. Other drugs gaining approval in the United States, but rejected in the last year and a half by NICE, include azacitidine (Vidaza, Celgene) for leukemia and temsirolimus (Torisel, Pfizer) for advanced kidney cancer.

Access to Drugs The disparate systems of the United States and England have resulted in differences in access to cancer drugs. One study comparing access to pharmaceuticals between the United States and the United Kingdom, including about two dozen oncology drugs, found that “the U.S. provides faster more flexible access to most, but not all, of the U.K.–approved pharmaceuticals” (Appl Health Econ Policy 2006;5:177-187). According to lead author Joshua P. Cohen, PhD, a senior research fellow at Tufts University, NICE takes an average of 52 weeks to make a decision regarding reimbursement, leaving affected patients in medical limbo. Dr. Cohen explained that life expectancy for cancer patients in the United Kingdom is lower than it is in the United States and much of Europe, and this is partly attributable to decreased access to newer therapies. But things are loosening up in England. A recent report, “Extent and Causes of International Variations in Drug Usage,” by the national cancer director at the U.K. Department of Health ranked the nation 12th out of 14 developed countries in the use of cancer drugs introduced in the last five years. Use was highest in the United States, followed by Spain and France. In response, England’s health secretary announced a $78 million interim fund to pay for cancer drugs not approved by NICE. A permanent and larger fund is scheduled for April 2011. The report also emphasized that higher drug expenditures do not necessarily correlate with longer survival. One major tradeoff for better access to costly treatments is, of course, that costs borne by patients are higher in the United States than in other countries— sometimes dramatically so. The cost of bevacizumab for the average patient in England is $5,000 per month; in the United States, it often exceeds $8,000, although that amount can vary widely

Hem/Onc Pharmacy 17

Pharmacy Practice News • September 2010

In Focus based on varying levels of insurance coverage and reimbursement.

Something Has To Give Despite incessant railings against the skyrocketing costs of prescription drugs, the United States tolerates the status quo. One reason is that any medical decision carrying large financial ramifications is as much a social issue as it is a medical one, according to Peter Bach, MD, director of the Center for Health Policy at Memorial Sloan-Kettering Cancer Center, in New York City. At least for now, the consensus in the United States is to provide medical treatment that prolongs life, no matter how much it costs. “That’s what our society has decided, and it’s certainly our behavior,” Dr. Bach said. “Most states have passed laws requiring insurers to cover these treatments. The health care reform legislation prominently addresses issues like rescission [cancellation of health care policies] and preexisting conditions, which anchors to this notion that insurers should cover people who are sick irrespective of the costs of doing so.” Knowing the overall cost of cancer drugs would be an essential step in plotting a strategy to reduce them, but unearthing that information is daunting, said Dr. Bach. “Go find the number for how much we spend on oncology drugs in the U.S. each year,” he said. “You can’t.” Something has to give, said Leonard Saltz, MD, professor of medicine at Weill Cornell Medical College, in New York City. “What we Americans ideally want is unlimited access to all care, with full coverage and no consideration of cost versus benefit. Of course, economically such an approach is unrealistic,” he said. The way he sees it, only when individuals must make economic choices when costly treatments with marginal benefits are involved will there be a financial incentive to evaluate just what these drugs offer for their cost. And frequently, what these drugs offer is less than impressive, and far less than most people realize. “What we fail to do as a society is set targets in terms of what is a clinically significant benefit,” Dr. Saltz said. “Meanwhile, all too many of the newer cancer drugs are marketed at prices that suggest they represent substantial advances, when often the benefits offered are extremely modest.” He pointed to erlotinib for pancreatic cancer. In a Phase III clinical trial, the drug, when added to standard chemotherapy, prolonged survival by a median of 12 days over chemotherapy alone (J Clin Oncol 2007;20;25:1960-1966). The FDA approved the drug for pancreatic cancer on the basis of this trial. “Yes, it was a statistically significant improvement in survival, but not a clinically significant one; and at an added cost of about $4,000 per month, it doesn’t meet the criteria that most people would accept for cost-

effective medicine,” e,” said Dr. Saltz. That’s the point oint at which NICE makes blunt decisions. “They say we can’t n’t afford everything, so if we spend money on a marginal therapy, we can’t spend it on something else,” Dr. Cohen said. The United States, he continued, avoids that debate because many Americans recoil at the prospect of explicit health care rationing. Yet, “We ration all the time by geographic variation and across socioeconomic and insurance status, and we do accept that,” he said.

A U.K. study (J Clin Oncol 2010;28:3234-3238) says as much: “anticancer drug coverage decisions that dr consider cost-effectiveness are con associated with greater restrictions and slower time to coverage.” However, “because newer oncology medicines can cost the patient thousands of dollars each month, these copayments [in the U.S.] can represent substantial barriers to access.” Considered in that light, NICE’s rejections often make both medical and economic sense, in Dr. Saltz’s opinion. Simi-

lar judgments, made through some as yet unformed mechanism, will ultimately be necessary to keep our health care system financially viable. “NICE is a necessary evil,” he said. “I wish there were a better way, but I don’t believe there is. Some form of it is probably going to be necessary for our health care system to survive. Without meaningful limitations on ineffective or marginally effective health care expenditures, our system will eventually collapse, and then we’ll have a real health care tragedy. But it’s political suicide to tell people what the reality is.” —Steve Frandzel

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Hem/Onc Pharmacy

Pharmacy Practice News â&#x20AC;˘ September 2010

In Focus

PANCREATIC

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Dr. Conroy added that the regimen delayed deterioration of quality of life. â&#x20AC;&#x153;FOLFIRINOX is more toxic, but overall has very manageable toxicities,â&#x20AC;? he said. In the French trial, 342 patients with metastatic pancreatic adenocarcinoma were randomized to standard treatment with gemcitabine or FOLFIRINOX, which is a combination of 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin. Patients were required to have adequate organ function, a PS of 0 or 1, bilirubin less than 1.5 upper limit of normal and no prior chemotherapy or radiotherapy. Patients were not included if they had non-ductal pancreatic cancer; adenocarcinoma of the ampulla of Vater; unresectable, locally advanced pancreatic cancer without distant metastases; central nervous system metastases; chronic diarrhea; or other previous or concomitant malignant disease. Patients in the FOLFIRINOX arm received oxaliplatin (85 mg/m2 over two hours), irinotecan (180 mg/m2 over 90 minutes), leucovorin (400 mg/m2 over two hours), and 5-FU (400 mg/m2 bolus then 2,400 mg/m2 over 46 hours), all on day 1, and then repeated every two weeks. Patients in the control arm received gemcitabine (1,000 mg/m2 IV over 30 minutes weekly for seven of eight weeks, one week rest, and then weekly for three of four weeks). At the planned interim analysis, the Independent Data Monitoring Committee recommended that the study be halted when it was determined that the median OS was significantly increased in the FOLFIRINOX arm (P<0.0001) and that the findings were unlikely to change with additional patients. At the final analysis, the median OS was 6.8 months for gemcitabine compared with 11.1 months in the FOLFIRINOX arm (hazard ratio [HR], 0.57; P<0.0001) (Figure 1). Median progression-free survival was 6.4 months in the FOLFIRINOX arm and 3.3 months in patients receiving gemcitabine (HR, 0.47; 95% confidence

interval [CI], 0.37-0.59; P<0.0001). The response rate was higher in the FOLFIRINOX group (31.6% vs. 9.4%; P=0.0001). A greater percentage of patients receiving FOLFIRINOX had a complete response, partial response or stable disease (70.2% vs. 50.8%; P=0.0003). Several grade 3/4 hematologic toxicitiesâ&#x20AC;&#x201D;neutropenia (45.7% vs. 18.7%), febrile neutropenia (5.4% vs. 0.6%) and thrombocytopenia (9.1% vs. 2.4%)â&#x20AC;&#x201D;were more common in patients receiving FOLFIRINOX (Figure 2). One toxicityrelated death occurred in each arm. Several nonhematologic grade 3/4 adverse events also were more frequent in patients receiving FOLFIRINOX; these included peripheral neuropathy (9% vs. 0), vomiting (14.5% vs. 4.7%), fatigue (23.2% vs. 14.2%), diarrhea (12.7% vs. 1.2%) and grade 2 alopecia (11.4% vs. 0.6%). In contrast, alanine aminotransferase elevations were more common in patients receiving gemcitabine (18.6% vs. 7.3%).

Hem/Onc Pharmacistâ&#x20AC;&#x2122;s Approach Dr. Patel said she and her colleagues were not totally surprised when the FOLFIRINOX results were announced. For several years, she explained, her team has been using FOLFOXâ&#x20AC;&#x201D;a combination that has all of the French regimenâ&#x20AC;&#x2122;s drugs, without irinotecanâ&#x20AC;&#x201D;as second-line therapy in patients with metastatic pancreatic cancer. â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;ve achieved decent results with that approach, so it makes sense that adding another potent chemotherapeutic agent would boost response in the first-line setting,â&#x20AC;? she said. Using the newer regimen as a firstline therapy, however, has to be handled carefully, she stressed. â&#x20AC;&#x153;The key really is patient selection. If a patient comes in already doing poorly up frontâ&#x20AC;&#x201D;that is, a lot of weight loss and low appetite, with lots of fatigueâ&#x20AC;&#x201D;he or she probably is not the best candidate for FOLFIRINOX,â&#x20AC;? Dr. Patel said. â&#x20AC;&#x153;This regimen can be toxic to the immune system, so one of the main side effects

