December 2013 by McMahon Group

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Volume 40 • Number 12 • December 2013

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in this issue UP FRONT

VTE, an underrecognized risk for chemotherapy patients.

POLICY

At Fall HOPA meeting, a plan for boosting hospital reimbursement.

2014 OPPS payment rules begin to take shape; here’s what to expect.

CLINICAL

Choosing the best local anesthetic for peripheral catheter placement.

Do financial penalties for medical errors have any place in a just culture of safety?

As Compounding Law Passes, Split Views Persist

he Drug Quality and Security Act, which aims to close holes in the regulation of compounding pharmacies, was recently voted into law. Both the House of Representatives and the Senate passed the bill by a voice vote. Speaking from the Senate floor on Nov. 12, Sen. Harry Reid (D-Nev.) called the bill “a matter of life and death,” referring to 2012’s deadly outbreak of fungal meningitis traced back to the New England Compounding Center. But outside of Washington, support for the new law is mixed. In a statement on Sept. 28, David G. Miller, RPh, chief executive officer of the International Academy of Compounding Pharmacists (IACP), said the bill “does not contain any provisions that speak directly to standards aimed at raising the quality of compounded medications.” The legislation “will not protect the American public” and “contains significant gaps,” the trade group added.

•

Is It Time To Cap Chemo Rx In Advanced Lung Cancer? Boston—A year ago, Leigh Boehmer, P PharmD, a clinical pharmacist at Barnes-Jewish Hospital in St. Louis, saw a patient with metastatic no on-small cell lung cancer (NSCLC) who had co omplete hearing loss in his right ear, acute kidneey injury and a serum sodium level of 114. Despite tthese clear signs of chemotoxicity, Dr. Boehmer wass astounded to find that the man had received 16 cyccles of cisplatin-paclitaxel. And yet the firsst question asked by the patient, despite hiss overly aggressive therapy, was, “When do o I get cycle number 17? It is due today.” At the recent Oncology Pharmacy Educcation Network meeting, Dr. Boehmer and a other pharmacists discussed the difficultty of deciding when to limit chemotherap py duration for stage IV lung cancer. Firsttline, second-line and even later cycles o of therapy, as well as palliative therapy, havve played a role in such patients, but questio ons abound regarding how long therapy sho ould be given and whether the benefits are worth w the risks, with respect to both quality of o life (QoL) and cost. Clinicians need to thin nk about the benefits and costs of a given cheemotherapy regimen, and how those factors might afffect a patient,

•

see COMPOUNDING, page 9

se ee LUNG CANCER, page 11

OPERATIONS & MGMT

25 26

FDA strengthens its ability to forestall drug shortages. Pharmacy leaders: Are you ‘ridiculously in charge’? Here’s how to tell.

EDUCATIONAL REVIEW

Pain, Sedation, and Delirium in the ICU: The Pharmacist’s Role See insert after page 18.

Into the Cloud For Enhanced Drug Adherence

loud-based computing has come to health systems, and it promises to be a powerful tool in the fight against medication nonadherence—a persistent problem that continues to boost 30-day hospital readmissions and trigger potentially steep payment penalties. MCS Carelink, a Danvers, Mass.based company, has developed a new service that uses algorithmic analyses

•

see INTO THE CLOUD, page 32

For Safer Smart Pumps, Setting Harder Drug Dose Limits Urged

wo health systems have revamped their procedures for establishing safe drug dosing ranges in “smart” IV infusion pumps and communicating the new ranges to key personnel on the care team. By doing so, the hospitals have eliminated at least one potentially dangerous dispensing habit—dosing heparin at a rate up to 45 times higher than its recommended upper soft limit. The primary fix was to add hard limits for the anticoagulant into the drug library. “The overall goal is to improve safety and reduce errors during the IV administration process

by making it difficult for users to do the wrong thing,” Cleveland Clinic pharmacist Silvana Balliu, PharmD, said during a Web conference hosted by the Institute for Safe Medication Practices (ISMP). “The only way to do this is [via] hard limits.” The need for more stringent programmed dosing guidelines at the Cleveland Clinic came to light when Dr. Balliu and her colleagues reviewed their smart pump data. They found that to administer boluses of heparin from the IV bag, clinicians had

•

see SMARTER PUMPS, page 34

Special Feature

The Year in Pharmacy Highlights of top stories in 2013 see page 28

Best in KLAS for Smart Pumps – LVP SIGMA Spectrum Infusion System Three Years Running! 1,2,3

KLAS, an independent research ﬁrm, has again awarded the SIGMA Spectrum Infusion System with its “Best in KLAS” S award for Smart Pumps — LVP as reported in the Best in KLAS Awards: Medical Equipment & Infrastructure Report.

Receiving the “Best in KLAS” award indicates a high level of customer 2

satisfaction with the SIGMA Spectrum Infusion System and its support services. For more information, contact your Baxter representative at 1-800-422-9837.

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References: 1 2013 Best in KLAS Awards: Medical Equipment & Infrastructure, SIGMA Spectrum, Best in KLAS for Smart Pumps — LVP, June 2013. ©2013 KLAS Enterprises, LLC. All rights reserved. www.KLASresearch.com 2 2012 Best in KLAS Awards: Medical Equipment & Infrastructure, SIGMA Spectrum, Best in KLAS for Smart Pumps — LVP, June 2012. ©2012 KLAS Enterprises, LLC. All rights reserved. www.KLASresearch.com 3 2011 Best in KLAS Awards: Medical Equipment & Infrastructure, SIGMA Spectrum, Best in KLAS for Smart Pumps — LVP, June 2011. ©2011 KLAS Enterprises, LLC. All rights reserved. www.KLASresearch.com

Rx Only. For safe and proper use of this device, refer to the complete instructions in the Operator’s Manual. Refer to manufacturers’ full Prescribing Information for Insulin Injection, USP. Baxter and SIGMA Spectrum are trademarks of Baxter International Inc. KLAS is a registered trademark of KLAS Enterprises, LLC. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 450725 07/13

Up Front 3

Pharmacy Practice News • December 2013

Capsules

by the

Real-World VTE Risk From Chemo Underestimated

numbers

The top 10 most problematic i medications di i ranked by pediatric pharmacists, based on patient safety concerns: 1. Insulin

6. Digoxin

2. Vancomycin

7. Morphine

3. Warfarin

8. Gentamicin

4. Heparin

9. Potassium phosphate

5. Methadone

10. Amphotericin B and fentanyl

Source: Abstract No. 335, presented at the American College of Clinical Pharmacy annual meeting. Research done by Harding University College of Pharmacy, in Searcy, Ark.

heard here

‘Revenue is not a four-letter word. It’s important. If the

first

doors close, we’re not providing care to anybody.’ —Philip E. Johnson, RPh, FASHP, the oncology director for Premier Healthcare Solutions

See article, page 4.

lood clots may be more prevalent in patients undergoing chemotherapy than previously thought, according to new research from Duke University and King’s College Hospital, London. Lung, pancreatic and stomach cancers were associated with the highest incidences of venous thromboembolism (VTE). “Importantly, this study suggests that the observed rates of symptomatic VTE in real-world practice are considerably greater than reported in patients eligible for randomized clinical trials,” said Gary H. Lyman, MD, MPH, in a statement on Nov. 6. Dr. Lyman is a professor of oncology at Duke University School of Medicine, in Durham, N.C. and an author of the study, which was published in the November 2013 issue of The Oncologistt (bit.ly/1jgXQmx). Previous studies had reported rates of thromboembolism from 2% to 8% in certain patient populations with cancer (Am J Med d 2006; 119:60-68; J Clin Oncoll 2006;24:484-490, respectively), and the authors of this study say chemotherapy poses an additional risk. Using the U.S. IMPACT health care claims database, researchers identified nearly 27,500 cancer patients who underwent chemotherapy between January 2005 and December 2008. To determine the number of patients affected by blood clots, the authors defined a positive case as a chemotherapy patient with at least one claim of VTE. The investigators compared the incidence of blood clots at 3.5 and 12 months after the start of chemotherapy to determine whether the occurrence of VTE changed over time. At 3.5 months, the researchers found VTE in 7.3% of patients undergoing chemotherapy, and at 12 months, the overall incidence increased to 13.5%. Prevalence of VTE varied by the type of cancer; at 12 months, 9.8% of patients receiving chemotherapy for bladder cancer developed VTE, whereas VTE occurred in 21.3% of patients treated for pancreatic cancer. Developing VTE within 12 months significantly increased the cost of health care (P<0.0001). For patients with VTE, health care costs in the first 12 months of chemotherapy averaged about $110,700, roughly $30,000 more than for those who did not develop blood clots. Dr. Lyman and his colleagues called for the increased use of thromboprophylactic treatment for patients at high risk for VTE. “Clinical oncologists need to be aware of the increased risk for this serious complication of cancer and cancer treatment,” he said, “and when the risk is sufficiently great and the balance of benefits and harms acceptable, oncologists should consider prophylactic anticoagulation.” Cindy L. O’Bryant, PharmD, BCOP, an associate professor at the University of Colorado Skaggs School of Pharmacy, in Denver, said the study “supports what oncology health care providers already know; VTE is a common and potentially fatal condition in cancer patients.” The results, she added, “emphasize the importance of incorporating VTE risk assessment into routine care for cancer patients prior to initiation of chemotherapy and during continued treatment. With this, high-risk patients can be identified and the risks and benefits of thromboprophylaxis can be weighed to determine what treatment is appropriate.” Dr. O’Bryant said such an approach “also offers an opportunity to educate cancer patients on the risk and signs and symptoms of VTE with the hope that prompt reporting of symptoms leads to timely interventions and improved outcomes.” —Ben Guarino

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

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

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

Volume 40 • Number 12 • December 2013 • pharmacypracticenews.com

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

INTERNAL MEDICINE

EDITORIAL STAFF

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

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

Robert L. Barkin, MBA, PharmD, Chicago, IL

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

BIOTECHNOLOGY

Jeffrey Norenberg, PharmD, Albuquerque, NM

Indu Lew, PharmD, Livingston, NJ

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

CARDIOLOGY

Robert Ignoffo, PharmD, San Francisco, CA

s CT C. Michael White, PharmD, Storrs,

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors

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

CNS/PSYCHIATRY

Cindy O’Bryant, PharmD, Aurora, CO

Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas

Ali McBride, PharmD, MS, BCPS, St. Louis, MO Sara S. Kim, PharmD, BCOP, New York, NY

Larry Ereshefsky, PharmD, San Antonio, T Texas

James Prudden, Group Editorial Director Robin B. Weisberg, Manager, r Editorial Services Elizabeth Zhong, Associate Copy Chief

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

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Cathy Rosenbaum, PharmD, Cincinnati, OH

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SALES

CRITICAL CARE

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Judi Jacobi, PharmD, FCCM, Indianapolis, IN

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INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

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TECHNOLOGY

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4 Policy

Pharmacy Practice News • December 2013

Reimbursement

Reimbursement and Revenue Integrity Chicago—Pharmacists need to know how to leverage changes in health care accountability and reimbursement rather than merely react to them, and a heightened focus on revenue integrity is a valuable strategy for doing so, an oncology pharmacy specialist said at the Fall 2013 Meeting of the Hematology/ Oncology Pharmacy Association. Indeed, as risk-sharing practice models continue to gain traction, “we must develop metrics to show the value of what we do, what would happen if we didn’t do it, and the true costs of health care,” said Philip E. Johnson, RPh, FASHP, the oncology director for Premier, Inc, a health care improvement company.