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To accommodate those requests, Dr. Patel and her colleagues quickly developed an order set for the FOLFIRINOX regimen, but with an added twistâ&#x20AC;&#x201D;most of the gastrointestinal physicians at MD Anderson start patients off with a dose reduction of about 15% for the two primary drugs in the regimen, irinotecan and oxaliplatin. â&#x20AC;&#x153;The regimen that was evaluated in the ASCO abstract employs a pretty aggressive dose, with a relatively high degree of toxicity,â&#x20AC;? she noted. â&#x20AC;&#x153;So we felt this was the safest way to get our patients startedâ&#x20AC;? on the new regimen. Several other cancer specialists said they welcomed FOLFIRINOX as a new treatment option for pancreatic cancer. But side effects came up as a common concern. â&#x20AC;&#x153;It has been vanishingly rare for an abstract in [this malignancy] to be practice-changing. This one probably is,â&#x20AC;? said Leonard Saltz, MD, professor of medicine at Memorial Sloan-Kettering Cancer Center, in New York City. â&#x20AC;&#x153;The outcome in the experimental arm was superior compared to the gemcitabine control arm; however, it was at a considerable priceâ&#x20AC;&#x201D;toxicity. So this is not a new standard of careâ&#x20AC;&#x201D;it is a new standard option. It is a reasonable consideration only in patients with excellent performance status [PS)]â&#x20AC;&#x201D;Eastern Cooperative Oncology Group status 0 or 1â&#x20AC;&#x201D;and within that population, the benefits versus toxicities need to be carefully [weighed].â&#x20AC;? The studyâ&#x20AC;&#x2122;s lead researcher agreed that the regimen was only for certain patients. â&#x20AC;&#x153;This is the first time in a randomized Phase III study that we have achieved an 11-month median overall survival [OS] in pancreatic cancer,â&#x20AC;? said Thierry Conroy, MD, Nancy University, in Vandoeuvre-lĂ¨s-Nancy, France. â&#x20AC;&#x153;We recommend FOLFIRINOX as the new international standard of care for patients with metastatic pancreatic cancer, but only in patients with normal or [near] normal level of bilirubin and performance status 0 or 1.â&#x20AC;?

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Figure 2. Comparison of selected adverse events.

is lowered blood counts, which could lead to infection. In addition, a patient who is already fatigued and battered down by their pancreatic cancer can really take an additional beating on this chemotherapy regimen.â&#x20AC;? Given those caveats, is FOLFIRINOX truly practice-changing? â&#x20AC;&#x153;Well, itâ&#x20AC;&#x2122;s certainly excitingâ&#x20AC;&#x201D;we just havenâ&#x20AC;&#x2122;t seen these types of gains in overall survival in patients with pancreatic cancer,â&#x20AC;? Dr. Patel said. â&#x20AC;&#x153;But we are waiting to see whether our patients continue to tolerate the regimen. Can they take it long enough to realize the OS gains documented in the clinical trial? We just donâ&#x20AC;&#x2122;t know yet. But weâ&#x20AC;&#x2122;re hopeful.â&#x20AC;? Dr. Patel said she has been considering one further tweak to the FOLFIRINOX regimenâ&#x20AC;&#x201D;starting patients with poor performance status off with a single chemotherapy drug, such as gemcitabine, and if they respond well, then possibly transitioning them to FOLFIRINOX as a second-line option. â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke, with additional reporting by David Bronstein

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IMPORTANT PRECEDEX SAFETY INFORMATION Clinically signiﬁcant episodes of bradycardia, sinus arrest and hypotension have been associated with Precedex infusion and may necessitate medical intervention. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex. Please see the brief summary of Prescribing Information on adjacent page.

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For step-by-step instructions on how to start using Precedex and what to expect, please visit us at www.Precedex.com. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex.2 Clinically signiﬁcant episodes of bradycardia and sinus arrest have occurred in young, healthy volunteers with high vagal tone or with different routes of administration such as rapid intravenous or bolus administration.2 Transient hypertension has been observed primarily during the administration of the loading dose. Treatment has generally not been necessary, although a reduction in loading dose infusion rate may be desirable.2

Hypotension and bradycardia can occur and may necessitate medical intervention such as —Decreasing or stopping Precedex infusion —Increasing rate of IV ﬂuid administration —Elevating lower extremities —Administering pressor agents such as atropine, ephedrine or glycopyrrolate2 Use with caution in patients with advanced heart block or severe ventricular dysfunction.2 The most common adverse effects (incidence >2%) are hypotension, bradycardia and dry mouth.2

Please see the brief summary of Prescribing Information on adjacent page. References: 1. Based on increases in weight of active ingredient sold (either mcg or mg). IMS Health National Sales Perspective 2Q 2009. US nonretail market, all channels injectables. 2. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2008. 3. Kamibayashi T, Maze M. Clinical uses of B2-adrenergic agonists. Anesthesiology. 2000;93:1345-1349. 4. Data on file. Hospira, Inc. Hospira, Inc. 275 North Field Drive, Lake Forest, IL 60045 P10-2830 Aug., 10. Printed in the USA.

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Hem/Onc Pharmacy

Pharmacy Practice News • September 2010

In Focus This is Part 1 of a two-part series

Adapting automation for oncology:

Fitting a Square Peg in a Round Hole Tampa, Fla.—Applying automated systems in the field of oncology requires persistence, flexibility and good oldfashioned ingenuity, according to a presentation at the American Society of Health-System Pharmacists 2010 Summer Meeting. There is a gap in oncology automation, with oncology specialists who want flexible systems that adapt to their everchanging needs on one side and vendor systems that, “by their nature, need to be somewhat rigid” on the other, said speaker Holly S. Lilly, PharmD, pharmacy informatics consultant, Shields Solutions, LLC, in Tampa. Oncology specialists tell the vendors, “ ‘the functionality of what you are offering doesn’t fit my needs’ ” and the vendors respond by saying, “ ‘this is different from what we usually service,’ ” said Dr. Lilly. “But, they’re both right.” Oncology is like “a square peg in a round hole,” which creates some challenges as automated systems are implemented in this area. One challenge that arises relates to normalized dosing, which incorporates indirect measures into dosing such as dose calculations based on lab indicators (absolute neutrophil count, serum creatinine), weight conventions (actual, adjusted) and dose adjustments based on therapeutic thresholds. Dr. Lilly referred to this as “the relationship between the commercially available products and that customized dose that’s appropriate for your patient.” She said, “the narrow therapeutic index of chemotherapeutic drugs makes this so important in the oncology setting.” For example, when measuring weight in adults for dosing of chemotherapeutic and biologic agents, clinicians can measure the actual weight, or they might use equations to calculate ideal weight or adjusted weight. Dr. Lilly noted that automated “systems need to be flexible enough to accommodate the appropriate equation for the drug being dosed and the disease state or therapeutic regimen specific to your patient.” For pediatric patients, weight-based dosing is common, but in patients with dynamic fluid shifts, the weight equation used becomes especially important, noted Dr. Lilly. She said some centers include two weights in the system for a given patient. “One is deemed the baseline or original weight for drug calculations, and the other is the fluctuating weight, so the team can monitor changes and adjust doses appropriately.” Another component of automated systems, clinical decision support with dose-range checking (DRC), plays an

important role in chemotherapy dosing, noted Dr. Lilly. These tools provide valuable information about maximum single doses, maximum daily doses, maximum lifetime doses and now systems include another important maximum—maximum treatment course dose. One lesson that Dr. Lilly said she learned with regard to treatment course dose limits was that vincristine 2 mg IV may be an appropriate dose, but vincristine 2 mg IV daily for three days is not. She noted that when she was working as a pharmacy informatics specialist at Moffitt Cancer Center, she and her colleagues “lobbied to get functionality into their system to isolate not only what’s going on during a day and during a lifetime, but also during specific courses of treatment.” Research protocols used so often in oncology add another complication to DRC in this setting. “When you’re working with your software vendors, keep in mind that you need a lot of flexibility to customize the rules that you need” based on the research protocols used. An oncology center that does extensive research will need the functionality to support this customization and the time to build the expanded options into the system. She said it is “critical” that rules are flexible with respect to the drugs involved as well as the protocols involved, so that warnings don’t fire inappropriately. This flexibility is important with respect to both clinical and billing terms. For example, she said, high-dose and low-dose methotrexate have different compounding protocols, and high-dose cytarabine is given in a bolus, whereas low-dose cytarabine is given as a continuous infusion. “If these are switched, there can be toxicities associated with it, so being able to differentiate those in your system is important.” These differences need to be built into the system, Dr. Lilly said, stressing that this provides “an opportunity for informaticists to include safety measures.” A second challenge to bringing technology into the oncology setting involves the scheduling and rescheduling of doses. Once a regimen is selected, Dr. Lilly said pharmacists need to recognize that “these are complex orders and the processing is front-end loaded from a time perspective.” If a regimen calls for the same medication to be administered every three weeks for three courses, she said, “it is better to enter the order once

with a duration of every 21 days times three than to enter three separate orders. We can benefit from consistency, and fewer keystrokes present less opportunity for error.” However, she added, “it also is important that system design recognizes the time line within the course of therapy; appropriate messaging should indicate cycle or course, such as: ‘this is the second of three courses.’ ” Dr. Lilly further noted that all the components of the chemotherapy order need to be “as ready as possible for treatment when the patient arrives.” Just-in-time does not just apply to automated dispensing cabinets in an outpatient oncology setting. Laboratory testing schedules and results also have a bearing on chemotherapy regimens and need to be considered. If Murphy’s law strikes in the form of side effects, which are expected with chemotherapy, the automated system must be able to handle any necessary changes, such as dose reductions, extensions of dosing intervals and so on. Dr. Lilly noted that there are some flexibilities that she has been able to work into systems that she has developed. These include treating the regimen of care as a single unit with multiple parts. “The timing relationships should not change,” she said, adding, “you still need antiemetics one hour prior to active therapy,” for example. Additionally, if the regimen needs to be rescheduled, she said, “we need to copy the plan of treatment and retain the calculated doses.” A final challenge in applying automation in oncology settings relates to Healthcare Common Procedure Coding System (HCPCS) billing issues. Reimbursement for treatment of Medicare or Medicaid patients requires billing in Centers for Medicare & Medicaid– defined minimum billable quantities, but Dr. Lilly noted that the problem is that there is “often an uneven or strained relationship between the minimum billable unit, your package size and the appropriate dose for your patient.” For example, she noted, “a potential system ‘gotcha!’ is the rounding logic for billable quantities themselves.” She pointed out that whether the pharmacy module is interfacing with another module within the clinical system or with an external billing system, “it is likely that the billing number and quantity need to be identified. At some

on oncology informatics. This article discusses system challenges that clinicians face when applying informatics in the oncology setting and offers techniques to address those challenges. Part 2 will describe the electronic chemotherapy process in place at St. Jude Children’s Research Hospital in Memphis, and discuss specific technologies that play an integral role in that process.

point, you’ve got to decide what your rounding logic is going to be.” She gave an example of a system that identified medications by their National Drug Code (NDC) number by strength. So, for a given a dose of 1,482 mg of gemcitabine (1,000 mg strength), for example, you would divide 1,482 mg by 1,000 mg (strength) and you would get 1.482. If you multiply 1.482 by 5 (the quantity conversion factor for HCPCS), that equals 7.41. Depending on the rounding logic used (always round up, always round down, round up if 0.5 or higher), you end up with seven or eight billable units. “If you bill for a quantity of seven rather than a quantity of eight, the financial impact of not billing your full potential may be significant,” stressed Dr. Lilly. However, she issued a caution about always rounding up, describing an error related to trastuzumab that she observed within one system. If the patient was prescribed a 70-mg dose of trastuzumab, the dose per product calculation would be 70 divided by 440 mg per vial, which equals 0.1591. When that is multiplied by the conversion for NDC (44.00), the result is 7.0004. Based on the “always round up” rounding logic, the quantity of eight was sent to the billing system, but because trastuzumab bills in 10-mg increments, a 70-mg dose generating a quantity of eight was not acceptable. “That little trailing .0004 was very problematic. So watch out for that type of error when you are transferring information between systems.” Commenting on the state of automated systems for oncology, Tom Van Hassel, RPh, director of pharmacy at Yuma Regional Medical Center in Arizona, acknowledged that the pitfalls Dr. Lilly refers to are real and of concern, but he cautioned that too much automation can pose problems when systems are not “smart enough” to keep up with clinical demands. Mr. Van Hassel said that “the currently available computer sophistication and technology available cannot handle the multivariate approach that oncology requires. Oncology is too complex with too many variables—patient variables, disease variables, lab variables—there’s no consistency.” This might change with future software advancements, but for now, he said, “you can isolate pieces of this process, but to try to put all of this together, you are asking for huge trouble.” Amy H. Seung, PharmD, BCOP, clinical

•

see SQUARE PEG, page 28

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FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical. Important Safety Information FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result. Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges. Do not use FLOSEAL in patients with known allergies to materials of bovine origin. FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation. RX only: For safe and proper use of these devices, please refer to full device Instructions For Use.

1. 2006 IMS Hemostat and Sealant Revenue, Unit, and ASP Sales Data. Baxter, FLOSEAL and ADVANCING SURGERY,ENHANCING LIFE are trademarks of Baxter International Inc. Gelfoam is a registered trademark of Pharmacia & Upjohn Company LLC., used under license. BS1889 4/2008

Pharmacy Practice News • September 2010

SPOTLIGHT ON

BLOOD FACTORS 2010 Part 1 of a Two-Part series. Next month: the role of the pharmacist in managing patients with coagulopathies.

Q&A

New Treatment Options for Coagulopathies Scott W. Savage, PharmD, MS, clinical manager, Department of Pharmacy, and clinical assistant professor, UNC Eshelman School of Pharmacy at University of North Carolina (UNC) Health Care, North Carolina Cancer Hospital, in Chapel Hill, talks with Pharmacy Practice News about current trends in the management of patients with hemophilia, von Willebrand disease and other coagulopathies. PPN: What’s new in the management of patients with hemophilia and von Willebrand disease (vWD) and other coagulopathies? Dr. Savage: In terms of product availability, particularly for hemophilia A and B, there are agents that are in preclinical or early Phase I trials. This may alter the formulations so that dosing for some may be extended when the patient is being treated prophylactically or for an active bleed. PPN: Can you comment on the recent FDA approval of a new formulation of Xyntha (antihemophilic factor [recombinant], Pfizer) for infusion in patients with hemophilia A? According to the manufacturer, this all-in-one syringe is

the first to supply freeze-dried, albuminfree recombinant factor VIII and also the diluent (0.9% sodium chloride), thereby eliminating the reconstitution transfer step and improving patient convenience. Dr. Savage: Some of the products that are available now require some manipulation to reconstitute and administer in a syringe. Xyntha eliminates some of those steps, so it is potentially a great patient care item that hopefully may continue to improve patient adherence to their drug regimens, especially for those who do dosing at home. The formulation of the recombinant product isn’t anything new, per se—it is not a new drug; rather, it is a new device for drug administration. But it is certainly an interesting addition to our treatment options for hemophilia.

‘We work with our hematologists to make sure that [ factor VIIa] is used correctly and to establish guidelines for patients undergoing surgery according to evidence-based medicine.’ —Scott W. Savage, PharmD, MS

The hope is that the formulation will help boost adherence to the prescribed regimen, so Xyntha may be a good thing from both a pharmacist’s and a patient’s perspective. PPN: Has dosing been one of the traditional problems for people with hemophilia? Dr. Savage: Dosing of exogenous factor replacement does continue to be a challenge, based on the individual patient and overall patient adherence. There are two types of dosing: prophylactic and treatment dosing. The goal of prophylactic dosing is to maintain a very minimum level of factor in the blood. You can do prophylactic dosing based on the individual patient, typically two to three times per week, depending on the patient. Researchers continue to evaluate prophylactic treatment of patients newly diagnosed with hemophilia A and B in the hope that minimum endogenous factor levels will proactively avoid an active bleed. PPN: Xyntha is not approved for vWD. Are there any new drugs on the horizon for this coagulopathy? Dr. Savage: It would be nice to have a new product that is more active in isolating the von Willebrand factor. There are some products available in Europe where the von Willebrand concentration is more pure than what is currently available on the market here in the United States. The trend in product development is to create a higherpurity exogenous factor. That enables you to give minimal volume, which for injections is kind of critical, so that product line, I think, has potential to be useful.

PPN: Are there any new developments in how patients with coagulopathies are being managed? Dr. Savage: I would reiterate that the trend in patient care for hemophilia treatment is to consider prophylactic dosing of factor to avoid potential hospitalization related to a bleed. There are data to support more proactive intermediate dosing of factor VIII or factor IX for hemophilia a and hemophilia b patients to avoid potential hospitalization. With vWD, we are still in a more reactive state. There are products in development that will allow specific dosing for some patients. The question is, for those patients who are short on von Willebrand factor, can we provide a product that just contains that factor? For those patients, having that in their armamentarium is something to which practitioners are looking forward. Manufacturers also are working on adjusting the formulations to allow extended interval dosing for patients with hemophilia, and are coming up with different devices that potentially could improve patient adherence to therapy. PPN: What about other coagulopathies? Are there treatments that have a significant impact on clinical practice?

•

see COAGULOPATHIES page 26

INSIDE Hemophilia Roundup Coverage highlights from the Hemophilia 2010 World Congress.

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Important Safety Information Privigen is indicated for the treatment of 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, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. WARNING: Renal dysfunction, acute renal failure, osmotic nephrosis, and death may be associated with the administration of Immune Globulin Intravenous (Human) (IVIg) products in predisposed patients. Administer IVIg products at the minimum infusion rate possible. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIg products containing sucrose. Privigen does not contain sucrose. See full Prescribing Information for complete Boxed Warning.

In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Thrombotic events have been reported with Privigen and other IVIg treatments. Monitor patients with risk factors for thrombotic events, including a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Aseptic meningitis syndrome (AMS) may occur infrequently with Privigen and other IVIg treatments; AMS may occur more frequently with high doses and/or rapid infusion of IVIg. Hemolysis, hemolytic anemia, and pulmonary adverse events have also been reported. There have been reports of noncardiogenic pulmonary edema in patients administered IVIg. If transfusion-related acute lung injury is suspected, test product and patient for antineutrophil antibodies.

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In clinical studies, the most common adverse reactions with Privigen were headache, pain, nausea, pyrexia/hyperthermia, fatigue, and chills.

26 Spotlight on Blood Factors

Pharmacy Practice News • September 2010

Q&A

COAGULOPATHIES continued from page 24

Dr. Savage: The other coagulopathies, whether it’s afibrinogenemia, factor XI, or factor XIII, are so rare, there are not that many products available. But the past 20 years have seen a monumental swing in what is available. We have gone from plasma-derived products to recombinant-derived products. Patients’ trust has increased. They now believe that the products they are getting are safe. Twenty years ago, the risk for viral contamination in the products that hemo-

philiacs were given was very high. But even today, there is definitely an entrenched fear that even the products that are available in a recombinant state may not be safe. There are still a lot of concerns—how well are they manufactured? Is there any plasma or humanderived cells in them? Is there a risk for viral contamination? There’s a lot of fear still in the community, but I think that over time, the products we have available will continue to build a trust in our patient population, that what they’re getting is safe. Obviously, that is 100%

the goal: to provide safe therapy. PPN: There are several economic considerations in managing patients with coagulopathies—many of the available drugs are quite expensive. One trend, the off-label use of factor VIIa, can be particularly costly because reimbursement can be a challenge. What’s your view on use of these drugs for nonapproved indications? Dr. Savage: Factor VIIa, at least in a hospital, indeed can be very costly. From a hospital perspective, there are definite