Cancer Center in Tampa, Fla. “Revenue is not a four-letter word. It’s important. If the doors close, we’re not providing care to anybody.” Mr. Johnson added that hospitals need to make sure “that when we do the right thing we’re compensated for it. Right now, pay-for-performance is penalized for doing the wrong thing. I’d like providers to be compensated for doing the right thing.” He pointed to the value of viewing changes in health care reimbursement through the more meaningful lens of net costs or margins rather than costs alone, and he urged pharmacists to help carry this message to senior leaders, stake-

‘We must develop metrics to show the value of what we do, what would happen if we didn’t do it, and the true costs of health care.’ —Philip E. Johnson, RPh, FASHP Protecting oncology drug–related revenue is a good place to start, given the huge dollar figures involved and the ease with which that revenue can slip from an institution’s grasp, said Mr. Johnson, who was previously the director of pharmacy at the Moffitt

holders and payors. “It doesn’t matter whether you lower the costs or increase the revenue. Drug costs are not necessarily the evil in our world. We have to look at the impact of both cost and revenue on financial margins.” Mr. Johnson offered the following

Commentary Anne T. Jarrett, MS, RPh Pharmacy Reimbursement Specialist High Point, North Carolina

wholeheartedly agree with Mr. Johnson’s well-put reminder that “revenue is not a four-letter word.” In fact, now is the time for all health care providers to accept that health care is a business. If that makes anyone feel uncomfortable, realizing that no one works without a paycheck quickly puts it into perspective. This is an important issue because health care has become a “pay-for-performance” environment, where hospitals that successfully report designated quality measures to the Centers for Medicare & Medicaid Services (CMS) receive higher annual payment rates. Positive outcomes are the key to demonstrating cost-effectiveness and quality. If pharmacists do not become involved in the selection of quality measures, those measures will be created by nonpharmacists. Although this arguably has not happened in health systems, retail pharmacy is a case in point: community pharmacists did not speak up on the issue of turnaround times on prescriptions, which led to the onerous requirement by some chains that prescriptions be ready in 15 minutes. Oncology is a target area because of the high cost of therapy, especially with the introduction of biopharmaceuticals. In some cases, treatment costs can be as much as hundreds of thousands of dollars per patient (nyti.ms/I8Pv9l). Pharmacists should be involved in creating, updating and documenting evidence-based chemotherapy protocols used at their health systems. At the very least, they should be familiar with the basic components of those protocols, how and if protocols differ among providers, and consider the effect that such variation may have on reimbursement, outcomes and quality. If significant variations do exist, pharmacists can use this opportunity to suggest that guidelines issued by the National Comprehensive Cancer Network be followed for consistency. As Mr. Johnson rightly points out, one of the most important reimbursement tools that pharmacists should become familiar with is the charge master, where

tips to maintain revenue integrity and raise those margins: • Seek faster payments. One strategy is to renegotiate the terms of your contracts with insurance companies to reimburse providers in less than 30 days. (Most insurers typically pay in 60 or 90 days.) “If you can do that, I guarantee your finance officer will be impressed,” he said. • Document your institution’s compliance with evidence-based guidelines. One benefit of this strategy is that it will help reduce deductibles on payments to insurance companies. “You can relate that compliance to a lowered reimbursement deductible, which means more revenue,” Mr. Johnson said. • Embrace the International Classification of Diseases, Tenth Revision, Clinical Modification. This established, accepted resource contains 68,000 codes, up from the 17,000 codes contained in the ninth revision. You should apply it to your metrics for oncology drugs as soon as possible, he noted. The increased specificity of the latest revision, which includes stage of disease as well as primary diagnosis, should help optimize reimbursements by providing detail beyond such broad metrics as “average drug cost per day.”

• Update the charge master. Within the charge capture portion of the revenue cycle, do this at least quarterly. Average sales prices for medications are updated quarterly by the Centers for Medicare & Medicaid Services (CMS; go.cms.gov/1hwToln). n • Gather people from each phase of the revenue cycle. This includes staffers from registration/authorization through claims submission and third-party follow-up. They should review patient charts and look for improvement opportunities. At Moffitt Cancer Center, Mr. Johnson and a case manager formed a revenue integrity committee representing every revenue cycle function. The committee worked to identify opportunities and stay abreast of regulatory changes. Adherence to the revenue process became part of the employee orientation process. “We wanted to make sure that the new people coming in were properly credentialed to do their jobs and were held accountable for doing what they were supposed to do,” he said. • Develop a working knowledge of the billing process. To that end, have someone in the billing department explain the key steps involved, including forms, medication management service codes and revenue

•

see INTEGRITY, page 8

the billing codes and the corresponding number of billing units dwell. This basic knowledge alone will help to decrease denials and bring more reimbursement dollars to the hospital. It is also advantageous to spend time with medical billers and coders and be reminded that proper documentation is crucial. I also agree that keeping an eye on drug waste is critically important. Basically, if you waste a product unnecessarily, then it can’t be charged to the patient and the hospital takes the financial hit. Looking at waste logs, as Mr. Johnson proposes, helps to identify whether there is a pattern of waste, and also to determine what is being wasted, and by whom. This is indeed a task that technicians can perform because they are the ones who prepare IVs for the pharmacist to check for accuracy. In my former experience as an assistant director of pharmacy at Wake Forest University Baptist Hospital, in Winston-Salem, N.C., waste logs for all drugs, especially injectables, were routinely used. Pharmacists also should be able to trace the complicated journey a drug takes, starting from when it is purchased to the charge for it appearing on a patient’s hospital bill. Additionally, they should seek to understand the details of payor contracts and pursue carve-outs to ensure reimbursement for expensive drug therapy. On the clinical side, pharmacists can become involved in the prevention of side effects, which can yield huge cost savings. They also should be keeping an eye on new or updated local and national coverage determinations. These payment decisions from Medicare and their local contractors, which often hinge on medical necessity, can have a huge effect on whether a given therapy will be paid for or denied. Moreover, pharmacists should be actively involved in efforts to prevent hospital readmissions, because facilities that fall below a ceiling established by CMS will have their payments sharply reduced. One contributor to readmissions is noncompliance with medications, which often occurs because patients either can’t afford their costly medications or don’t understand how to take them. Pharmacists can help by making sure patients understand their discharge drug regimens and providing follow-up to ensure compliance. They also can provide information on patient assistance programs and other means for making drugs more affordable to those in need. Clearly, pharmacists already have a unique skill set. Adding to those skills by developing a strong working knowledge of reimbursement issues can only lead to positive outcomes, increasing both quality and accountability.

6 Policy

Pharmacy Practice News • December 2013

Reimbursement

Getting Ready for 2014: What To Do Now! T

he proposed rules for the Outpatient Prospective Payment System (OPPS) have been published; the comment period is over; the results are being tabulated and discussed; and the final rules will be published early next year. Perhaps there will be a few changes to the proposed rules, perhaps not. In any case, it’s time to take immediate action to ensure maximum payments for your health system.

Part B Drugs and Biologics: An Overview Let’s start with a basic understanding of the four categories through which the Centers for Medicare & Medicaid Services (CMS) pays for Part B drugs and biologics under OPPS: 1. New drugs not yet assigned unique Healthcare Common Procedure Coding System (HCPCS) codes. When an injectable drug first comes to market and has pass-through status, in most cases it will not yet have a HCPCS code assigned to it. In such cases, it will be paid for at 95% of average wholesale price (AWP) using code C9399, unclassified drugs or biologics. This coding procedure and payment rate is proposed to remain for 2014. 2. New pass-through drugs with HCPCS codes. If, on the other hand, the manufacturer has worked diligently to obtain a HCPCS code for a new drug, then the product may have the code assigned to it at the time of FDA approval. If so, that code must be used, and no payment will be made if the miscellaneous unclassified code persists in your system. This category is paid at wholesale acquisition cost (WAC) plus 6% until the average sales price (ASP) is available, then at ASP plus 6%. Pass-through status is timelimited, usually lasting two to three years. This also is proposed to remain for 2014.

The ABCs Of Payment OPPS:

Outpatient Prospective Payment System

CMS:

Centers for Medicare & Medicaid Services

AWP:

Average wholesale price

ASP:

Average sales price

HCPCS: Healthcare Common Procedure Coding System WAC:

Wholesale average cost

CDM:

Charge description master

PDM:

Pharmacy drug master, or pharmacy drug dictionary

APC:

Ambulatory Payment Classification

CPT:

Current Procedural Terminology

3. Specified covered outpatient drugs (SCODs) costing more than $90 per day. This reimbursement “basket” is where the majority of drug payment lies and where most drugs land once their pass-through status expires. Each year, cost per day is assessed: According to the proposed 2014 payment rules, only drugs costing more than $90 per day will be separately reimbursed, at a rate of ASP plus 6%, both in the physician office setting and by OPPS. 4. Lower-cost packaged products costing less than $90 per day. There is no separate reimbursement for these products; payment for them is included in the bundled payment for the specific procedure or visit for which they were used. However, if they were administered as infusions, payment for drug administration is available separately from the bundle and includes preparation costs of the infusion drug. The key in both of these cases is making sure that the right cost centers get the right portions of the bundled payment. This is left to the hospital to process and divide up.

istration charges. 5. Work with the finance team to unbundle payments and correctly assign revenue gained from the payment bundle to the pharmacy cost center. Q: Separately paid products are changing in 2014 as well; what actions are needed? A: Follow these key steps: 1. Determine which products this applies to at your facility. 2. Calculate the proposed revenue loss from the products moving from separately payable into no-separatepayment bundles and build this into your budget. 3. Continue to charge for these IV products because it is the only way you will be able to get paid for their associated drug administration charges. 4. Work with the finance team to

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

unbundle payments and correctly assign cost center disbursement. Q: I see that drug administration reimbursement may be changing. What do I need to know? A: This is one of the most misunderstood areas of reimbursement. A variety of Current Procedural Terminology (CPT)

•

see GETTING READY, page 8

Key Questions Answered Each year, the proposed OPPS payment updates tend to trigger the same set of questions among pharmacists and other staffers involved in reimbursement. Here are my answers along with some action points for streamlining the payment process. Q: What’s happening with passthrough products in 2014? A: Proposals for 2014 call for 15 products to lose their pass-through status and for 18 to either retain or obtain theirs. Of those losing pass-through status, only nine will qualify for separate payments and six will be packaged into bundles with no separate payments. In almost all cases, the HCPCS code for each of these 15 products has changed. Of those proposed to retain pass-through status, HCPCS codes may change as well. What to do: 1. Determine whether the drugs in these categories are ones you use. 2. Determine if there is a HCPCS code change and, if so, apply it to the charge description master (CDM), which is a comprehensive listing of items that could be billed to a patient, payor or health care provider, and the pharmacy drug master (PDM) component of your pharmacy computer system. 3. Calculate the proposed revenue loss from the products moving from passthrough status into no-separate-payment bundles and build this into your budget. 4. Continue to charge for these IV products at zero price because it is the only way you will be able to get paid for their associated drug admin-

Cancer Versus Noncancer Drug Reimbursementt

MS guidance regarding the use of “chemo” versus “non chemo” administrations is in the Medicare Claims Processing Man nual, Chapter 12, Section 30.5 (excerpt belo ow). Note the caveat that local carriers may have further details (i.e., preferences): • Chemotherapy administration codess apply to parenteral administration of non-radionuclide antineoplastic drug gs; to antineoplastic agents for treatment nt of noncancer diagnoses (e.g., cyclophosphamide for autoimmune conditions) and to monoclonal antibody agents and other biologic response modifiers. • The category of monoclonal antibodies includes infliximab, rituximab, alemtuzumab, gemtuzumab and trastuzumab. • The category of hormonal antineoplastics includes leuprolide acetate and goserelin acetate. • The drugs cited are not intended to be a complete list of drugs that may be administered using the chemotherapy administration codes. Local carriers may provide additional guidance as to which drugs may be considered as chemotherapy drugs under Medicare.

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8 Policy

Pharmacy Practice News • December 2013

Reimbursement

INTEGRITY continued from page 4

codes. “I’m not suggesting that you learn how to do this, but I am suggesting that you go to the people who are doing it, have them explain it to you and make sure that all the components are intact,” Mr. Johnson said. “Failure in any one of these decisions could affect your revenue. Make sure you’re comfortable that they know what they’re doing. If a claim is rejected, it could be because the revenue code is wrong, or some other process problem that is easy to fix.” The bottom-line questions are: Did we get paid? If not, why not? And “if a claim is rejected, a payor is required to give you an explanation of benefits. You may have to request it, but they have to give it to you,” he said. • Develop a policy for addressing rejected claims, and appeal them. Insurance companies may be more likely to accept the appeal than to spend time arguing about it. • Build procedures for billing new drugs into the patient-billing pathway. For example, new biologics are reimbursed at 106% of the wholesale acquisition cost (WAC) once approved by the FDA. Be sure coders are aware of the optimal coding choice (C9399) on the CMS1450/ UB92 form. • Develop a system for billing for wasted drugs. Providers are encour-

aged to schedule patients in a way that makes the most efficient use of drugs. However, if you must discard the remainder of a single-use vial after administering part of it to a Medicare patient, you can bill for the amount of drug discarded along with the amount administered. “It might not seem like a lot, but you’d be surprised if you have your technicians keep a waste log. The money generated will probably cover the cost of a couple salaries in your pharmacy.” • Obtain prior authorizations. Your admissions department should do this for specific therapies. Doing this is important because some payors refuse to pay for a covered drug if it isn’t preauthorized. Verification of insurance often is mistaken for preauthorization by admissions staff. Shadow someone in the admissions department, even if only for half a day, to see what is really happening. Many providers make the mistake of beginning therapy without waiting for preauthorization, thinking it’s for the patient’s convenience, when most patients would rather be assured that their medication costs are covered before beginning therapy. • Have a procedure for obtaining an advance beneficiary notice (ABN). An ABN informs patients of their obligation to pay if a medication is not covered, and also is required to appeal a denied claim by CMS. Take the lead on starting

GETTING READY continued from page 6

administration codes are available, covering such equipment and services as using local anesthesia; accessing an IV, catheter or port; starting the IV; preparing a drug; using hydration fluid and routine tubing, syringe, and supplies; and flushing at completion. The codes fall into two categories: those used for easily administered products, which are reimbursed at lower rates; and those used for more difficult or complicated products that, understandably, are reimbursed at higher rates. Using their guidance, CMS expects the facility to be able to correctly determine which products fall into which class and to code appropriately. Proposed for 2014 are slight increases in drug administration rates for six codes and decreases for the remainder, some of which are significant. What to do: 1. Understand how drug administration codes are used at your facility and identify problems.