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. WARNING: ACUTE RENAL DYSFUNCTION/FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those 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. For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]). 1 INDICATIONS AND USAGE Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions. 1.1 Primary Humoral Immunodeficiency Privigen is indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 1.2 Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts. 3 DOSAGE FORMS AND STRENGTHS Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion. 4 CONTRAINDICATIONS Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. Because it contains the stabilizer L-proline, Privigen is contraindicated in patients with hyperprolinemia. Privigen is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [4]). In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Privigen contains trace amounts of IgA ( 25 mcg/mL) (see Description [11]). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4]). 5.2 Renal Failure Ensure that patients are not volume depleted before administering Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction, administer Privigen at the minimum infusion rate practicable (see Boxed Warning, Dosage and Administration [2.3]). 5.3 Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Privigen and other IGIV product treatments. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Privigen and other IGIV products.3-5 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Privigen at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Weigh the potential risks and benefits of IGIV against those of alternative therapies in all patients for whom Privigen therapy is being considered. 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Privigen (see Adverse Reactions [6, 6.1]) and other IGIV product treatments. Discontinuation of IGIV treatment has resulted in remission of AMS

benefits to the use of recombinant factor VIIa in patients who have disorders for which the drug is not FDA-approved. From a pharmacist perspective, it is critical to understand the data that support the indications for the product and also what dose is effective. The use of factor VIIa will continue to evolve. We work with our hematologists to make sure that it is used correctly and to establish guidelines for patients undergoing surgery according to evidence-based medicine. —Compiled by Fran Lowry

within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information [17]). Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.7-9 Hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.10 Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study (see Adverse Reactions [6, 6.1]). These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data. Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information [17]). If these are present after Privigen infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. 5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions (see Patient Counseling Information [17]). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Volume Overload The high-dose regimen (1 g/kg/day for 2 days) used to treat patients with chronic ITP is not recommended for individuals with expanded fluid volumes or where fluid volume may be of concern (see Dosage and Administration [2.2]). 5.9 Transmissible Infectious Agents Privigen is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description [11]), Privigen carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Privigen. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to CSL Behring Pharmacovigilance at 1-866-9156958. Before prescribing Privigen, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17]). 5.10 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If signs and/or symptoms of hemolysis are present after an infusion of Privigen, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.11 Interference With Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. 6 ADVERSE REACTIONS The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >10% of clinical study subjects with PI were headache, pain, nausea, fatigue, and chills. The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects. Six other subjects in the ITP study experienced hemolysis as documented from clinical laboratory data (see Warnings and Precautions [5.5, 5.6]). The most common adverse reactions observed in >10% of clinical study subjects with chronic ITP were headache, pyrexia/hyperthermia, and anemia. 6.1 Clinical Trials Experience Because different clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice. Treatment of Primary Humoral Immunodeficiency In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen intravenously every 3 or 4 weeks for up to 12 months (see Clinical Studies [14.1]). All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 57.5% were male and 42.5% were female. The safety analysis included all 80 subjects, 16 on the 3-week schedule and 64 on the 4-week schedule. The median doses of Privigen administered intravenously ranged from 200 to 888 mg/kg every 3 weeks (median dose 428.3 mg/kg) or 4 weeks (median dose 440.6 mg/kg). A

Spotlight on Blood Factors 27

Pharmacy Practice News • September 2010

Meeting Coverage Hemophilia 2010 World Congress:

Studies Highlight Efforts To Improve Treatment of Hemophilia The effect of patient self-infusion versus caregiver infusion on hemophilia treatment adherence, the value of acupuncture for pain in patients with hemophilia and results on a new drug that could reduce dosing for those with a rare form of the disease were the hot topics at the Hemophilia 2010 World Congress held in July in Buenos Aires, Argentina.

Adherence Drops Outside Parental Oversight Young adults with hemophilia veer from their factor infusion schedules once they leave the care of their parents, according to researchers presenting findings of a nationwide survey at the Congress. The researchers suggested that interventions may be necessary to educate adolescents and adults who manage their own infu-

total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Of the 1038 infusions, 435 were administered to females and 603 to males. Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered. Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% conﬁdence interval for the proportion of Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 397 (a rate of 0.38 AEs per infusion), reﬂecting that some subjects experienced more than one AE during the observation period. Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Privigen infusion or within 72 hours after the end of an infusion, irrespective of causality. Table 2: Adverse Events* Occurring in >5% of Subjects With PI During a Privigen Infusion or Within 72 Hours After the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=80] Infusions (%) [n=1038] Headache 35 (43.8) 82 (7.9) Pain 20 (25.0) 44 (4.2) Fatigue 13 (16.3) 27 (2.6) Nausea 10 (12.5) 19 (1.8) Chills 9 (11.3) 15 (1.4) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 10 (1.0) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections.

Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be related to the infusion of Privigen (including 5 serious, severe AEs described below). Of the 187 non-serious AEs related to the infusion of Privigen, 91 were mild, 81 were moderate, 14 were severe, and 1 was of unknown severity. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (29% of subjects), pain (14% of subjects), nausea (11% of subjects), fatigue (11% of subjects), and chills (11% of subjects). Sixteen subjects (20%) experienced 41 serious AEs. Five of these were related severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject and resulted in the subject’s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen treatment (chills and headache in one subject; vomiting in the other). Seventy-seven of the 80 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia. During this study, no subjects tested positive for infection due to human immunodeﬁciency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V). Treatment of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg intravenous infusions daily for 2 consecutive days (see Clinical Studies [14.2]). Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male. Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine. Table 3 lists the temporally associated AEs that occurred in more than 5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality. Table 3: Adverse Events Occurring in >5% Subjects With Chronic ITP During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle*, Irrespective of Causality Adverse Event Headache Pyrexia/hyperthermia Nausea Epistaxis Vomiting Blood unconjugated bilirubin increased Blood conjugated bilirubin increased Blood total bilirubin increased Hematocrit decreased

Subjects (%) [n=57] 37 (64.9) 21 (36.8) 6 (10.5) 6 (10.5) 6 (10.5)

Infusions (%) [n=114] 41 (36.0) 22 (19.3) 6 (5.3) 6 (5.3) 6 (5.3)

6 (10.5)

6 (5.3)

5 (8.8)

5 (4.4)

4 (7.0) 3 (5.3)

4 (3.5) 3 (2.6)

sions about the importance of adherence to their treatment regimens in preventing episodes of bleeding and keeping them out of the hospital. The researchers used the Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) to assess prophylactic treatment adherence, recognized as an important variable in the management

Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen. One subject withdrew from the study due to gingival bleeding, which was not related to Privigen. Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention. Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis. In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period. 6.2 Postmarketing Experience Because postmarketing reporting of adverse events is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. Privigen Postmarketing Experience Adverse reactions reported during worldwide postmarketing use of Privigen do not differ from what has been observed in clinical studies with Privigen and from what is known for IGIV products. General The following mild to moderate reactions may occur with the administration of IGIV products: headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, skin reactions, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, myalgia, arthralgia, and changes in blood pressure. Immediate hypersensitivity and anaphylactic reactions are also a possibility. The following adverse reactions have been identified and reported during the post-approval use of IGIV products.12 Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors 7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, and rubella.13 The immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken (see Patient Counseling Information [17]). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen. It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.14,15 8.3 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated. 8.4 Pediatric Use Treatment of Primary Humoral Immunodeficiency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI. There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3. Treatment of Chronic Immune Thrombocytopenic Purpura Safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15. 8.5 Geriatric Use Clinical studies of Privigen did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed recommended doses, and administer Privigen at the minimum infusion rate practicable. Manufactured by: CSL Behring AG Bern, Switzerland

US License No. 1766 Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Acupuncture Relieves Severe Hemarthritic Pain Another study at the Hemophilia World Congress found that acupuncture may offer relief for patients with

* Two consecutive daily infusions.

Of the 183 temporally associated AEs reported for the 57 subjects with chronic ITP, the investigators judged 150 to be related to the infusion of Privigen (including the one serious AE described below). Of the 149 non-serious AEs related to the infusion of Privigen, 103 were mild, 37 were moderate, and 9 were severe. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (65% of subjects) and pyrexia/hyperthermia (35% of subjects).

of hemophilia but difficult to measure consistently. VERITAS-Pro asks 24 questions to determine how well caregivers or patients adhere to the prescribed treatment schedule and dosage, plan ahead to keep supplies for infusion ready and communicate with health care professionals about issues that arise during treatment. The researchers e-mailed the survey to a database of patients with hemophilia A. Respondents could score from 24 to 120 on the scale, with a lower score indicating greater adherence. Respondents included 70 adults (mean age, 37.4 years) and 46 caregivers (patient mean age, 10.4 years) who provided information about prophylactic or episodic treatment regimens. Among them, 23 (34.3%) self-infusers using prophylaxis and 44 (65.7%) caregivers administering prophylactic therapy completed the VERITAS-Pro. Caregivers significantly increased adherence to the patient’s treatment regimen (score, 38) over that seen when the patients selfinfused (score, 45.8; P<0.05), especially with respect to infusing the prescribed dosage (score, 5.1 vs. 6.7; P<0.05) and diligently communicating with health care professionals about treatment issues (score, 6.7 vs. 9.3; P<0.05). Caregivers were responsible for the treatment of 96% of children under 12 years old and 24% of adolescents (12-18 years old). Adherence was significantly increased when family members were in charge of infusing pediatric patients with hemophilia than when pediatric patients self-infused (score, 36.7 vs. 42.1, respectively; P<0.05). The findings highlight a need for patient and caregiver education on hemophilia treatment adherence, especially during the transitions from caregiver infusion to patient self-infusion and adolescence to adulthood, the researchers said. “We found that pediatric patients are consistently more adherent than adult patients and that seems to be because they’re often infused by family members. So, parents are taking the responsibility a little more seriously,” said Natalie A. Duncan, MPH, manager of the Disease Management Program at the Indiana Hemophilia & Thrombosis Center, in Indianapolis. The study was sponsored and conducted by Baxter BioScience in collaboration with Ms. Duncan and Amy D. Shapiro, MD, co-medical director and pediatric hematologist at the Indiana center.