2. Ensure that computerized prescriber order entry and electronic medication administration records are correctly set up to capture and provide documentation for IV drug administration in the outpatient arena (including the emergency room and procedural areas, as well as for observation patients, regardless of their physical location). 3. Create a default list of medications that are eligible for complex drug administration codes and ensure that the revenue cycle team knows how to use these. 4. Carefully look at hard edits or stops in the revenue cycle process that may be preventing correct code assignment. For example, not all chemother-

the process and then turn that responsibility over to others. “It is your revenue, and if nobody else is getting an ABN, you need to make sure it’s being done,” Mr. Johnson said. When claims are rejected by CMS, appeal them. CMS has 30 days to determine if the appeal is valid, and if it is, CMS makes a decision within 90 days of the appeal. Know the many reasons for nonpayment. These reasons can include deliberate undercharges (noncharting) by staff or patients who cannot afford the medication. Failure to document administration of a medication has important medical liability as well as revenue implications, he noted. Patient assistance programs (PAPs) are your friends! Have a multidisciplinary team, including case managers, office nurses and social workers, identify medically indigent patients who may be eligible for PAPs and pursue all of the available options, including the HealthWell Foundation, the Partnership for Prescription Assistance, the Association of Community Cancer Centers and the American Society of Health System Pharmacists’ Pharmaceutical Reimbursement Resource Center. Target patients who have the highest probability of needing help. These include Medicaid or

Medicaid-pending patients; patients with no insurance, including those with exhausted insurance benefits or no prescription benefits; patients with insurance whose specific medication is not covered or who cannot afford the copay or the deductible; and charity patients. • Develop a strategy for demonstrating quality. Oncology pharmacists need to develop pay-for-performance “quality indicators” for oncology that can be used for accountable care organizations (ACOs), Mr. Johnson noted. “There currently are no ACO standards for oncology,” he explained. Taking their cue from existing ACO standards for unnecessary readmissions and antibiotic stewardship, pharmacists could develop oncology standards for decreasing visits between cycles of therapy with toxicity management and patient contact. Antibiotic stewardship is important for oncology too, but “we need to impress the fact that we have some different standards that include antifungal therapy as well. We need to get together. If we don’t, the standards will be set for us.” —Susan Birk

apy or immunotherapy products fall into the J9000 series of HCPCS codes. Forgetting to include these would significantly decrease IV drug administration revenue. 5. Calculate the proposed revenue changes due to proposed drug administration code changes and build this into your budget. Q: What else is new in the proposal? A: Even more packaging or bundling! The rule proposes that all medications provided by the hospital for delivery during a comprehensive service pursuant to a physician order, regardless of the route of administration, would be considered as adjunctive supplies and, therefore, packaged as part of the comprehensive Ambulatory Payment Classification (APC). Self-administered drugs will now be considered packaged supplies. This concept also will apply packaging to selected HCPCS codes when the item or service is “integral, ancillary, supportive, dependent, or adjunctive to the provision of care that was reported by another HCPCS code” (78

FR 43570). New packages will include: 1. Products that function as supplies when used in a diagnostic test or procedure (e.g., stress agents, including dipyridamole and dobutamine). 2. Products that function as supplies when used during surgical procedures, such as skin substitutes. We will continue this discussion in the January 2014 column, with information on both actual changes as well as any surprises that the final rules may bring. Good luck in ensuring that these basic concepts are understood in your institution and getting needed changes under way. As always, your comments or questions are welcome!

•

Mr. Johnson reported no relevant ﬁnancial conﬂicts of interest.

Reading Material Federal Register / Vol. 78, No. 139 / Friday, July 19, 2013 / Proposed Rules found at: http:// www.gpo.gov/fdsys/pkg/FR-2013-07-19/pdf/ 2013-16555.pdf. [Two sources in the Federal Register are particularly relevant and helpful: Table 19, Proposed Drugs & Biologicals with Expiring Pass-through Status 12.31.2013 (page 43599); and Table 20, Proposed Drugs & Biologicals with Pass-through status in CY 2014 (page 43600).

Policy 9

Pharmacy Practice News • December 2013

Drug Safety

COMPOUNDING continued from page 1

One such safety gap, critics point out, is the voluntary nature of a central component of the new legislation—its creation of a separate outsourcing facility category. Under Title I of the bill, compounding pharmacies that choose to register as an outsourcing facility will be able to make large volumes of compounded drugs for anticipatory demand, unlike the pharmacies that compound drugs based on existing prescriptions. Beginning in 2015, those facilities will pay an annual fee, up to $15,000 if sales exceed more than $1 million per year. The fee will cover the cost of a yearly FDA inspection; if the outsourcing facilities must be inspected subsequently in the year, the company will pay an additional $15,000, adjusted for inflation, to cover the cost. (Less controversially, the Drug Quality and Security Act also establishes an electronic “track-and-trace” system, which aims to record the supply of pharmaceuticals from manufacturer to patient, in order to prevent the sale of counterfeit medication.) “This bill is an important first step in assuring that compounded sterile products are prepared safely,” said Paul W. Abramowitz, PharmD, ScD (Hon.), chief executive of the American Society of Health-System Pharmacists. “While ASHP is somewhat disappointed that the final agreement makes [the outsourcing facility] category voluntary rather than mandatory, we believe the new category, along with ... enhanced communication between state boards and FDA, will help improve the safety of products that health care providers and the public receive from compounding outsourcers.” Other stakeholders in pharmacy share ASHP’s disappointment in the voluntary nature of the new outsourcing category. “My preference would have been to have it be mandatory,” said Scott Knoer, PharmD, the chief pharmacy officer of the Cleveland Clinic in Ohio, “though it’s better than what we had before.” “A voluntary category of outsourcing facilities is not the answer,” Mr. Miller of the IACP said. “Would [the New England Compounding Center], with its alleged myriad violations of law and regulations, have voluntarily enrolled in this new category? We think the answer is clear.” Even if compounders register with the FDA, the law does not hold outsourcing facilities to the same standards as other manufacturers, according to Michael Carome, MD, director of Public Citizen’s Health Research Group. “It creates a double standard and an uneven playing field,” he said. In the case of drug shortages, the fed-

eral compounding bill could allow outsourcing facilities to create select medications without premarket approval. This approval, he said, is an essential aspect of existing law, which “has helped to ensure the safety and quality of drugs for more than half a century.” Instead of the intended effect, Dr. Carome said relying on outsourcing facilities could make the problem of drug shortages worse—if these facilities can produce drugs without approval, at lower cost, he argues they might be able to price other manufacturers

out of the market. The FDA currently has the authority to inspect compounding facilities, according to Dr. Carome. Had the FDA acted more aggressively, he believes last year’s tragedy could have been prevented.

Debate over Hospital Exemption Hospitals and health-system pharmacies, regardless of their size, are exempt from being categorized as compounding manufacturers under the

new bill, even if they do ship products to their affiliates in other states. As with the voluntary clause of the new bill, that exemption has been a source of contention. At the time the bill was first proposed, Eric Kastango, RPh, MBA, the president and chief executive of Clinical IQ, a firm that consults on sterile compounding systems, said the exemption was “a terrifying part of the legislation.” It is “only a matter of time,” he added, “before we have a catastrophic event in a hospital because

•

see COMPOUNDING, page 10

10 Policy

Pharmacy Practice News • December 2013

Drug Safety

COMPOUNDING continued from page 9

of poor oversight.” Allen J. Vaida, PharmD, executive vice president of the Institute for Safe Medication Practices, said he was not troubled by the exemption. “I don’t think the legislation necessarily needed to address hospital and retail pharmacies,” Dr. Vaida said. That task, he noted, could be handled by the state boards of pharmacy, which “should regulate that any licensed pharmacy adheres to

U.S. Pharmacopeial Convention [USP] standards for sterile compounding.” He acknowledged, however, that not every state inspects hospital pharmacies, and “less than half of the states mandate that licensed pharmacies follow USP standards.” But the risk posed by such uneven oversight, he noted, is tempered by the fact that “the majority of hospital pharmacies have been adhering to the [USP Chapter <797>] standards for sterile compounding.” “Frankly, the bill is a little watereddown from my point of view,” said Wil-

liam L. Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, in Memphis, Tenn. “But, pragmatically, it may be the best thing we can get out of Congress.” Dr. Greene said he was encouraged that the new legislation requires pharmacies that register as outsourcing facilities to submit annual reports to the Secretary of Health and Human Services, including all accounts of adverse events. Because such pharmacies also submit themselves to FDA inspection, he noted, the implication

is that these facilities will adopt the FDA’s better manufacturing standards. “And that’s a good thing,” he stressed.

A Manufacturer’s Reaction Although the reaction among pharmacies has been mixed, at least one company that manufactures compounded drugs expressed support for the new legislation. PharMEDium, one of the nation’s top outsourcing compounders, sent a letter to its customers saying that the bill “will finally instill clarity and certainty into the oversight of compounding facilities—ensuring that large-scale sterile compounding operations that conduct interstate commerce are subject to appropriate federal oversight.” Rich Kruzynski, RPh, the president of PharMEDium, said the firm intends to take an active part in the legislation’s new outsourcing category. “Recognizing how the law enhances protections for patients and hospitals, we want to be one of the first outsourcing facilities [to register for it],” Mr. Kruzynski told Pharmacy Practice News. Because it adds a layer of transparency to the process of validating a compounder, he added, “this outsourcing category should be a very welcome thing.”

Easier Vetting of Vendors Under section 503B of the bill, the FDA will create a website with a list of registered compounders. This new registry should make it easier for hospital pharmacies to vet outsourcing compounders, experts note, and is in stark contrast to the process that was required prior to the new law being passed, when choosing among several outsourcers often required a lengthy due diligence process, including background checks and site visits. “Hospitals should note that entities [that] don’t become 503B registrants [and] are engaged in large-scale compounding without a prescription, specifically anticipatory, are likely in violation of one or more provisions of the FD&C Act,” Mr. Kruzynski said, adding that such companies “are not inspected to the higher level of the FDA.” Many pharmacists asked to comment on the new compounding bill stressed that no piece of legislation is perfect, and that the new compounding bill has much to offer. As the Cleveland Clinic’s Dr. Knoerr noted, the profession should be pleased that the FDA will now have a more active role in the safety of compounding drugs. “Overall,” he said, “we’re very happy that we got a bill passed in a difficult legislative environment.” —Ben Guarino None of the sources had any relevant conﬂicts of interest to disclose.

Clinical 11

Pharmacy Practice News • December 2013

Oncology

LUNG CANCER continued from page 1

the treating physician and the clinic’s financial health. “How can we use that information from a [health care] reform perspective going forward to come up with an effective means of utilizing our resources in today’s economy?” Dr. Boehmer questioned.

What’s the Benefit? Currently, the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend four to six cycles of first-line chemotherapy for advanced NSCLC patients. “Are we capping the number of cycles of chemotherapy recommended in the available guidelines (four to six), or … are we not enforcing any caps at all? At my institution, it is some kind of mix,” Dr. Boehmer said. There are some survival data supporting going beyond the guidelines’ recommendations. A 2009 meta-analysis of 13 randomized clinical trials involving 3,027 patients with advanced NSCLC compared outcomes in those who received a fixed number of chemotherapy cycles for first-line therapy (two to eight) with those who continued chemotherapy until disease progression. Continuing chemotherapy until disease progression improved progression-free survival (PFS) substantially (hazard ratio [HR], 0.75; P<0.0001) and overall survival (OS) modestly (HR, 0.92; P=0.03), and patients using newer targeted agents, such as pemetrexed (Alimta, Eli Lilly) had even better outcomes ((J Clin Oncoll 2009;27:3277-3283). Three other studies have shown that continuing to provide chemotherapy after four cycles of first-line doublet chemotherapy extended PFS, with the benefit ranging from two weeks to two months (Lancet ( 2010;11:521-529; Proc Am Soc Clin Oncoll 2009;27:18s:abstract LBA8002; Lancet 2009;374:1432-1440). For second-line therapy of metastatic NSCLC, the FDA-approved agents—erlotinib (Tarceva, Genentech), docetaxel and pemetrexed—improve median PFS by 2.2, 2.7 and 2.9 months, respectively, and median OS by 6.7, 5.7 to 7.9, and 8.3 months. “When we go beyond a second-line therapy, however, typically our response rates fall to less than 2% in the third-, fourth- and fifthline settings,” Dr. Boehmer said. Although extended-duration therapy, particularly as first-line, has been shown to improve outcomes, it is not without its drawbacks. It generally causes higher rates of adverse events and, thus, can diminish health-related QoL measures. Of seven trials that included healthrelated QoL indices, two showed that patients receiving a set duration of chemotherapy had a better QoL as judged

Table. Advanced NSCLC Treatment Costs, Medicare 1992-2003 Stage IV (N=9,117)

Number of Patients

Total Cost Per Month, $

CancerPatient Attributable Liability Cost Per Month, $ Per Month, $

No treatment

1,269

3,398

2,557

264

Radiotherapy

2,576

5,391

4,857

899

Chemotherapy

1,192

7,677

7,132

1,326

Chemotherapy and radiotherapy

3,209

8,927

8,466

1,698

NSCLC, non-small cell lung cancer Based ased o on Va Value ue Health ea t . 2011;14:41-52. 0 ; 5

‘We see a lot of … restrictions associated with palliative care, due to cost control.’ —Ali McBride, PharmD by the European Organisation for the Research and Treatment of Cancer Core QoL questionnaire, perhaps due to cumulative toxicities ((J Clin Oncol 2009;27:3277-3283).

Price Tag Beyond the questions of potentially diminished QoL, another drawback of extended-treatment regimens is the hefty price tag of all this therapy, overall and for the patient. A study analyzing Medicare data from 1992 to 2003 for stage IV patients with NSCLC revealed costs nearing $8,000 per month for chemotherapy (Table) (Value Health 2011:14:41-52). Newer, first-line targeted therapies, such as afatinib (Giotrif, Boehringer Ingelheim) and crizotinib (Xalkori, Pfizer), can cost from $5,000 to $20,000 per month. Physicians are cognizant of the financial challenges. In one survey, 76% of physicians reported being aware of costs and 85% said trying to contain costs was the responsibility of every physician ( (JAMA 2013;310:380-388). In addition to physician awareness, there have been some other downward pressures on costs, particularly end-of-life care costs. “We see a lot of cost restrictions associated with palliative care, due to cost control,” said Ali McBride, PharmD, the clinical coordinator of hematology/oncology at University of Arizona Cancer Center, in Tucson. In some cases, clinicians are prevented from providing palliative chemotherapy and radiation in hospice care. Dr. McBride pointed out that in 2011, the Medicare base rate for lung cancer patients in hospice care was $151 per day, adding that “more than 60% of hospices will not take a patient on chemotherapy due to high costs.” An analysis of data from 235,821 patients revealed that the Medicare

Modernization Act, which reduced physician reimbursement for drugs, had a dramatic effect on physician prescribing of chemotherapy ((J Oncol Pract 2012;8:e6s-e13s). Between 2003 and 2004, 18% of patients received chemotherapy in the last 14 days of life in the outpatient setting; this number dropped by 20% between 2006 and 2007, after the reduced reimbursement took effect. “That accounted for about 546,000 fewer cycles of chemotherapy that were administered to outpatients with metastatic non-small cell lung cancer and over $400 million in cost savings,” Dr. Boehmer said. Many would argue this decrease was an encouraging trend in an incurable patient population, he pointed out. But others would say that although responses are diminished with such later lines of chemotherapy, it can have other benefits. Radiation and chemotherapy that reduces tumor size, for example, can be palliative and improve QoL, according to Dr. McBride. He added that, compared with placebo, erlotinib can improve QoL measures, including pain control, dyspnea and cough ((J Clin Oncol 2006;24:38313837). Thus, “limiting chemotherapy at the end of life isn’t always the best practice,” he stressed.

More Communication So, how much chemotherapy is too much? In 2005, a study created benchmarks for providing non-overly aggressive care for cancer patients ((Int J Qual Health Care 2005;17:505-509). The study concluded that less than 10% of patients should receive chemotherapy in the last 14 days of life and less than 2% should start a new chemotherapy regimen in the last 30 days of life. The Quality Oncology Practice Initiative (QOPI) measures fall along similar lines.

Studies show these goals are not being met. In a study of advanced lung cancer patients on Medicare between 2003 and 2007, 62% received chemotherapy in the last 14 days of life ((Health Aff 2012;31:786-795). To meet these goals, clinicians need to improve communication. A recent study revealed that 69% of patients receiving palliative chemotherapy for incurable lung cancer did not understand that the intent of the treatment was palliative, not cure ((N Engl J Med 2012;367:16161625). Dr. McBride pointed out that in a study of 95 consecutive patients with advanced cancer at a European academic medical center, only 53% of oncologists explained the disease course, 35% discussed symptoms and 39% discussed prognosis ((Eur J Cancer 2004;40:225235). In this study, patients were willing to undergo mildly toxic chemotherapy for a median survival improvement of 4.5 months and severe toxicities for a survival improvement of nine months. When patients were given the choice of extending their life by three months with chemotherapy or opting for supportive care, only 22% of patients chose chemotherapy. Patients with lung cancer who have end-of-life discussions before the last 30 days of life are less likely to receive chemotherapy ((P=0.003) or acute care ( <0.001), and more likely to receive (P hospice care ((P<0.001) ((J Clin Oncol 2012;30:4387-4395). “Perhaps,” Dr. Boehmer said, “we need to do a better job of catching our patients’ intent.” —Kate O’Rourke Drs. McBride and Boehmer reported no relevant ﬁnancial conﬂicts of interest.

Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular ﬁbrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy. Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE, including iodine • Cardiogenic shock • Marked sinus bradycardia • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available • NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits fi of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. • Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Clinically significant fi hypotension during infusions was seen most often in the first several hours of treatment and appeared to be related to the rate of infusion. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion. • In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. • Elevations of blood hepatic enzyme values ALT, AST, GGT are commonly seen in patients with immediately life-threatening VT/VF. / In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE. • Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. • There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings included pulmonary infi filtrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. Two percent (2%) of patients were reported to have acute respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary toxicity including pulmonary fifibrosis is a well-recognized complication of long-term amiodarone use. • Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. • The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%). • Drug Interactions • Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. • Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required. • Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in effi ficacy. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. Please see brief summary of Full Prescribing Information on the following pages.

Baxter Healthcare Corporation Deerﬁeld, IL 60015

Drug Delivery.

Nexterone (amiodarone HCl)

For the way you pharmacy.

Premixed Injection It’s About Time. Two-year shelf life Extended stability for greater convenience.

No admixing Helps minimize errors due to compounding.

Ready to use Because every second counts.

It’s the only cGMP manufacturer-prepared, premixed amiodarone on the market. Find out how Nexterone (amiodarone HCl) can help you. Contact your Baxter representative to place an order at 888.229.0001. For more information on how Nexterone (amiodarone HCl) can enhance patient care, visit nexterone.com.

DESCRIPTION

PRODUCT CODE

STRENGTH/ VOLUME

CONCENTRATION

NDC #

PACK FACTOR (cartons/case)

2G3451

150 mg/100 mL

1.5 mg/mL

43066-150-10

2G3450

360 mg/200 mL

1.8 mg/mL

43066-360-20

NEXTERONE (amiodarone HCl) Premixed Injection

Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

111932 07/13

NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available. 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE. 5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP , in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information].

Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias. 5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone). 5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone. 5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information]. Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear. Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism. The institution of antithyroid drugs, Ƶ-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients.

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

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

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

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

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

Thyroid: d thyroid nodules/thyroid cancer

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days. The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%). Table 4 lists the most common (incidence *2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

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

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

24 (2.9%) Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

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

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%) Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial ﬁbrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identiﬁed during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever

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

Vascular: r vasculitis 7 DRUG INTERACTIONS Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D Reproductive and teratology studies performed in rabbits and rats at doses of up to 100 mg/kg per day (about 1.4 times the maximum recommended human dose on a body surface area basis) revealed no evidence of embryotoxicity at 5 mg/kg and no teratogenicity was observed at any dosage in rabbits. Maternal toxicity and embryotoxicity were observed in rats in the 100 mg/kg group. Use NEXTERONE during pregnancy only if the potential benefit to the mother justifies the risk to the fetus. 8.2 Labor and Delivery It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. 8.3 Nursing Mothers Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. 8.4 Pediatric Use The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended. 8.5 Geriatric Use Clinical studies of amiodarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carefully consider dose selection in an elderly patient. 10 OVERDOSAGE There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of intravenous amiodarone include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Treat hypotension and cardiogenic shock by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Monitor hepatic enzyme concentrations closely. Amiodarone is not dialyzable.

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

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

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

Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal:l myopathy, muscle weakness, rhabdomyolysis

111923 04/13

16 Clinical

Pharmacy Practice News • December 2013

Infectious Disease

Probiotics in Practice: What’s the Evidence? Orlando, Fla.—Is it time for infectious disease pharmacists to include recommendations for probiotics in their antibiotic stewardship and discharge planning efforts? The use of probiotics has certainly caught on as a means of alleviating a variety of gastrointestinal (GI) afflictions, experts note. However, a lack of clinical evidence regarding their efficacy remains, according to a presentation at the 2013 Digestive Disease Week (DDW) meeting. Stefano Guandalini, MD, a professor of pediatrics and the section chief of Pediatric Gastroenterology, Hepatology and Nutrition at the University of Chicago Medicine, led a discussion on the topic at the DDW meeting. “We have patients rushing out to buy probiotics, but the majority of the products have shown no evidence of benefit,” Dr. Guandalini said. “Patients do express a desire for more information, and they need this from their physicians.” For example, data from a multicenter, focus group–based study found that patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) were interested in using probiotics to improve their digestive health but remained somewhat skeptical due to a lack of endorsement by their physicians, lax governmental regulations and limited empirical evidence supporting their efficacy ((J Clin Gastroenterol 2012;46:138-144). “Patients are interested in probiotics but have many unanswered questions about their use,” the authors of that study concluded.

Although publications concerning probiotics are increasing in number, clinical research is still scarce. A search of the 2012 literature on probiotics revealed only 10 original research papers but nearly 60 editorials, coming primarily from outside the United States. Despite a lack of research, a trend towards increased acceptance of probiotics among physicians was documented in a 2011 survey of 220 doctors in the United Kingdom. Among this group, 81% of gastroenterologists and 53% of surgeons reported recommending or prescribing probiotic supplements to their patients ((J Dig Dis 2011;12:489-496). “At least in the [United Kingdom], physicians are inclined to think seriously about probiotics,” Dr. Guandalini said, noting that most of the recommendations were for patients with IBS. Importantly, evidence supports the use of some but not all strains of probiotics. “Not all probiotics are created equal, and it’s a mistake to think that one can use any of them,” Dr. Guandalini noted.

Strain-Specific Evidence There is clinical evidence to support the use of probiotics in selected patients with some GI disorders, but it is important to distinguish among different probiotic strains. Lactobacillus rhamnosus GG (LGG) is one of the most extensively investigated probiotics, and its overall benefit in children with abdominal pain–related functional GI disorders was confirmed in a 2011 meta-analysis ((Aliment

Pharmacol Ther 2011;33:1302-1310). Compared with placebo, LGG was associated with a significantly higher proportion of treatment responders among the overall population with functional abdominal pain and in a subgroup of children with IBS. However, treatment response did not differ between children with functional abdominal pain or functional dyspepsia who received LGG and those receiving placebo. Intensity of pain was significantly reduced both in the overall and IBS populations, whereas frequency of pain was reduced only in patients with IBS. Bifidobacterium lactis strain DN-173 010 has been shown to increase stool frequency in women with constipation; however, in a prospective randomized, double-blind controlled trial of 159 children with constipation, the strain showed no benefit over placebo when delivered as a fermented dairy product containing B. lactis (Pediatrics ( 2011;127:e1392-e1399). Stool frequency after three weeks increased in both groups; therefore, clinical evidence is insufficient to recommend this product for these patients, the authors maintained. Some evidence backs dietary supplements containing Lactobacillus reuteri. In a 30-day randomized, double-blind, placebo-controlled trial of 30 preterm infants, newborns who received L. reuteri ATCC 55730 had significant decreases in regurgitation and in mean daily crying time, and had more frequent stools, as well as an increase in gastric emptying rate and a reduction in fast-

‘They may well represent an attractive therapeutic option; however, we need to better define the strain, optimal dosage, mode of action, safety and especially long-term efficacy and tolerability. We have established evidence of benefit, but we need to build on the data.’ —Stefano Guandalini, MD

Lactobacillus rhamnosus, Bifidobacterium lactiss and Streptococcus thermophilus.

ing antral area ((J Pediatr 2008;152:801806). Authors of the study concluded that L. reuteri improves feeding tolerance and gut function in formula-fed preterm newborns. In another double-blind, randomized, placebo-controlled study involving 44 infants with chronic constipation, L. reuteri DSM 17938 supplementation was associated with a significantly higher frequency of defecation compared with placebo at weeks 2, 3 and 8; however, there was no improvement in stool consistency or crying episodes. In another study, lower pain intensity, although not lower frequency of pain, was observed in 60 children with functional abdominal pain who received L. reuteri DSM 17938 ((J Paediatr Child Health 2010 Jul 8. [Epub ahead of print]).

‘Not all probiotics are created equal, and it’s a mistake to think that one can use any of them.’ —Stefano Guandalini, MD Streptococcus thermophilus VSL#3 is a combination of eight different strains, in high concentrations, and its use is supported by a study from a team of researchers led by Dr. Guandalini. In a crossover study of 59 children with IBS, VSL#3 provided significantly greater relief of symptoms, including abdominal pain/discomfort and bloating/gas, compared with placebo, and was associated with less “life disruption” (J ( Pediatr Gastroenterol Nutr 2010;51:2430). However, stool pattern in this population was not improved compared with the pattern in the placebo group. For the primary end point of improvement in global assessment of symptom relief, the average score of 4 at baseline dropped to approximately 3.5 in the placebo group and to less than 2.5 in the VSL#3 group at six weeks (P ( <0.05). “There was some improvement with placebo, but the change from baseline was much greater with the probiotic,” Dr. Guandalini noted. He concluded that probiotic supplementation with Lactobacilli, Bifidobacteria and Streptococcus is “promising,” as these strains offer statistically significant—albeit modest—benefits in children with functional GI disorders. “They may well represent an attractive therapeutic option; however, we need to better define the strain, optimal dosage, mode of action, safety and especially long-term efficacy and

Clinical 17

Pharmacy Practice News • December 2013

Infectious Disease tolerability. We have established evidence of benefit, but we need to build on the data,” he said.