•

Based on November 2009 revision.

see HIGHLIGHTS, page 28

28 Spotlight on Blood Factors

Pharmacy Practice News • September 2010

Meeting Coverage

HIGHLIGHTS continued from page 27

hemophilia who have debilitating endstage hemarthritic joint pain and who have few medications on which they can depend for relief. During the small study, six of the nine patients treated reported less pain on a daily basis. The use of acupuncture needles did not precipitate bleeding episodes in any of the patients during any of the sessions, regardless of whether or not clotting factor was prophylactically administered beforehand. “Pain medicines alone are not the answer to help manage pain,” said Angela Lambing, MSN, nurse practitioner and coordinator of the Hemophilia Treatment Center at Henry Ford Health System in Detroit. Nonsteroidal antiinflammatory drugs may increase the risk for bleeding, and acetaminophen is contraindicated in many hemophilia patients who were infected with hepatitis C in the 1970s and 1980s, when they were treated with contaminated blood products before screening laws took effect. Opioids may be the only drug available to patients with severe arthritic pain, she said. Given the limitations of pain medications, Ms. Lambing and her colleagues sought to evaluate acupuncture as an alternative therapy. “We wanted to prove that there was no bleeding with acupuncture,” she said. “It uses a very small needle, which is about 36-gauge, the width of a human hair. And then it only goes

into the second or third dermal layer.” The study was conducted at two centers, the Henry Ford Center and the Karnataka Hemophilia Treatment Center in India; the sites were connected by a twinning program of the World Federation of Hemophilia, which pairs emerging centers with established ones to help them learn from each other and better treat hemophilia around the world. Adults with hemophilia A or B were enrolled at both centers. The patients received acupuncture twice weekly for four weeks and then once weekly for four to six weeks, for a total of 12 sessions.

Patients in Michigan were pretreated with prophylactic factor before each session, whereas patients in India, where access to factor concentrates is limited, had acupuncture without prophylaxis. Pain was measured using a visual analog scale scored from 0 to 10. Most patients rated their pain at 5 or higher before treatment began and experienced a decrease in pain, including one patient whose score dropped from 10 to 5, Ms. Lambing said. Quality of life for the patients before and after treatment with acupuncture was measured using the Short Form-36 (SF-36) questionnaire.

Patients reported that their ability to perform normal physical and social activities and their mental health had improved, that they had fewer problems with work and other daily activities, that their pain had decreased and that their health had changed for the better. Ms. Lambing urged those involved in the treatment of patients with hemophilia to take a multimodal approach to pain management, including different drug types, alternative therapies including acupuncture and other targeted treatments such as physical therapy and massage.

HEMONC

In Focus

SQUARE PEG continued from page 22

specialist in hematologic malignancies, The Johns Hopkins Hospital, in Baltimore, agreed that the complexities of oncology make automation in this area especially challenging. She noted that “the oncology specialty is constantly changing,” with new therapies, dosing patterns and research protocols coming out on a weekly basis. Understanding Mr. Van Hassel’s concerns about the current software meeting those needs, she said, “you need somebody watching that piece all the time” to make sure that the system is up to date and addresses the evolution of the field. Dr. Seung also pointed out that although much time and emphasis needs to be put into building a system, “maintenance is just as important.” Echoing Dr. Lilly’s comments, she said that flexibility is crucial. “From the start you need to think through what could happen down the road.”

Humulin N is now available in a smaller vial.*

Indication, continued

Lilly also offers Humalog and Humulin R U-100 in a smaller vial size.*

Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

The smaller vials are designed to give hospitals ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. Same bar-coding technique, same color-differentiating system, smaller size. • Humalog® (insulin lispro injection [rDNA origin]) NDC Number - 0002-7510-17 • Humulin® N (NPH human insulin [rDNA origin] isophane suspension) NDC Number - 0002-8315-17 • Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]) NDC Number - 0002-8215-17 * Smaller vials contain 3 mL of insulin in a 5 mL vial.

Humalog Indication Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia.

HI65435

—Sarah Tilyou

0710 PRINTED IN USA

Humalog Important Safety Information Contraindications Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. Warnings Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes. The safety and effectiveness of Humalog in patients less than 3 years of age have not been established.

Spotlight on Blood Factors 29

Pharmacy Practice News • September 2010

Abstract Roundup Novel Factor Gets Past Inhibitors A long-acting glycopegylated recombinant activated factor VIIa (N7-GP) being developed by Novo Nordisk is safe in patients with hemophilia A and B with inhibitors, according to the results of a Phase I study presented at the Congress. Researchers from Novo Nordisk found that N7-GP exhibited a prolonged halflife, making it a good candidate for prophylaxis in this subgroup of patients who develop antibodies that attack their clotting factor, whether it is naturally produced or therapeutically infused. The

condition affects 10% to 15% of people with hemophilia, according to the Centers for Disease Control and Prevention. A recombinant FVIIa (NovoSeven, Novo Nordisk) is approved by the FDA for the treatment of bleeding episodes in patients with hemophilia with inhibitors, but it has a relatively short half-life and requires daily injections, said Judi Møss, PhD, international clinical pharmacologist at Novo Nordisk in Denmark. “This regimen causes immense demand on the patient and may negatively impact treatment compliance,” Dr. Møss said, adding that N7-GP had been developed

to address this issue and to improve compliance during prophylaxis. “The results of the current study demonstrate the safe use of N7-GP in hemophilia patients,” Dr. Møss said. “Pharmacokinetic analysis suggests that it is able to be administered every other day, a more convenient option for prophylaxis in hemophilia patients.” The single-center Phase I trial studied eight patients with hemophilia with inhibitors (mean age, 31.4 years). Four patients were given a single dose of 200 mcg/kg of N7-GP and four patients received three doses of 100 mcg/kg,

Introducing our newest small vial for an even larger range of options.

Important Safety Information, continued

Warnings, continued There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.

Other Side Effects, continued Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level).

Starting or changing insulin therapy should be done cautiously and only under medical supervision. Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening.

Please see reverse side for Brief Summary of full Prescribing Information. Please see full user manual that accompanies the pen. Humalog® and Humalog® KwikPen™ are registered trademarks of Eli Lilly and Company and are available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.

with each dose given every 48 hours. The patients were monitored for eight weeks after their final dose of the factor. Investigators were able to measure FVIIa activity for at least 72 hours after both the single dose and the last of the multiple doses. The mean half-life of N7-GP was 15.6 hours. The investigators reported that there were no serious adverse events, and they did not detect binding or neutralizing antibodies in any of the patients. A Phase II study of N7-GP is underway. —Sandhya George

30 Clinical

Pharmacy Practice News â&#x20AC;˘ September 2010

Osteoporosis

Online Tool Helps Guide Osteoporosis Therapy Organization for predicting 10-year fracture risk in individuals with low bone mass, has proven useful in helping clinicians to differentiate between those who might require medication and those who could do just as well with general bone health measures, such as weight-bearing exercises and calcium and vitamin D supplementation. At the American Society of HealthSystem Pharmacistsâ&#x20AC;&#x2122; Summer Meeting, pharmacists from Mercy Family Health

Center in Chicago presented a study showing how the fracture prediction model, known as FRAX, could be employed in an urban outpatient setting to help guide cliniciansâ&#x20AC;&#x2122; treatment choices. The pharmacists retrospectively reviewed the charts of 164 patients seen at their osteoporosis clinic from May 2006, when the clinic opened, to June 2008. â&#x20AC;&#x153;We wanted to know more about the FRAX model and how it might have an impact on our practice,â&#x20AC;? said Jill Burk-

HUMALOGÂŽ INSULIN LISPRO INJECTION (rDNA ORIGIN) BRIEF SUMMARY: Consult package insert for complete prescribing information. INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents. Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes. CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients. WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump). External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturerâ&#x20AC;&#x2122;s instructions and the â&#x20AC;&#x153;PATIENT INFORMATIONâ&#x20AC;? leaďŹ&#x201A;et before using Humalog. Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturerâ&#x20AC;&#x2122;s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identiďŹ cation and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION). Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage. PRECAUTIONS: Generalâ&#x20AC;&#x201D;Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemiaâ&#x20AC;&#x201D;As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensiďŹ ed diabetes control. Renal Impairmentâ&#x20AC;&#x201D;The requirements for insulin may be reduced in patients with renal impairment. Hepatic Impairmentâ&#x20AC;&#x201D;Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary. Allergyâ&#x20AC;&#x201D;Local Allergyâ&#x20AC;&#x201D;As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergyâ&#x20AC;&#x201D;Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin RÂŽ (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053). Antibody Productionâ&#x20AC;&#x201D;In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy. Usage of Humalog in External Insulin Pumpsâ&#x20AC;&#x201D;The infusion set (reservoir syringe, tubing, and catheter), DisetronicÂŽ D-TRONÂŽ2,3 or D-TRONplusÂŽ2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37Â°C (98.6Â°F). In the D-TRON ÂŽ2,3 or D-TRONplus ÂŽ2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less. When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage). Information for Patientsâ&#x20AC;&#x201D;Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the â&#x20AC;&#x153;PATIENT INFORMATIONâ&#x20AC;? leaďŹ&#x201A;et for timing of Humalog dosing (< _15 minutes before or immediately after a meal), storing insulin, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the â&#x20AC;&#x153;PATIENT INFORMATIONâ&#x20AC;? leaďŹ&#x201A;et that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMedÂŽ1 Models 506, 507, and 508 insulin pumps using MiniMedÂŽ1 PolyďŹ nÂŽ1 infusion sets. Humalog was also tested in the Disetronic ÂŽ2 H-TRONplus ÂŽ V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON ÂŽ2,3 and D-TRONplus ÂŽ2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic RapidÂŽ2 infusion sets. The infusion set (reservoir syringe, tubing, catheter), D-TRONÂŽ2,3 or D-TRONplus ÂŽ2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37Â°C (98.6Â°F). A Humalog 3 mL cartridge used in the D-TRON ÂŽ2,3 or D-TRONplus ÂŽ2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. Laboratory Testsâ&#x20AC;&#x201D;As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control. Drug Interactionsâ&#x20AC;&#x201D;Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY). Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulinsâ&#x20AC;&#x201D;Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, â&#x20AC;&#x153;On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.â&#x20AC;? Mixing Humalog with HumulinÂŽ N or HumulinÂŽ U does not decrease the absorption rate or the total bioavailability of Humalog. Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin. Pregnancyâ&#x20AC;&#x201D;Teratogenic Effectsâ&#x20AC;&#x201D;Pregnancy Category Bâ&#x20AC;&#x201D;Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with Humalog in pregnant women. Because

animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the ďŹ rst trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothersâ&#x20AC;&#x201D;It is unknown whether Humalog is excreted in signiďŹ cant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Useâ&#x20AC;&#x201D;In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Useâ&#x20AC;&#x201D;Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed. ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Wholeâ&#x20AC;&#x201D;allergic reactions (see PRECAUTIONS). Skin and Appendagesâ&#x20AC;&#x201D;injection site reaction, lipodystrophy, pruritus, rash. Otherâ&#x20AC;&#x201D;hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patientâ&#x20AC;&#x2122;s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and HumulinÂŽ R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5Â°C (41Â°F) and for 14 days when stored at 30Â°C (86Â°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be reďŹ lled with insulin. External Insulin Pumpsâ&#x20AC;&#x201D;Humalog was tested in MiniMedÂŽ1 Models 506, 507, and 508 insulin pumps using MiniMedÂŽ1 PolyďŹ nÂŽ1 infusion sets. Humalog was also tested in the Disetronic ÂŽ2 H-TRONplus ÂŽ V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ÂŽ2,3 and D-TRONplus ÂŽ2,3 pumps (with Humalog 3 mL cartridges) using Disetronic RapidÂŽ2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges 3 5 x 3 mL preďŹ lled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL preďŹ lled insulin delivery devices (HumalogÂŽ KwikPenâ&#x201E;˘ ) NDC 0002-8799-59 (HP-8799)

1 2 3

MiniMedÂŽ and PolyďŹ nÂŽ are registered trademarks of MiniMed, Inc. DisetronicÂŽ, H-TRONplusÂŽ, D-TRONÂŽ, and RapidÂŽ are registered trademarks of Roche Diagnostics GMBH. 3 mL cartridge is for use in Eli Lilly and Companyâ&#x20AC;&#x2122;s HumaPenÂŽ MEMOIRâ&#x201E;˘ and HumaPenÂŽ LUXURAâ&#x201E;˘ HD insulin delivery devices, Owen Mumford, Ltd.â&#x20AC;&#x2122;s AutopenÂŽ 3 mL insulin delivery device, and Disetronic D-TRON ÂŽ and D-TRONplus ÂŽ pumps. AutopenÂŽ is a registered trademark of Owen Mumford, Ltd. HumaPenÂŽ, HumaPenÂŽ MEMOIRâ&#x201E;˘ and HumaPenÂŽ LUXURAâ&#x201E;˘ HD are trademarks of Eli Lilly and Company. Other product and company names may be the trademarks of their respective owners.

Storage â&#x20AC;&#x201D;Unopened Humalog should be stored in a refrigerator (2Â° to 8Â°C [36Â° to 46Â°F]), but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30Â°C [86Â°F]) 12 vials, cartridges, Pens, and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light. Use in an External Insulin Pumpâ&#x20AC;&#x201D;A Humalog 3mL cartridge used in the D-TRONÂŽ2,3 or D-TRONplusÂŽ2,3 should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON ÂŽ2,3 and D-TRONplus ÂŽ2,3 cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less. Literature revised December 7, 2009 KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France. Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France. Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA. www.humalog.com Copyright ÂŠ 1996, 2008, Eli Lilly and Company. All rights reserved.

iewicz, PharmD, BCPS, a clinical pharmacist and professor of pharmacy practice at Midwestern University Chicago College of Pharmacy in Downers Grove, Ill. In reviewing the charts, the pharmacists excluded patients diagnosed with osteoporosis and those with a history of hip or vertebral fracture. Others were eliminated for various additional reasons. They were left with 47 patients who fulfilled the study criteria of having a BMD score diagnostic of osteopenia and no history of taking osteoporosis medications. (BMD is determined by dual-energy x-ray absorptiometry % ;\ 3?.E

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Tampa, Fla.â&#x20AC;&#x201D;Some 34 million people in the United States have osteopenia, a preosteoporosis condition marked by low bone mineral density (BMD) and increased fracture risk, according to the National Osteoporosis Foundation. But determining which patients might actually benefit from pharmacologic management can be a challenge. In the past two years, however, a free online tool (www.sheffield.ac.uk/ FRAX) developed by the World Health

3?.E

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Figure. Medications advised. [DXA], which assesses the degree of bone loss at several critical points, including hip, femoral neck or spine. It yields a T score that determines if a person has normal BMD [>â&#x20AC;&#x201C;1], osteopenia [â&#x20AC;&#x201C;1 to <â&#x20AC;&#x201C;2.5], or osteoporosis [>â&#x20AC;&#x201C;2.5]). The patients selected for the study were mostly women (95.7%), black (89.4%), and older than age 65 at the time of their DXA (age, 67.13+12.3 years).

Risk Profiling Over a Decade The pharmacists used FRAX to determine the patientsâ&#x20AC;&#x2122; 10-year risk for hip fracture as well as for any major osteoporotic fracture, including cervical spine, forearm, hip or shoulder. A 3% or greater probability of hip fracture or 20% or greater probability of any major fracture indicated the probable need for medication such as a bisphosphonate, according to the model. To calculate the scores, the pharmacists entered 12 pieces of data, including patient age, sex, weight and height, along with history of previous fracture, parental history of hip fracture, current smoking status and alcohol consumption, use of glucocorticoids, presence of rheumatoid arthritis or secondary osteoporosis, and femoral neck BMD. They found a significant difference between actual therapeutic recommendations shown in the patientsâ&#x20AC;&#x2122; charts and the FRAX recommendations for the same patients. Without the benefit

Clinical 31

Pharmacy Practice News • September 2010

Osteoporosis of FRAX, medication was advised for 38.3% of the 47 patients. Using FRAX, the pharmacists found that only 3.4% would have qualified. One factor that might explain the difference, Dr. Burkiewicz noted, was that black women, who comprise a major portion of the clinic’s population, have a lower 10-year probability of osteoporotic fracture compared with white counterparts with the same risk factors. For patients in the United States, FRAX uses four different algorithms for calculating scores: white, black, Hispanic and Asian. Based on the results of the study, Dr. Burkiewicz stressed, there is certainly reason to remain confident about FRAX’s effectiveness as a tool for guiding osteoporosis therapy. “We continue to use FRAX, as it is recommended by the National Osteoporosis Foundation guidelines, to assess fracture risk and determine whether therapy is needed.”

presented to the physician for interdisciplinary discussion. “The physician and the pharmacist discuss the plan with the patient and the pharmacist provides additional education,” she said. At each session, she added, the pharmacists and physicians typically also discuss three to six additional patients who are not present but who may have new lab results, such as 25-hydroxy vitamin D levels, or new DXA scores. “The pharmacists communicate with these patients via phone for interim follow-up between visits,” she said. Eric J. MacLaughlin, PharmD, BCPS,

associate professor and head of adult medicine at Texas Tech University Health Sciences Center School of Pharmacy in Amarillo, said that the study “is interesting, and certainly merits further investigation. While there are limitations with the retrospective study design, this study is hypothesis-generating. I think a closer examination into who is treated for osteoporosis and how the decision is made merits closer examination, particularly those in whom the decision was made prior to availability of the FRAX tool or for osteopenic women who have begun

treatment since availability of FRAX, but in whom their risk of fracture was not calculated.” Dr. Burkiewicz works with an interdisciplinary team that also includes Kathy Komperda, PharmD, BCPS, Brooke Griffin, PharmD, rheumatology specialist Catherine Meyer, MD, and a rotating cast of pharmacy students. The Mercy Family Health Center, an affiliate of Mercy Hospital & Medical Center, serves a diverse patient population on Chicago’s South Side.

The commitment to

—Bruce and Joan Buckley

ZOSYN ( p i p e ra c i l l i n /

Comprehensive Histories Taken The clinic typically sees four to five patients each session. Dr. Burkiewicz said a pharmacist or pharmacy students take a comprehensive history, evaluate laboratory data and DXA results and develop a plan for bone health, which is

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32 Clinical

Pharmacy Practice News • September 2010

Critical Care

CDC calls for stronger control strategy

Misuse of Opioids Doubles Over Five-Year Period: Study T he rates of emergency department visits involving nonmedical use of prescription drugs—particularly opioid analgesics and benzodiazepines— increased dramatically from 2004 to 2008, with the inappropriate use of prescription and over-the-counter medications accounting for all of the growth of overall drug misuse and abuse rates for those years. This is according to a new study done by the Centers for Disease Control and Prevention (CDC) and the Substance Abuse and Mental Health Services Administration (SAMHSA). As a result of the study report—published in Morbidity and Mortality Weekly Report (2010;59:705-709)—the CDC has acknowledged that efforts to prevent misuse of these drugs have not been effective, calling for “stronger measures to reduce the diversion of prescription drugs to nonmedical purposes.” Investigators from the CDC used data from SAMHSA’s Drug Abuse Warning Network (DAWN), which tracks the use

(as well as misuse) of drugs by monitoring emergency department (ED) visits in the United States. Information was collected from approximately 220 hospitals covering 2004 to 2008, the most recent five years for which data were available. The DAWN review showed that the number of ED visits for the nonmedical use of opioid analgesics increased 111% during the five-year period; the number of ED visits for the nonmedical use of benzodiazepines rose 89% during that period. An estimated 1.6 million ED visits for misuse and abuse of drugs occurred in 2004, according to DAWN. By 2008, that number had increased to 2 million. Illicit drugs were involved in 1 million cases in both years; nonmedical use of prescription and over-the-counter drugs accounted for 500,000 visits in 2004 but rose to 1 million visits in 2008. The number of cases involving the nonmedical use of opioid analgesics increased from 144,600 in 2004 to