Evidence Strong Enough? “I agree with virtually every aspect of this review by Dr. Guandalini,” said J. Marc Rhoads, MD, a professor, in the Department of Pediatrics at the University of Texas Medical School, in Houston. “Probiotics are taking their niche in [clinical] practice, as well they should. In fact, there is more evidence at the meta-analysis level for the use of probiotics than there is for many of the other things that are done in practice, including the use of stool softeners over laxatives, the treatment of gastroesophageal reflux in infants and the treatment of infants with hematochezia with hypoallergenic formula. All of these are examples of standard practice with limited evidence,” he noted. “There is strong evidence from metaanalyses for the use of probiotics to reduce the severity of acute gastroenteritis, to prevent necrotizing enterocolitis [and] antibiotic-associated diarrhea, and to reduce the severity of IBS,” he continued. “There is also very promising evidence that probiotics are efficacious in babies with colic ... for children with ulcerative colitis, infants with atopic eczema and children with constipation.” But despite the firm evidence of some efficacy, the magnitude of that effect is unclear, Dr. Rhoads added. “For example, it seems that probiotics have a major impact in preventing necrotizing enterocolitis but only modifying effects on IBS,” he said. “It is not at all clear if one probiotic is better than another, or one combination better than an individual probiotic for any of the above-mentioned conditions. I personally believe that dose is not as important, and most of the commercially available probiotics do have at least 108 CFUs [colony-forming units] per unit dose.” In addition to efficacy and dosing, there may be issues of product homogeneity, product quality and safety, Dr. Rhoads noted. “The [FDA] and the National Institutes of Health’s National Center for Complementary and Alter-

native Medicine are concerned about safety in the vulnerable infant population, which is reasonable,” he said. However, to date, studies have not reported more than a fraction of a percentage who develop serious adverse events, he noted (“Safety of Probiotics to Reduce Risk and Prevent or Treat Disease,” available at www.ncbi.nlm. nih.gov/books/NBK56091). “Finally,” Dr. Rhoads said, “duration of effect and of colonization is a very interesting question. In adults, within two weeks, virtually all the probiotic is gone.

This may not be true in infants, although the colonization may be limited to three to six months. What I think is fascinating,” he added, “is the profound [effect] that some probiotics have on the neonatal immune system. We have found that administration of L. reuteri to newborn rat or mouse pups produces a significant increase in regulatory T-cell numbers [[PLoS One 2013;8:e56547] and dramatically reduces the severity of necrotizing enterocolitis, at least in part by reducing NF [nuclear factor]-κB signaling and the inflammatory cascade

((Am J Physiol Gastrointest Liver Physiol 2012;302:G608-G617). This effect was not produced by all strains of the probiotics we studied, pointing to the importance of preclinical trials and carefully selected biomarkers for human trials, for example, cytokine levels and regulatory T-cell percentages.” —Caroline Helwick Dr. Guandalini reported no relevant ﬁnancial conﬂicts of interest. Dr. Rhoads has received a research grant from BioGaia.

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Clinical 19

Pharmacy Practice News • December 2013

Practice Pearl

Reducing the Burn Choosing the optimal local anesthetic for peripheral IV catheter placements David Gurda, PharmD Staff Pharmacist Abbott Northwestern Hospital, part of Allina Health Minneapolis, MN

uring a hospitalization, patients often have a peripheral intravenous (PIV) catheter placed for medication administration. The placement of a PIV can cause discomfort for patients that may contribute to their anxiety when undergoing this procedure. Many health systems use local anesthetics as premedications to alleviate this distress. These medications are more effective than using no premedication at all.1 Choosing an ideal local anesthetic, however, can be a challenge, given the overall lack of evidence in this area. But there are some useful guideposts and new data to consider. The Infusion Nurses Society recommends lidocaine as the anesthetic of choice in its latest edition of Infusion Nursing Standards of Practice,2 but due to its acidic property, lidocaine may cause a burning sensation upon infiltration. To overcome this obstacle, many hospital pharmacies will “buffer” the lidocaine by adding sodium bicarbonate and increasing the pH to a neutral value. Published literature comparing buffered lidocaine with lidocaine has been inconsistent,3,4 but there are some data showing that buffered lidocaine results in less pain.1 Buffered lidocaine, however, poses several problems for hospital pharmacies, including a short expiration date and a tedious compounding process that demands extra time from pharmacy technicians and pharmacists for compounding and verifying the medication. These issues were front and center

No pain

Moderate pain

Worst possible pain

Figure. Pain scale for assessing response to local anesthetics.

at my postgraduate year 1 residency institution, United Hospital (Allina Health System), a 546-bed acute care hospital in downtown Saint Paul, Minn. Before abandoning the use of buffered lidocaine due to a sodium bicarbonate drug shortage (an additional problem all pharmacies face), United Hospital spent approximately 25 hours of technician and 12.5 hours of pharmacist work time compounding the buffered pain reliever in the final quarter of 2010. To help determine whether those considerable efforts to compound buffered saline were warranted, proof of superior efficacy over other available anesthetic agents was needed. Thus, for my pharmacy residency major project I conducted an institutional review board–approved clinical trial comparing the efficacy of pain reduction by 1% lidocaine, 1% buffered lidocaine, and 0.9% bacteriostatic normal saline (an alternative anesthetic typically used in

patients with a lidocaine allergy), using patient-reported average pain scores as the primary outcome.

Trial Design Using results reported in a similar study by Ganter-Ritz et al5 as a baseline, my project advisor and I assumed that a difference of means of 1 in pain scores between groups would be considered clinically significant. Based on this assumption, a sample size of 150 patients was used, with 50 patients randomized to each group. I prepared treatment dose syringes in a sterile products area, and they were verified by a second pharmacist. Then the syringes were blinded by being labeled with a respective treatment number and paired with a matching data collection sheet. This sheet contained pertinent information such as the patient’s medical record number (MRN), pain scales (Figure), and reports of adverse drug reactions.

Table 1. Average Pain Scores in Patients Given Local Anesthetics Average Pain Scoresa

Group 1: 1% Lidocaine (n=50)

Group 2: 1% Buffered Lidocaine (n=50)

Group 3: 0.9% Bacteriostatic Normal Saline (n=50)

Overall (N=150)

Significance

Baseline

Following anesthetic injection

P=0.023b 1 vs 2 = P<0.05 1 vs 3 = NS 2 vs 3 = NS

Following PIV insertion

ANOVA, analysis of variance; HSD, honestly significant difference; NS, not significant; PIV, peripheral intravenous a

A difference of means of 1 in pain scores is considered clinically significant.

Kruskal-Wallis one-way ANOVA; P<0.05 is clinically significant.

Tukey’ss HSD test Tukey

P=0.005b 1 vs 2 =NSc 1 vs 3 = P<0.05c 2 vs 3 = P<0.05c

Upon receiving a consult for a new PIV placement, my nursing colleagues and I determined patient eligibility using prespecified inclusion criteria. Once consented, patients were asked to report 2 pain scores: the first following subdermal infiltration of the local anesthetic and the second following cannulation of the PIV. The IV resource nurse was tasked with administering the medication and inserting the PIV while I verbally obtained the pain scores. Participating nurses and enrolled patients were blinded to the study medication, and any patient who declined participation received lidocaine before PIV placement, consistent with the standard of care at United Hospital.

Significant Findings The goal sample size of 150 patients was achieved and baseline demographic data was evenly distributed among the 3 groups. Gastrointestinal complaints were the primary reason for hospitalization, occurring in 22.4% of patients. PIV insertion site and size were also evenly distributed among groups (88.7% of PIVs placed in forearm) and in 84% of cases, PIVs were successfully placed on the first insertion attempt. A single-factor analysis of variance was conducted to test for differences in pain scores between groups (Table 1). For subdermal injection of the anesthetic, 1% buffered lidocaine was significantly more effective for pain reduction than regular 1% lidocaine (1.64 vs 2.81; P<0.05), but it was equivalent to 0.9% bacteriostatic normal saline (1.64 vs 2.05; P=NS). There was no significant difference found between 1% regular lidocaine and bacteriostatic normal saline for this measure. When measuring the pain reduction associated with cannulation of the PIV, 1% lidocaine and 1% buffered lidocaine were equally effective in relieving pain (1.81) and significantly more effective than bacteriostatic normal saline (3.05; P=0.005). For patients receiving pain medications within 12 hours of enrollment, reported average overall pain scores actually were higher for those who had received pain medications, although this result was not statistically significant.

Cost and Medication Use As noted, 2010 was the last year in which United Hospital was consistently compounding 1% buffered lidocaine. Using compounding records, it was estimated that approximately 2,400 vials of this anesthetic were compounded during the fourth quarter and because this was a consistent practice within our pharmacy, it could be extrapolated that

•

see THE BURN, page 20

20 Clinical

Pharmacy Practice News • December 2013

Practice Pearl

THE BURN continued from page 19

about 10,000 vials of 1% buffered lidocaine were compounded in all of 2010. By calculating the per-mL cost of 1% lidocaine and 8.4% sodium bicarbonate, as well as taking into account technician and pharmacist work time, it was determined that compounding buffered lidocaine cost the United Hospital pharmacy approximately $13,400 per year, requiring 1,515 minutes of total technician and 525 minutes of total pharmacist work time. Because regular 1% lidocaine and bacteriostatic normal saline are commercially available, compounding these products is not required. Assuming an equal amount of these medications were used, the annual cost of purchasing 1% lidocaine and bacteriostatic normal saline would be $9,100 and $4,840, respectively. As each buffered lidocaine vial contains 20 mL of the anesthetic formulation and the IV resource team uses 0.5-mL syringes for catheter placement, it could be assumed that 40 syringes per vial would be available for patients. If the IV resource team used even half of the 10,000 vials compounded in 2010 (with the other half used for procedural areas, such as interventional radiology), this means approximately 200,000 syringes could have been available for PIV starts. Using nursing administration data, in 2012 the IV resource team at United placed 17,000 PIVs. If 2 to 3 syringes were used per patient (a liberal estimate), that still would only demand 34,000 to 51,000 syringes of buffered lidocaine for PIV insertions, out of a supply of almost 200,000. Hence, the waste potential for buffered lidocaine at my institution was deemed to be approximately 80%.

Where Do We Go From Here? The findings of this study correlate well with those of Ganter-Ritz et al,5 and there have been multiple prospective randomized trials published in the literature comparing the efficacy of local anesthetics for PIV placement. Unfortunately, many of these studies report on anesthetics not commonly used in everyday practice (eg, EMLA cream), and the pain scales used for measuring outcomes are variable. Although it seems that buffered lidocaine is the most tolerable anesthetic for initial subdermal administration, the fact that it is equal to 1% lidocaine for pain reduction during insertion of the PIV catheter raises the question of whether hospitals should continue using regular 1% lidocaine and ignore this initial discomfort. If buffered lidocaine were commercially available at an affordable price, the answer would be easy: 1% buffered lidocaine should be used on all patients receiving PIV catheter placement. Simply stated, to solve

Table 2. Beyond-Use Dates Risk Category

Room Temperature, h

Refrigeration

Frozen (<10°C)

Immediate use

N/A

Low risk

14 d

45 d

Low risk with 12-h BUD

12 h

N/A

Medium risk

45 d

High risk

45 d

BUD, beyond-use date

refrigerated per USP <797> (Tables 2 and 3). For simplification purposes, my institution chose to use a 24-hour expiration time at room temperature (rather than 30 hours) and 7 days if refrigerated, rather than 9 days). The syringes were stored in the IV resource nursing office without a refrigeration system, which reveals how many of the syringes likely went unused and thus expired.

A Potential Solution for Waste

Based on reference 6.

this dilemma hospital pharmacies can take 2 approaches: Find a cheap commercially available product or reduce the amount of waste. Several admixed commercial products are available from multiple suppliers, but this issue is complicated because these products, available as unit-dose prefilled syringes, are very expensive, and at least 2 companies that have shipped buffered lidocaine have been plagued by questions surrounding compliance with the Federal Food, Drug, and Cosmetic Act. Indeed, in October 2012 Ameridose was forced to recall all products and, in 2013, multiple compounders have been issued an FDA Form 483 on several occasions, indicating that drugs may have been prepared or stored under noncompliant conditions.6,7 Thus, in the short term, hospital pharmacies

likely will continue to be required to compound buffered lidocaine if choosing to move forward with this admixture as the anesthetic of choice. My study found a significant waste potential with 1% buffered lidocaine, likely due to hospital supply exceeding demand, resulting in large amount of expired drug. The beyond-use dates (BUDs) of the anesthetic preparations were chosen to comply with United States Pharmacopeia (USP) Chapter <797> sterile compounding guidelines. Because compounding buffered lidocaine requires multiple additives and this admixture is used for batching syringes, this process falls under the definition of medium-risk compounding, demanding a BUD of 30 hours at room temperature and 9 days when

For health systems facing similar challenges, I believe an initial solution for reducing this kind of waste could be to work with the PIV placement service at your institution to determine the amount of anesthetic syringes required based on the annual number of PIV catheters placed. The hospital pharmacy could compound the syringes in batches, as many hospital pharmacies do with other medications such as IV antibiotics, all the while assuring a sterile compounding environment in compliance with USP Chapter <797>. By investing in a refrigerated stocking station within the PIV placement service department (eg, PYXIS SMART Remote Manager, CareFusion Corp), pharmacy staff could deliver the weekly stock of compounded syringes for use by the IV resource team. Although this proposed solution

•

see THE BURN, page 24

Table 3. Pharmacy Compounding: USP Chapter <797> Risk Level Assessment Classification

Requirements

Immediate-use

• For emergent use, or situations where low-risk compounding would add risk due to delays. • No storage or batch compounding. • Continuous compounding process lasting <1 h. • Aseptic technique used. • Administer <1 h after preparation begins, or discard. • Simple transfer of sterile nonhazardous drugs or diagnostic radiopharmaceuticals.

Low-risk level

• Simple admixtures compounded using closed system transfer methods. • Prepared in ISO Class 5 LAFW. • Located in ISO Class 7 buffer area with ISO Class 8 ante area. • Examples include reconstitution of single-dose vials of antibiotics or other small-volume parenterals, preparation of hydration solutions.

Low-risk level with <12-h BUD

• Simple admixtures compounded using closed-system transfer methods. • Prepared in ISO Class 5 PEC. • Compounding area is segregated from noncompounding areas. • Administration must start no later than 12 h after preparation.

Medium-risk level

• Admixtures compounded using multiple additives and/or small volumes. • Batch preparations (eg, syringes). • Complex manipulations (eg, TPN). • Preparation for use over several days. • Prepared in ISO Class 5. • Located in ISO Class 7 buffer area with ISO Class 8 ante area. • Examples include pooled admixtures, parenteral nutrition solutions using automated compounders, batch-compounded preparations that do not contain bacteriostatic components.

High-risk level

• Nonsterile (bulk powders) ingredients. • Open-system transfers. • Prepared in ISO Class 5. • Located in ISO Class 7 buffer area with separate ISO Class 8 ante area. • Examples include CSPs prepared from bulk, nonsterile components, or final containers that are nonsterile and must be terminally sterilized.

Yes

BUD, beyond-use date; CSPs, compounded sterile preparations; ISO, International Organization for Standardization; LAFW, laminar air flow workbench; PEC, primary engineering control; TPN, total parenteral nutrition; USP, United States Pharmacopeia Based on reference 6.

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

Increased risk for hospitals and patients11

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

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References: 1. Amin A, Deitelzweig S, Christian R, et al. Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US. J Hosp Med. 2012;7(8):634-639. 2. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119:71.e1-71.e8. 3. Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Effect Resource Alloc. 2006;4(10):1-11. 4. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11A):S1-S21. 5. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatremia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant. 2006;21:70-76. 6. Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleveland Clin J Med. 2006:73(3):S4-S12. 7. Callahan MA, Do HT, Caplan DW, Yoon-Flannery K. Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study. Postgrad Med. 2009;121(2):186-191. 8. Adrogué HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol. 2005;25:240-249. 9. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med. 2009;122:857-865. 10. Congressional Record. Patient Protection and Affordable Care Act. 2010;156:1-906. 11. Inouye SK, Brown CJ, Tinetti M. Medicare nonpayment, hospital falls, and unintended consequences. N Engl J Med. 2009;360(23):2390-2393. 12. The Joint Commission. 2011-2012 National Patient Safety Goals. © Copyright 2012, The Joint Commission. ©2013 Otsuka America Pharmaceutical, Inc.

August 2013

0713A-8921C

Clinical 23

Pharmacy Practice News • December 2013

Hospital Medicine

When Errors Occur, Are Fines the Best Response? 10 California hospitals recently hit with penalties for range of errors

series of shocking medical errors— including the bizarre case of two surgeons who implanted fecal bacteria in the brains of patients with advanced tumors—has resulted in stiff fines being levied against 10 California hospitals where the errors occurred. The California Department of Public Health (CDPH) issued administrative penalties to the hospitals, whose “noncompliance with licensing requirements caused, or was likely to cause, serious injury or death to patients,” according to a CDPH press release. The fines ranged from $50,000 for a first-time offense, to $75,000 for a second and $100,000 for a third or subsequent violation. The injured patients likely will welcome the CDPH’s actions. But several safety experts say they are worried that the punitive nature of those actions may have a chilling effect on voluntary reporting of future errors, not to mention preventing the mishaps from occurring elsewhere. “We could do better things than punishing people,” said Michael R. Cohen, RPh, MS, the president of the Institute for Safe Medication Practices (ISMP), in an interview. “For example, perhaps the [involved] hospitals could be called upon to educate others on how they fixed the problem and how they’re ensuring that it never happens again.”

They Did What? In the case of the fecal bacterial transplants, it’s hard to imagine how anyone would uld willingly let such a procedure hap ppen at all, let alone again. The CDPH reeported that two neurosurgeons at the Un niversity of California (UC), Davis Medical Center implanted live Enterobacter aeerogenes bacteria, commonly found in n feces, into the brains and surround ding bone tissue of three patients with end-stage glioblastoma mu ultiforme. According to the surgeeons, their intent was to cause an n infection that would in turn triggger an immune response against the t brain tumor tissue. The resu ults: one patient developed en ncephalitis, became septic and died d from the blood infection; another died due to brain swelling caused by the bacteria; and the third was dischargeed to a skilled nursing facility and requ uired additional operations due to the inffection. Shockiingly, according to state records, the expeerimental treatment was conducted at a the UC Davis Medical Center without the knowledge of the institutional reeview board (IRB) or the FDA A. As a first

offender, the hospital was fined $50,000. CDPH has been issuing such penalties since 2007, and does so three to four times a year. In an email interview, Debby Rogers, RN, MS, FAEN, the deputy director of CDPH’s Center for Health Care Quality, in Sacramento, wrote, “CDPH has issued a total of 286 administrative penalties, including those issued on August 15, 2013, to 155 California hospitals. CDPH learns of the incidents when a facility self-reports to the Department, while conducting a complaint investigation, or during a survey.” The penalized hospitals are required to file a plan of correction to prevent similar incidents. Ms. Rogers said that she could not say whether other states have a similar system of penalties, but ISMP’s Dr. Cohen said, “I haven’t seen anything like this in other states.” Asked for his view of California’s system of penalties, Mr. Cohen said that, due to its punitive approach, “I don’t think it’s going to change anything,” in terms of promoting a culture of safety at the cited hospitals.

Enteral, IV Confusion Alta Bates Summit Medical Center, in Oakland, Calif., was another hospital

involved in the recent fines. Alta Bates Summit was penalized $50,000 because an enteral feeding formula was administered into a peripherally inserted catheter, resulting in the patient’s death from a pulmonary embolus. “Fining people for that [error] really isn’t the answer,” Mr. Cohen said. “The answer is changing the ends of the catheters so that they’re not compatible, and that is taking place now as we speak, but it’s going to be a couple of years” for this safer practice to gain traction, he noted. Robert Lagasse, MD, a professor of anesthesiology at Yale University School of Medicine, in New Haven, Conn., agreed that the California penalties likely would not be helpful. “I think this is kind of a step back from the performance improvement initiatives that you see in other industries,” he said. “They’re probably going to inhibit people from reporting and looking into the system errors that caused the problems.” Dr. Lagasse pointed to the case at Sharp Memorial Hospital, in San Diego, in which a surgeon who was charged with removing a left testicle that had an abnormal lesion instead made an unnecessary incision on the right side before being alerted to his error. This happened

‘I think this is kind of a step back … [Fines are] probably going to inhibit people from reporting and looking into the system errors that caused the problems.’

—Robert Lagasse, MD

despite the fact that the su urgical team had conducted a time-out to focus on verifying the correct patientt, the correct procedure and the correct side or site. The penalty to the hospital w was $75,000. “The fact of the maatter is [that] wrong-sided surgeery has gone up three- to fou urfold since the initiation of tthe time-out procedure,” Dr. Lagasse L said. “It’s quite possiblee that [these] attempts to makee things better are not work king. … That might be whaat happens when you have a group as opposed to everryone believing that it’s their [individual] responsibilities.” In another case of the reecently fined hospitals, Ronald Reagan UC CLA Medical Center in Los Angeles was fiined $50,000 when a sponge was left insid de a patient’s body after gallbladder remo oval and pancreatic tumor resection. “Th here are some systems available now th hat people are trialing with R RFID [radio-

frequency identification] built into the sponges,” Dr. Lagasse said. “The hospital that has to pay a … fine could use that money to invest in a solution.”

Fines are Fine—Iff Steep Enough Another expert in patient safety suggested that the penalties might be too small to have much effect. “One of the concerns with this approach is that an executive may mistake writing a check for fixing the system,” said Peter J. Pronovost, MD, PhD, FCCM, the senior vice president for patient safety and quality and the director of the Armstrong Institute for Patient Safety and Quality at Johns Hopkins Medicine, in Baltimore. “To the state department’s credit, one of the things that is underdeveloped is an accountability system.” However, he indicated, penalties need to be more significant than California’s penalties to be effective, on the order of closing the hospital or withholding Medicaid funding. Ms. Rogers noted that the penalties are expected to go up to a maximum of $125,000 in 2014. Marin General Hospital, in Greenbrae, Calif., was fined $100,000 for failure to connect a ventilator to an endotracheal tube, resulting in a patient’s death. Dr. Pronovost said this might have been prevented by “an alarm that shows the ventilator’s not connected.” (The state deficiency report stated there were alarms, but they were not working.) Such technological solutions should take place alongside checklists and better safety culture, Dr. Pronovost noted, adding that “getting a culture that encourages teamwork and collaboration is really key and may be the most potent intervention we have.” Regarding the use of bacteria to treat brain cancer, Lawrence J. Brandt, MD, a professor of medicine and surgery at Albert Einstein College of Medicine, in New York City, said, “If you ask the question, can bacteria and infection be used to alter the course of tumor, that’s not outlandish. That’s a reasonable question. You just need a safe way of doing it.” However, when told that the surgeons had conducted their research without IRB approval, he said, “That, you see, is outlandish. That is not appropriate. That is bad.” Asked for comment, representatives from four of the five hospitals named in this article stated that their hospitals had developed safeguards to ensure that the errors for which they were fined did not happen again. Marin General Hospital did not respond to a request for comment. —George Ochoa

24 Clinical

Pharmacy Practice News • December 2013

Practice Pearl

THE BURN continued from page 20

continues to use hospital pharmacy compounding resources and requires purchasing a refrigeration system, the increased efficiency and reduced waste potential could result in lower costs and improved compliance with state compounding standards. At my current institution, Abbott Northwestern Hospital, located in south Minneapolis, we follow a documented policy in accordance with the USP guide-

lines that is reviewed on a regular basis. This document is transparent, available online, and details several key aspects of our operations, including a sterile products area and equipment design, processes for assigning risk levels to sterile products, and cleaning and sterilization standards. The document also outlines daily compounding activities as well as steps that need to be taken to ensure that pharmacy staff is reviewed annually for competency for working in the sterile products area. For health systems interested in setting up a sterile products area

for compounding medications such as buffered lidocaine, having an established system for ensuring compliance with the USP Chapter <797> guidelines, similar to the one employed at Abbott Northwestern, is not only vital for patient safety but also enforceable by state boards of pharmacy and other accrediting organizations, such as the Joint Commission. In recent years, the American Society of Health-System Pharmacists (ASHP) and its journal AJHP have released several informative and helpful documents reviewing the details of USP Chapter

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<797>, including easy-to-read tables and a “checklist” for assigning BUDs to medications based on risk assessment.8.9 Review of these “blueprints” would be a practical initial step for hospital pharmacies interested in implementing compounding systems.

Conclusion To date, there has been conflicting research done in the area of anesthetics used before PIV catheter placement. This is an important issue because there are several medication options available and a consensus is lacking regarding which anesthetic is most effective, resulting in a barrier to establishing a standard of practice. The findings of my study indicate that 1% buffered lidocaine is the superior anesthetic for pain reduction with PIV placement, but is significantly affected by drug shortages, increased costs, and the potential for very costly waste of unused preparations. Until a low-cost commercial product of 1% buffered lidocaine is available or hospital pharmacies implement processes for reducing waste while maintaining compounding standards, 1% lidocaine is a practical alternative and should be considered by all health systems. Dr. Gurda reported no relevant ﬁnancial conﬂicts of interest.

References Monograph or Webinar M

Monograph or Webinar M

2. Infusion Nurses Society. Infusion nursing standards of practice. J Infus Nurs. 2006; 29(1 suppl):s1-s92.

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4. Nakayama, M, et al. Efficacy of alkalinized lidocaine for reducing pain on intravenous and epidural catheterization. J Anesth 2001;15:201-203. 5. Ganter-Ritz V, Speroni KG, Atherton M. A randomized double-blind study comparing intradermal anesthetic tolerability, efficacy, and cost-effectiveness of lidocaine, buffered lidocaine, and bacteriostatic normal saline for peripheral intravenous insertion. J Infus Nurs. 2012;35(2):93-99.

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3. Steinbrook RA, et al. Effects of alkalinization of lidocaine on the pain of skin infiltration and intravenous catheterization. J Clin Anesth 1993;5:456-458.