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Figure. Increases in emergency department visits associated with specific opioids, 2004-2008. Source: SAMHSA Drug Abuse Warning Network

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Clinical 33

Pharmacy Practice News • September 2010

Critical Care 305,900 in 2008 (P<0.001), with the highest number of ED visits recorded for oxycodone, hydrocodone and methadone (Figure). Cases involving the nonmedical use of benzodiazepines increased from 143,500 in 2004 to 271,700 in 2007 (P=0.01), with alprazolam, clonazepam, diazepam, lorazepam and zolpidem the most common agents in this class involved. Over the five years studied, the largest increases in misuse or abuse rates of prescription drugs occurred in people aged 21 to 29 years—reflecting a shift away from the 35- to 54-year-old group. In 2008, the misuse rates for both opioids and benzodiazepines increased sharply after age 17 years and peaked in the 21- to 24-year age group before declining after age 54. A number of potential study flaws were noted by the researchers. For example, whereas documentation and identification of specific misused drugs have no doubt improved in the ED setting, there was no assurance that the specific drug had been accurately identified in all cases in the study. Further, it is not always possible to know, beyond a reasonable doubt, whether a drug is being used for medical or nonmedical purposes. Despite those flaws, the underlying message of the study still stands, the researchers noted. There has been a dramatic increase in opioid- and benzodiazepine-related ED visits in the past five years, and a major cause is the tremendous jumps in the prescribing of these drug classes during the study. CDC estimates that 8 million people in the United States use opioids long-term to manage their chronic pain—a marked increase from a decade ago.

ED Pharmacist’s Perspective Daniel Hays, PharmD, BCPS, emergency pharmacist at the University of Arizona Medical Center in Tucson, said he is not surprised that ER visits for opioid misuse have doubled over the past five years. “It certainly dovetails with what I’ve seen in my clinical practice in the ED,” Dr. Hays said, adding that several contributing factors are at play. “The economy is still a problem for many people, and they are looking to illicit drugs for an escape. Also, there are folks who can’t afford health care, who have some kind of chronic pain condition, and

they are turning to opioids to essentially self-medicate.” Without the oversight of a prescribing physician, “it’s only a matter of time before they get into trouble with these extremely potent drugs, and that’s when we see them in the ED.” As for where such patients get their opioids, Dr. Hays said, “when we ask them about their source for the medications, a lot of people say they bought them online. So people no longer have to run the risk of going to the street corner to buy illicit drugs—they just have to turn on their computer.” Doctor shopping, drug diversion and

other established strategies for obtaining opioids “are also still in play,” Dr. Hays said. “If an individual is motivated to get these drugs, they’ll get them.” As far as the impact these patients are having on the practice of ED pharmacy, “it’s about what you’d expect. We are seeing more and more patients who present with narcosis, and so we respond to their resuscitation needs and assist with that process. It could be as extreme as needing intubation, or simply providing reversal agents.” —Kate Lu, Donald Pizzi, David Bronstein

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Results “Inadequate” In an editor’s note accompanying the CDC report, it was theorized that some of the increase in ED visits must be attributed to recent spikes in the rate of nonmedical use of opioids per 1,000 prescriptions. “These increases in nonmedical use of pharmaceuticals suggest that previous prevention measures, such as provider and patient education and restrictions on use of specific formulations, have not been adequate,” the CDC maintained. The report suggested that additional, stronger intervention measures are needed to reduce the abuse of prescription medications, including increased and “systematic” provider education; routine monitoring of insurance claims “for signs of inappropriate use”; and interventions on the part of provider and insurers in cases of inappropriate prescription drug use. “This report also reinforces the value of timely, population-based national surveillance for nonmedical use of drugs,” wrote the CDC, “which can be used to assess the effects of such interventions.”

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34 Clinical

Pharmacy Practice News â&#x20AC;˘ September 2010

SURGICAL SITE continued from page 1

Shirin Towfigh, MD, associate professor of surgery at Cedars-Sinai Medical Center in Los Angeles, and lead author of the study, said, â&#x20AC;&#x153;We are really excited about [the results], as I personally feel [the technique] will revolutionize how we manage contaminated/ dirty wounds with improved outcomes for the patient.â&#x20AC;? In the studyâ&#x20AC;&#x201D;a randomized trial of 76 patients undergoing open appendectomy for perforated appendici-

tisâ&#x20AC;&#x201D;surgical site infections were significantly lower in patients who had daily wound probing compared with a similarly matched control group without this procedure (2.6% vs. 18.9%; P=0.028). Wound probing is a simple technique that was carried out daily by a member of the surgical team. The wound was swabbed with iodine, then penetrated with a sterile cotton-tipped applicator. Any extra fluids are patted dry before the wound is redressed. Dr. Towfigh was introduced to the concept of wound probing while she

was a resident at the University of California, Los Angeles, where pediatric surgeon Eric Fonkalsrud, MD, now a professor emeritus of surgery, was probing wounds. In the 1980s, Dr. Fonkalsrud started probing wounds in pediatric patients and published a small paper describing his results in 1993 (Am Surg 59:838-841). In the study, 22 of 90 (24.4%) colectomy patients given antibiotics intravenously developed wound infections, compared with four of 93 (4.3%) patients who underwent five postoperative days of wound probing with

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a disinfectant solution (P<0.0001; Figure). â&#x20AC;&#x153;I assumed everyone was probing wounds. It worked great,â&#x20AC;? said Dr. Towfigh. But at her first job after residency, she was surprised that surgeons and residents had never heard of wound probing. â&#x20AC;&#x153;When I asked the residents to probe the wound daily, they looked at me like I was crazy.â&#x20AC;? To convince the residents and her colleagues, Dr. Towfigh devised a randomized trial. Between 2007 and 2009, investigators randomized 77 patients with perforated appendicitis to either loose primary wound closure with staples (n=39) or loose primary wound closure with staples and daily wound probing (n=38). In addition to the reduction in surgical site infections, patients treated with wound probing had a shorter hospital length of stay (4.7 vs. six days; P=0.049), with no increase in pain (P<0.05). Other complications were similar between groups.

Mechanism of Action Proposed The investigators could not say definitively why wound probing reduces

Clinical 35

Pharmacy Practice News • September 2010

Infection Control infection. They believe that the probing expedites wound healing by releasing contaminated fluid and decreasing local bacterial burden. Patients underwent wound probing until the wound was closed and no longer draining, a process that took, on average, three days. In a few cases, the wound took up to five days to heal. “We recommend that wound probing be practiced for contaminated wounds due to open appendectomy for perforated appendicitis,” Dr. Towfigh said. “We would argue, too, that it be practiced in the first-line management of other abdominal contaminated wounds, regardless of incision length.”

of subjecting a wide range of patients to wound probing would have to be carefully considered, he stressed. “This is a very elegant study, conducted prospectively in a controlled manner that adds considerably to our knowledge of surgical site infections,” added Kamal Itani, MD, chief of the surgical service at the VA Boston Medical Center and professor of surgery at Harvard Medical School, in Boston.

Focus of Future Research The University of Kentucky’s Dr. Rapp, an editorial board member of

Pharmacy Practice News, said that future researchers should cast a wider net when evaluating wound probing to confirm that the technique is effective in reducing a wide range of postoperative infections. The infection control strategy “would need to be tried with other patients following surgery where the wound and peritoneal cavity has fecal contamination,” he said. “Such studies would require standard procedures for peritoneal irrigation as well as standard preoperative administration of antibiotics with both aerobic (Escherichia coli) and

anaerobic (Bacteroides) activity given at diagnosis as well as [pre- and postoperatively].” It will also be important, Dr. Rapp stressed, to assess “the actual technique used from surgeon to surgeon in doing the wound probing.” Assuming such variables can be accounted for, “overall, the technique offers promise in surgical procedures that carry relative high postoperative infection rates.” Full details of the study will be published in Archives of Surgery. —Christina Frangou

‘Overall, the technique offers promise in surgical procedures that carry relative high postoperative infection rates.’ —Robert P. Rapp, PharmD She said she believes the technique may improve long-term outcomes such as fascial dehiscence and incisional hernias, reduce labor for care of infected wounds by nursing staff and physicians, improve cosmetic results and reduce overall costs of care. The investigators also conducted a chronological study of the bacterial flora in contaminated wounds. Analysis revealed a mixed flora of aerobic bacteria in the wounds, with one-third also having anaerobic bacteria. There was little correlation between the intraabdominal cultures and the wound cultures, with much higher ratios of gram-positive to gram-negative bacteria in the wound cultures. Anaerobic gram-positive bacilli and a streptococcus were the predominating bacteria in the wound cultures. Almost all bacterial counts fell to less than 105 cfu/mL by the first postoperative day, likely attributable to preoperative initiation of antibiotics. Several surgeons who spoke with Pharmacy Practice News said they are intrigued by the results and are considering the technique. “This is a simple and potentially very useful technique. Intuitively, it makes sense. I certainly would consider trying [it],” said Michael Englesbe, MD, assistant professor of surgery in the transplantation division of the University of Michigan Health System, in Ann Arbor. Dr. Englesbe said his only concern is identifying the patients who will benefit from this approach. “Most patients do not develop a surgical site infection,” he pointed out. Thus, the impact