6. US Food and Drug Administration. FDA reports voluntary recall of all Ameridose drug products. http://www.fda.gov/newsevents/ newsroom/pressannouncements/ucm326361. htm. Accessed September 17, 2013.

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1. Brown J. Using lidocaine for peripheral i.v. insertions: patients’ preferences and pain experiences. Medsurg Nurs. 2003;12(2):95-100.

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US Food and Drug Administration. Pharmacy Compounding: FDA Actions. http://www. fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ ucm339771.htm. Accessed September 17, 2013.

8. American Society of Health-System Pharmacists (ASHP). The ASHP discussion guide on USP Chapter <797> for compounding sterile preparations. http://www.ashp.org/s_ashp/ docs/files/discguide797-2008.pdf. f Accessed September 16, 2013. 9. Kastango ES. Blueprint for implementing USP chapter 797 for compounding sterile preparations. Am J Health Syst Pharm. 2005;62(12):1271-1288.

Operations & Management 25

Pharmacy Practice News â&#x20AC;˘ December 2013

Supply Chain

FDA Creates Plan To Combat Drug Shortages

ver the past few years, the FDA has made significant strides in the prevention of drug shortages, circumventing 200 shortages in 2011 and more than 280 in 2012. By the end of December 2012, however, 300 drugs remained in short supply. In October, the FDA outlined a plan to mitigate ongoing drug shortages while averting future supply problems. â&#x20AC;&#x153;Preventing drug shortages before they begin is a top priority for the FDA,â&#x20AC;? said FDA Commissioner Margaret A. Hamburg, MD, during a media briefing on Oct. 31. â&#x20AC;&#x153;Drug shortages pose a significant public health threat because they can result in serious, or even deadly, outcomes.â&#x20AC;? Although the FDA currently prevents a large number of shortages each year, the scarcities are occurring at higher frequencies than a decade ago. There were about 60 new drug shortages in 2005, according to the FDA. By 2011, the number of new shortages had increased to more than 250. In response, Washington took two actions that would provide the impetus for the FDAâ&#x20AC;&#x2122;s newest plan: an executive order issued by President Barack Obama in 2011 and the passage of the FDA Safety and Innovation Act (FDASIA) in 2012, which gave more muscle to the agencyâ&#x20AC;&#x2122;s regulatory capabilities. At the heart of the FDAâ&#x20AC;&#x2122;s new strategy are improved lines of communication, with respect to both drug manufacturers and the public. In the short term, the agency plans to streamline its internal response whenever a manufacturer gives notice about a supply problem. Through a proposed rule, any company that produces â&#x20AC;&#x153;medically necessaryâ&#x20AC;? drugs must alert the FDA about a discontinuance or interruption in the production of a drug. That way, the agency will be able to provide information about drug shortages to the public. â&#x20AC;&#x153;It might help individual purchasers make plans for the future,â&#x20AC;? said William L. Greene, PharmD, the chief pharmaceutical officer of St. Jude Childrenâ&#x20AC;&#x2122;s Research Hospital, in Memphis, Tenn. â&#x20AC;&#x153;If [the FDA] can update that information quickly, that would probably be a benefit.â&#x20AC;? A potential hitch, however, could be a discrepancy between what the FDA considers a shortage and a hospital pharmacistâ&#x20AC;&#x2122;s definition. â&#x20AC;&#x153;If premixed heparin bags are in short supply, it can be tremendously difficult for hospital pharmacies,â&#x20AC;? said Erin R. Fox, PharmD, the director of the Drug Information Service at University of Utah Health Care, in Salt Lake City. â&#x20AC;&#x153;The FDA may not see that as a true shortage.â&#x20AC;? Patients have been harmed when hospitals mix heparin improperly, Dr. Fox said. Health-system pharmacists seeking information about drug shortages have two primary options: a list of shortag-

es and other resources maintained by the American Society of Health-System Pharmacists (bit.ly/I834FR), and a drug shortages database maintained by the FDA (1.usa.gov/1bXUZy9). â&#x20AC;&#x153; I tend to not use the FDA database as frequently as I use the [ASHP] database,â&#x20AC;? Dr. Greene said. â&#x20AC;&#x153;Thereâ&#x20AC;&#x2122;s more information thatâ&#x20AC;&#x2122;s more meaningful to me there.â&#x20AC;? As part of a long-term approach, the FDA laid out plans to tackle the under-

lying cause of shortages. â&#x20AC;&#x153;The majority of drug shortages, an estimated 70%, are the result of a breakdown in quality and manufacturing,â&#x20AC;? Dr. Hamburg said. Under some life-threatening circumstances, the FDA will exercise regulatory discretion as a temporary fix to quality issues. When rubber particles were discovered in Genentechâ&#x20AC;&#x2122;s Cathflo Activase (alteplase) in March 2013, for example, the FDA allowed the drug to be distribut-

ed with a warning that it must be filtered before administration. But such regulatory discretion is not sufficient when drugs are contaminated with bacteria and fungus, or when the production of a drug has been halted. An estimated 30% of U.S. drug-manufacturing capacity is currently offline as a result of FDA actions, Dr. Fox noted. â&#x20AC;&#x153;We cannot solve the challenges of

â&#x20AC;˘

see SHORTAGES, page 27

NOW AVAILABLE

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

IMPORTANT SAFETY INFORMATION INDICATIONS/CONTRAINDICATIONS InjectaferÂŽ (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. InjectaferÂŽ is contraindicated in patients with hypersensitivity to InjectaferÂŽ or any of its inactive components. WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving InjectaferÂŽ. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after InjectaferÂŽ administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer InjectaferÂŽ when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving InjectaferÂŽ. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each InjectaferÂŽ administration. In the 24 hours following administration of InjectaferÂŽ, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in InjectaferÂŽ. ADVERSE REACTIONS In two randomized clinical studies, a total of 1775 patients were exposed to InjectaferÂŽ, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by â&#x2030;Ľ2% of InjectaferÂŽ-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%). The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

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

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

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

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

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

InjectaferÂŽ is manufactured under license from Vifor (International) Inc., Switzerland. ÂŠ2013 American Regent, Inc. Printed in USA FCM002 Rev. 09/2013

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

26 Operations & Management

Pharmacy Practice News â&#x20AC;˘ December 2013

Leadership in Action

Are You â&#x20AC;&#x2DC;Ridiculously in Chargeâ&#x20AC;&#x2122;?

he present atmosphere within health care is unlike any other I can remember in my 37 years of pharmacy practice. The health care system is being turned on its head, forcing the formation of broad health networks through mergers, acquisitions or affiliations. Layered on top of this growing complexity is the development of risk models such as accountable care organizations (ACOs), which often require

Brief Summary of Full Prescribing Information

INJECTAFERÂŽ (ferric carboxymaltose injection)

new modes of thinking, planning, developing and collaborating. One could view these developments as a fearful time or instead could see opportunities for pharmacy to flourish by bringing value to the health care table. There are many examples of health systems that have a strong track record of meeting these challenges head-on and prospering. What are some of the common traits of such organizations? I

Rx Only

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

s WHO HAVE NON DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE DOSAGE AND ADMINISTRATION: &OR PATIENTS WEIGHING KG LB OR MORE 'IVE )NJECTAFERÂŽ in TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE &OR PATIENTS WEIGHING LESS THAN KG LB 'IVE )NJECTAFERÂŽ IN TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG KG BODY WEIGHT FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE InjectaferÂŽ TREATMENT MAY BE REPEATED IF IRON DElCIENCY ANEMIA REOCCURS Administer InjectaferÂŽ INTRAVENOUSLY EITHER AS AN UNDILUTED SLOW INTRAVENOUS PUSH OR BY INFUSION 7HEN ADMINISTERING AS A SLOW INTRAVENOUS PUSH GIVE AT THE RATE OF APPROXIMATELY MG M, PER MINUTE 7HEN ADMINISTERED VIA INFUSION DILUTE UP TO MG OF IRON IN NO MORE THAN M, OF STERILE SODIUM CHLORIDE INJECTION 530 SUCH THAT THE CONCENTRATION OF THE INFUSION IS NOT LESS THAN MG OF IRON PER M, AND ADMINISTER OVER AT LEAST MINUTES )NSPECT PARENTERAL DRUG PRODUCTS VISUALLY FOR THE ABSENCE OF PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION 4HE PRODUCT CONTAINS NO PRESERVATIVES )NJECTAFERÂŽ IS A SINGLE USE VIAL $ISCARD UNUSED PORTION !VOID EXTRAVASATION OF )NJECTAFERÂŽ SINCE BROWN DISCOLORATION OF THE EXTRAVASATION SITE MAY BE LONG LASTING -ONITOR FOR EXTRAVASATION )F EXTRAVASATION OCCURS DISCONTINUE THE )NJECTAFERÂŽ ADMINISTRATION AT THAT SITE DOSAGE FORMS AND STRENGTHS: 3INGLE USE VIALS CONTAINING MG ELEMENTAL IRON PER M, IN THE FOLLOWING PRESENTATION MG IRON M, CONTRAINDICATIONS: (YPERSENSITIVITY TO )NJECTAFERÂŽ OR ANY OF ITS INACTIVE COMPONENTS WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving InjectaferÂŽ. Patients may present with shock, clinically signiďŹ cant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after InjectaferÂŽ administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer InjectaferÂŽ when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. )N CLINICAL TRIALS SERIOUS ANAPHYLACTIC ANAPHYLACTOID REACTIONS WERE REPORTED IN OF SUBJECTS RECEIVING InjectaferrÂŽ /THER SERIOUS OR SEVERE ADVERSE REACTIONS POTENTIALLY ASSOCIATED WITH HYPERSENSITIVITY WHICH INCLUDED BUT NOT LIMITED TO PRURITUS RASH URTICARIA WHEEZING OR HYPOTENSION WERE REPORTED IN OF THESE SUBJECTS Hypertension: )N CLINICAL STUDIES HYPERTENSION WAS REPORTED IN OF SUBJECTS IN CLINICAL TRIALS AND 4RANSIENT ELEVATIONS IN SYSTOLIC BLOOD PRESSURE SOMETIMES OCCURRING WITH FACIAL mUSHING DIZZINESS OR NAUSEA WERE OBSERVED IN OF SUBJECTS IN THESE TWO CLINICAL TRIALS 4HESE ELEVATIONS GENERALLY OCCURRED IMMEDIATELY AFTER DOSING AND RESOLVED WITHIN MINUTES -ONITOR PATIENTS FOR SIGNS AND SYMPTOMS OF HYPERTENSION FOLLOWING EACH )NJECTAFERÂŽ ADMINISTRATION Laboratory Test Alterations: )N THE HOURS FOLLOWING ADMINISTRATION OF )NJECTAFERÂŽ LABORATORY ASSAYS MAY OVERESTIMATE SERUM IRON AND TRANSFERRIN BOUND IRON BY ALSO MEASURING THE IRON IN InjectaferÂŽ ADVERSE REACTIONS Adverse Reactions in Clinical Trials: "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REmECT THE RATES OBSERVED IN CLINICAL PRACTICE )N TWO RANDOMIZED CLINICAL STUDIES A TOTAL OF PATIENTS WERE EXPOSED TO )NJECTAFERÂŽ MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON !DVERSE REACTIONS REPORTED BY t OF TREATED PATIENTS ARE SHOWN IN THE FOLLOWING TABLE 4ABLE !DVERSE REACTIONS REPORTED IN t OF 3TUDY 0ATIENTS IN #LINICAL 4RIALS AND

/RAL IRON InjectaferÂŽ 0OOLED #OMPARATORSa . . . .AUSEA Hypertension &LUSHING (OT &LUSH "LOOD 0HOSPHORUS $ECREASE $IZZINESS 6OMITING )NJECTION 3ITE $ISCOLORATION Headache Alanine Aminotransferase Increase $YSGEUSIA Hypotension #ONSTIPATION a Includes oral iron and all formulations of IV iron other than InjectaferÂŽ 4RANSIENT DECREASES IN LABORATORY BLOOD PHOSPHORUS LEVELS MG D, HAVE BEEN OBSERVED IN OF PATIENTS IN CLINICAL TRIALS 4ERM

posit that connectednessâ&#x20AC;&#x201D;the ability of key pharmacy personnel to forge positive relationships both within a department and with colleagues at other institutionsâ&#x20AC;&#x201D;is a critical piece of the puzzle.