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36 Clinical

Pharmacy Practice News â&#x20AC;˘ September 2010

Practice Pearl

Low-dose Escitalopram Eases Ventilator Weaning Katie Taylor Boyd, PharmD, RPh Critical Care Pharmacist Saint Francis Hospital & Health Centers, Poughkeepsie, New York*

n the critical care setting, length of mechanical ventilation is an important marker for both clinical outcomes and cost. As such, any technique that can shorten ventilator days is of wide interest. Weaning from mechanical ventilation can be stressful and anxiety provoking, causing hyperventilation and agitation, which may lead to the need for intensifying sedation. This, in turn, can lead to prolongation of mechanical ventilation and its attendant costs and complications. We have found that implementing low-dose

escitalopram (Lexapro, Forest Labs) in such patients shortens time to extubation by rapidly reducing patient anxiety with minimal side effects. Historically, the anxiolytics of choice used during the weaning process have been the IV benzodiazepines lorazepam and midazolam. Although these agents are very effective in curbing patient anxiety, they often produce excessive sedation, which could greatly impede the weaning process.1 Additionally, the need for repeated dosing can cause drug accumulation, extending the time to extubation even farther.1 Benzodiazepines also carry the risk for severe side effects, including dependence, as well as undesirable drug interactions.2 Another agent evaluated to treat ventilator-associated anxiety was paroxetine (Paxil, GlaxoSmithKline). In

our experience, this medication was not overly sedating, but did not exert its anxiolytic effects until several days had passed. Furthermore, of all the selective serotonin reuptake inhibitors (SSRIs), paroxetine has been shown to elicit withdrawal symptoms, sometimes severe, when it is abruptly discontinued.3,4 Ventilator weaning is intended to be of a limited duration, making abrupt discontinuation a significant concern. In our clinical experienceâ&#x20AC;&#x201D;based on 15 patientsâ&#x20AC;&#x201D;low-dose escitalopram, an alternative SSRI, is both safe and effective when used to facilitate the weaning process. A 5- or 10-mg escitalopram dose facilitated successful weaning in persons who 24 hours earlier could not have been weaned due to excessive anxiety. The tablet also is easily crushed to facilitate administration via a naso-

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gastric tube. Escitalopram generally was Taylor Boyd, well tolerated, pro- Katie PharmD, RPh ducing minimal side effects; most significantly, it produced no withdrawal symptoms upon discontinuation. The one drug interaction of note when using escitalopram is between the SSRI and linezolid (Zyvox, Pfizer). In some cases, the drug combination can lead to serotonin syndrome, a potentially lifethreatening condition in which the neurotransmitter builds to toxic levels in the body. (Symptoms include altered mental status and neuromuscular and nervous system problems.5) Although serotonin syndrome is a class effect between linezolid and SSRIs, we have taken precautions against it in our patients by discontinuing either drug or increasing monitoring. We have not witnessed any cases of serotonin syndrome at the time of submission. In conclusion, escitalopram is our current drug of choice for patients with panic-like behavior in whom ventilatorweaning readiness cannot be assessed. Previous agents either did not work fast enough (paroxetine) or caused excessive sedation (benzodiazepines), both increasing time to extubation. In contrast, short-term, low-dose escitalopram facilitated faster weaning and subsequent extubations in our study of 15 patients, all with an acceptable safety profile. An estimation of the faster weaning would be 24 to 36 hours as opposed to 48 to 72 hours or longer. However, this is an experiential observation; a formal study still needs to be conducted. Dr. Boyd would like to thank Steven Ritter, MD, Maqbool Murtuza, MD, and David Schaff, PharmD, for their help in writing this article.

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* Position at the time of writing; Dr. Boyd is now a clinical pharmacist at St. Lukeâ&#x20AC;&#x2122;s Cornwall Hospital, in Newburgh, N.Y.

References

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information, unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current monthâ&#x20AC;&#x2122;s issue, as well as breaking news ahead of print.

1. Tietze KJ, Fuchs B. Use of sedative medications in critically ill patients. Up To Date Online, updated Jan. 10. Accessed May 1, 2010. 2. Cammarono WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med. 1998;26(11):676-684. 3. Taman L, Oxpoyaz N. Selective serotonin reuptake inhibitor discontinuation syndrome: a review. Adv Ther. 2002;19(1):17-26. 4. Withdrawal syndrome of selective serotonin reuptake inhibitors. Micromedex DrugDex Consults. Last modified May 15, 2009. Accessed May 1, 2010. 5. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;325(11):1112-1120.

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38 Technology

Pharmacy Practice News • September 2010

Infectious Disease

Technology Helps Hone Antibiotic Stewardship A

ntimicrobial stewardship programs that use technology to map antibiotic sensitivity patterns and “course-correct” when treating health care–associated infections (HAIs) can significantly improve several infectious disease outcomes. Two improvements of particular note— more appropriate antimicrobial use and the development of fewer multidrugresistant organisms (MDROs)—have been documented by several hospitals contacted by Pharmacy Practice News.

St. Elizabeth Targets UTIs At the 201-bed St. Elizabeth Medical Center, in Utica, N.Y., an internal financial analysis of urinary tract infections (UTIs) showed that it cost $6,226 to treat each UTI, some 10 times more than their earlier estimate, according to Linda Kokoszki, RN, BSN, CIC, director of infection prevention. UTIs were also the most frequently occurring HAIs at the facility, accounting for 30% of all HAIs, she noted. With a goal to reduce UTIs by 10% within a year, the Infection Prevention Department formed a multidisciplinary care team that developed 15 interventions around Foley catheter use—including the ongoing surveillance of nosocomial infection markers in the urine. “Infection preventionists reviewed this data and ... taught hospital staff about the clinical manifestation, epidemiology and control measures...stressing good hand hygiene and meticulous adherence to isolation protocols,” said Ms Kokoszki.

Using CareFusion’s MedMined Data Mining Surveillance and Nosocomial Infection Markers (NIMs) tools, the

hospital reduced the incidence of UTIs by 26.8% in the six months that ended Feb. 28, 2009, compared with the baseline six-month period that ended Aug. 31, 2008. St. Elizabeth saved $224,486 in variable costs and avoided 185 additional days in length of stay hospitalwide during this period. More recently, during the six months that ended Feb. 28, 2010, there was a 26.4% decline in the incidence of UTIs compared with the 2008 baseline. “If we could sustain these results with five fewer UTIs per month, that would translate into a variable cost savings of $417,660 per year,” Ms. Kokoszki said. Recognizing that infection prevention is an ongoing process that requires continuous monitoring and updating, Ms. Kokoszki said that they have to come up with new approaches so the staff does not get complacent. To that end, another strategy that the team has put in place is to “set up competition among units to reduce NIMs, [and placing a] NIMs report card in everyone’s paycheck.”

Bronx-Lebanon Focus: ADEs Bronx-Lebanon Hospital Center, a 500bed acute care facility in New York City, used another CareFusion system—MedMined Patient Event Advisor—to facilitate real-time identification and tracking of medical ICU and pulmonary patients at high risk for antibiotic-related adverse drug events. The system issued alerts on drug class mismatches (the initial antibiotic prescribed was not designed to treat the particular organism); susceptibility mismatches (once a lab culture comes back, a better-targeted drug can be ordered to sidestep resistant strains); and

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Figure. Leading causes of health care–associated infections. IV to oral switches (the earlier the better for easy-to-absorb fluoroquinolones such as ciprofloxacin, moxifloxacin and trimethoprim-sulfamethoxazole). When Frank Palmieri, PhD, RPh, antibiotic clinical pharmacist at Bronx-Lebanon and his colleagues compared three months of pre- and post-implementation data, they found that the probability that these issues would be resolved in less than 12 hours rose by 2.5 times after launching the MedMined system. Another tool hospitals can use to track resistance and keep HAIs in check is taking an antibiogram “snapshot” every six to 12 months. This helps pharmacists assess the effectiveness of their formulary’s antibiotics against specific HAI-causing organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile and Acinetobacter baumannii, and change antibiotics as necessary. The antibiogram also helps infection prevention specialists strategize to address resistance patterns showing up hospital-wide or within specific units.

Synergy, Savings

Bronx-Lebanon Hospital Center uses CareFusion’s MedMined Patient Event Advisor dashboard to track antibiotic therapy in critically ill patients. The dashboard displays customized user alerts that pharmacists can view and prioritize. Alerts can be filtered by time frame; patient data relevant to the alert is displayed in the “hover” illustrated in the patient’s box.

These synergistic steps against HAIs improve patient outcomes and save considerable dollars—a motivator for hospitals that have seen cuts in staff, resources and education due to the ongoing economic downturn. The economic pressure is further intensified by the scant reimbursement dollars that hospitals receive

for treating HAIs, which have been increasing at a breakneck pace. “The last decade alone has seen an estimated 36% increase in HAIs,” according to an article in the May issue of Medical Care (2010;48;433-439) by Stone et al. “The estimated 100,000 deaths per year associated with HAIs rank this as the sixth-leading cause of death in the United States … [and] the excess hospital cost of HAIs across the nation was estimated to be between $28 billion and $45 billion annually,” the investigators reported. According to Centers for Disease Control and Prevention (CDC) estimates, HAIs cost health systems an average of $5,018 per patient. The four leading causes of HAIs (Figure) are UTIs (32%), surgical site infections (22%), pneumonia (15%) and bloodstream infections (14%). Pat Rosenbaum, RN, CIC, an infection prevention specialist and spokesperson for the Washington, D.C.-based Association for Professionals in Infection Control and Epidemiology (APIC), stressed that “as organisms continue to develop resistance, we must be more prudent in the use of antibiotics.” To address this, APIC has developed an actionable program based on CDC guidelines that hospitals can follow to work to reduce HAIs. Ms. Rosenbaum noted that the challenge grows more complicated when “patients ping-pong back and forth between health care settings and can carry infections from one to the other.” She suggested that hospitals should “identify patients carrying MDROs, and enter them into a computerized surveillance system upon readmission. Information would be in their charts and staff alerted to take precautions.” —Al Heller

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SAMSCA® (tolvaptan), the first and only oral vasopressin V2-receptor antagonist that increases free water clearance and serum sodium concentrations 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%). 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 the 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 trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

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