Sharing Battle Scars To become successful, I encourage every pharmacy leader to have a group of colleagues to meet with regularly to share battle scars and ideas. This type

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

BACK PAIN ARTHRALGIA AND SYNCOPE /NE CASE OF HYPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A SUBJECT WHO RECEIVED MG OF )NJECTAFERÂŽ EVERY WEEKS FOR A TOTAL OF WEEKS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ DRUG INTERACTIONS: &ORMAL DRUG INTERACTION STUDIES HAVE NOT BEEN PERFORMED WITH )NJECTAFERÂŽ USE IN SPECIFIC POPULATIONS Pregnancy 0REGNANCY #ATEGORY # !DEQUATE AND WELL CONTROLLED STUDIES IN PREGNANT WOMEN HAVE NOT BEEN CONDUCTED )NJECTAFERÂŽ SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENElT JUSTIlES THE POTENTIAL RISK TO THE FETUS Nursing Mothers: ! STUDY TO DETERMINE IRON CONCENTRATIONS IN BREAST MILK AFTER ADMINISTRATION of InjectaferÂŽ N OR ORAL FERROUS SULFATE N WAS CONDUCTED IN LACTATING WOMEN WITH POSTPARTUM IRON DElCIENCY ANEMIA -EAN BREAST MILK IRON LEVELS WERE HIGHER IN LACTATING WOMEN RECEIVING )NJECTAFERÂŽ THAN IN LACTATING WOMEN RECEIVING ORAL FERROUS SULFATE Pediatric Use: 3AFETY AND EFFECTIVENESS HAS NOT BEEN ESTABLISHED IN PEDIATRIC PATIENTS Geriatric Use: /F THE SUBJECTS IN CLINICAL STUDIES OF )NJECTAFERÂŽ WERE YEARS AND OVER WHILE WERE YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE SUBJECTS AND YOUNGER SUBJECTS AND OTHER REPORTED CLINICAL EXPERIENCE HAS NOT IDENTIlED DIFFERENCES IN RESPONSES BETWEEN THE ELDERLY AND YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT OVERDOSAGE: %XCESSIVE DOSAGES OF )NJECTAFERÂŽ MAY LEAD TO ACCUMULATION OF IRON IN STORAGE SITES POTENTIALLY LEADING TO HEMOSIDEROSIS ! PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS DEVELOPED HEMOSIDEROSIS WITH MULTIPLE JOINT DISORDER WALKING DISABILITY AND ASTHENIA (YPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ DESCRIPTION: Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1ŕľş4)-O-Ë&#x17E;-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately 150,000 Da. InjectaferÂŽ FERRIC CARBOXYMALTOSE INJECTION IS A DARK BROWN STERILE AQUEOUS ISOTONIC COLLOIDAL SOLUTION FOR INTRAVENOUS INJECTION %ACH M, CONTAINS MG IRON AS FERRIC CARBOXYMALTOSE IN WATER FOR INJECTION 3ODIUM HYDROXIDE AND OR HYDROCHLORIC ACID MAY HAVE BEEN ADDED TO ADJUST THE P( TO 4HE VIAL CLOSURE IS NOT MADE WITH NATURAL RUBBER LATEX CLINICAL PHARMACOLOGY Mechanism of Action: &ERRIC CARBOXYMALTOSE IS A COLLOIDAL IRON ))) HYDROXIDE IN COMPLEX WITH CARBOXYMALTOSE A CARBOHYDRATE POLYMER THAT RELEASES IRON Pharmacodynamics: 5SING POSITRON EMISSION TOMOGRAPHY 0%4 IT WAS DEMONSTRATED THAT RED CELL UPTAKE OF Fe and Fe from InjectaferÂŽ RANGED FROM TO )N PATIENTS WITH IRON DElCIENCY RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS )NJECTAFERÂŽ DOSE )N PATIENTS WITH RENAL ANEMIA RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS )NJECTAFERÂŽ DOSE Pharmacokinetics: !FTER ADMINISTRATION OF A SINGLE DOSE OF )NJECTAFERÂŽ OF TO MG OF IRON IN IRON DElCIENT PATIENTS MAXIMUM IRON LEVELS OF ÂŤG M, TO ÂŤG M, WERE OBTAINED RESPECTIVELY AFTER MINUTES TO HOURS POST DOSE 4HE VOLUME OF DISTRIBUTION WAS ESTIMATED TO BE , 4HE IRON INJECTED OR INFUSED WAS RAPIDLY CLEARED FROM THE PLASMA THE TERMINAL HALF LIFE RANGED FROM TO HOURS 2ENAL ELIMINATION OF IRON WAS NEGLIGIBLE NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility: #ARCINOGENICITY STUDIES HAVE NOT BEEN PERFORMED WITH FERRIC CARBOXYMALTOSE &ERRIC CARBOXYMALTOSE WAS NOT GENOTOXIC IN THE FOLLOWING GENETIC TOXICOLOGY STUDIES in vitro MICROBIAL MUTAGENESIS !MES ASSAY in vitro CHROMOSOME ABERRATION TEST o IN HUMAN LYMPHOCYTES in vitroo MAMMALIAN CELL MUTATION ASSAY IN MOUSE LYMPHOMA , 9 4+ CELLS in vivoo mouse MICRONUCLEUS TEST AT SINGLE INTRAVENOUS DOSES UP TO MG KG )N A COMBINED MALE AND FEMALE FERTILITY STUDY FERRIC CARBOXYMALTOSE WAS ADMINISTERED INTRAVENOUSLY OVER ONE HOUR TO MALE AND FEMALE RATS AT IRON DOSES OF UP TO MG KG !NIMALS WERE DOSED TIMES PER WEEK ON $AYS AND 4HERE WAS NO EFFECT ON MATING FUNCTION FERTILITY OR EARLY EMBRYONIC DEVELOPMENT 4HE DOSE OF MG KG IN ANIMALS IS APPROXIMATELY OF THE HUMAN DOSE OF MG BASED ON BODY SURFACE AREA CLINICAL STUDIES: 4HE SAFETY AND EFlCACY OF )NJECTAFERÂŽ for treatment of iron deďŹ ciency anemia WERE EVALUATED IN TWO RANDOMIZED OPEN LABEL CONTROLLED CLINICAL TRIALS 4RIAL AND 4RIAL )N THESE TWO TRIALS )NJECTAFERÂŽ WAS ADMINISTERED AT DOSE OF MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON PATIENT COUNSELING INFORMATION s 1UESTION PATIENTS REGARDING ANY PRIOR HISTORY OF REACTIONS TO PARENTERAL IRON PRODUCTS s !DVISE PATIENTS OF THE RISKS ASSOCIATED WITH )NJECTAFERÂŽ s !DVISE PATIENTS TO REPORT ANY SIGNS AND SYMPTOMS OF HYPERSENSITIVITY THAT MAY DEVELOP DURING AND FOLLOWING )NJECTAFERÂŽ ADMINISTRATION SUCH AS RASH ITCHING DIZZINESS LIGHTHEADEDNESS SWELLING AND BREATHING PROBLEMS InjectaferÂŽ IS MANUFACTURED UNDER LICENSE FROM 6IFOR )NTERNATIONAL )NC 3WITZERLAND

)SS

â&#x20AC;&#x153;Leadership in Actionâ&#x20AC;? is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at anderson489@ comcast.net.

Ernest R. Anderson Jr., MS, RPh

of outreach fosters the realization that you are not the only one facing difficult pressures. It creates a degree of emotional support that often leads to action, which results in a great sense of confidence in your ability to solve dilemmas and move forward. These connections also help us move our thinking out of the emotional limbic portion of our brain and into the prefrontal cortex where problem solving takes place. As Henry Cloud stated in his book â&#x20AC;&#x153;Boundaries for Leadersâ&#x20AC;? (HarperCollins, 2013), â&#x20AC;&#x153;When we are emotionally and relationally connected to others, stress levels in the brain diminish.â&#x20AC;? Our brains need positive relationships to grow and function well. Yet if everyone is cooped up in their disparate offices and never gets out, how will connection and a sense of unity develop? It wonâ&#x20AC;&#x2122;tâ&#x20AC;&#x201D;so itâ&#x20AC;&#x2122;s time to take a look at staff meetings as a potential solution. Weâ&#x20AC;&#x2122;ve all heard that dysfunctional meetings are a waste of time, so how do we avoid this pitfall? First, we need to focus the discussion on workplace issues that connect the staff based on shared concerns, rather than on issues that separate and disengage us. Talking about how your team works together, the roles and responsibilities required, the values, the governance, the identity and cohesiveness of the team is a good template to follow and to revisit often. You also need to create a climate of trust and vulnerability. This can be done through having a shared purpose or goal, and making sure there is a mutual awareness of purpose that operates from the same set of facts and realities. As the leader, you must take an active role in fostering this shared purpose and connectedness. This can be done in a variety of ways, some of which are as simple as being engaged and communicating with your body language the desire to connect with your entire team. As the leader you sometimes also will be called on to be the peacemaker when conflict arises. Remember that people are not thinking at their best when they are emotionally charged and operating out of the limbic portion of their brain. In teams with a high trust level, emotions and misunderstandings can be more easily repaired through apologies, humility and even humor. Aggressive listening is another crucial componentâ&#x20AC;&#x201D;itâ&#x20AC;&#x2122;s critical to

Operations & Management 27

Pharmacy Practice News • December 2013

Leadership in Action building connection and strong teams. People want to feel known before they will trust a leader and be led by that leader. Seek first to understand, then to be understood. When something goes wrong in your group, fix it together. Trust may take time to develop, but unity will be the result. It’s also important to keep in mind that quality, not quantity, should be a governing principle in your meeting strategy. Here’s a good template to follow: • Daily check-in: 5-10 minutes • Weekly tactical: 45-90 minutes • Monthly strategic: 2-4 hours • Quarterly or semi-annual off-site review: 1-2 days.

I see this as an opportunity for a positive-thinking leader to change the atmosphere. The place to start is by actively listening to the people in the department. Make sure they feel understood. Ask for ideas for change. Next, gather the managers to discuss how pharmacy can be a catalyst to solve institution-wide problems at the hospital. Remember, with all the health care changes upsetting the status quo, new entrepreneurial thinking is required. Then take steps to ensure the staff understands how critical they are to moving the process

of innovation forward. When people feel their views are being heeded, and they see change and progress occurring based, in part, on their suggestions, a new optimism will emerge. In my new role as a consultant to hospitals and health care systems, I am always trying to determine how pharmacy can be a solution and problem solver across the institution. This often allows advancement of collaborative drug therapy management and other aspects of the Pharmacy Practice Model Initiative, which has the goal of advancing the

health and well-being of patients via innovative practice models that employ pharmacists as direct patient-care providers. When these types of models flourish, it is at least partly due to the efforts of pharmacy leaders who took pains to get their staff excited about their role and the profession of pharmacy. As leaders, we have a keen responsibility to be in charge and foster these positive attitudes and innovation. In fact, as Henry Cloud put it: “We are ridiculously in charge.” Serve your departments well.

The Power of Your Thinking I often hear about pharmacy departments where the morale is said to be low.

SHORTAGES

Unit Do s Bar Cod e, ing, Pharma Nursing cy & Supp Experts ly !

continued from page 25

The sources had no relevant ﬁnancial conﬂicts of interest to disclose.

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drug shortages alone,” said Douglas Throckmorton, MD, the deputy director of the FDA’s Center for Drug Evaluation and Research. He called for a greater emphasis on the quality and stability of the drug supply. “As the FDA has indicated, the current supply chain does not reward manufacturers for quality,” Dr. Greene said. Although the FDA is limited in what it can accomplish, he said, the agency could help the marketplace make decisions that would reward manufacturers for quality. FDASIA asks the FDA to consider the creation of a qualified manufacturing partner program, which Dr. Greene called “a slam dunk” for purchasers. Under such a program, the price of medications may increase—but drug shortages also contribute to higher costs of medication, Dr. Greene said. The FDA warned that pharmaceuticals purchased from the secondary gray market might worsen the effects of a shortage because these products may be improperly stored or handled. “It troubles me that we have people who are willing to purchase drugs from the gray market,” Dr. Greene said. “I just can’t believe we actually do that.” Dr. Fox said the University of Utah made a decision in 2001 to prohibit the purchase of drugs from the gray market. “If no one was buying from the gray market,” she said, “it wouldn’t exist.” Dr. Fox said she is “hopeful” that the FDA’s methods will prioritize manufacturing quality. “What’s evident in the plan is the tremendous amount of work the FDA has done. Kudos to them for doing what they can.” —Ben Guarino

MediDose.com

28 Special Feature

Pharmacy Practice News • December 2013

The Year in Pharmacy By any measure, 2013 has been a dynamic year for health-system pharmacy. Continuing fallout from the sterile compounding debacle, the approval of at least two breakthrough drugs for blood cancers and a call for better preparedness plans for responding to catastrophic medication errors were just a few of the noteworthy events covered in Pharmacy Practice News. What follows are highlights from our coverage, culled from each issue.

Fungal Meningitis Deaths Trigger a Salvo From NABP

y mid-December 2012, the tragic scope of the fungal meningitis outbreak tied to tainted steroids from the New England Compounding Center (NECC) was in stark evidence: More than 650 individuals had been sickened in 19 states and nearly 40 patients had died. In response, inspectors from the National Association of Boards of Pharmacy (NABP) and state pharmacy boards descended on six compounding pharmacies in four states as part of a broad effort to bolster the safety of customized medicines being shipped across state lines—efforts that continued well into 2013. The dual inspections were part of the NABP’s contractual agreement with the Iowa State Board of Pharmacy to strengthen surveillance of compounding pharmacies licensed by Iowa but located outside its borders.

“We’re moving full-bore ahead,” said Carmen Catizone, MS, RPh, DPh, NABP’s executive director, who summarized the preliminary findings of the inspections in an exclusive interview with PPN. Four of the six compounders were found to distribute non–patient-specific, preservative-free sterile injectables, which can be in violation of “traditional” compounding—that is, the preparation of medications prescribed in small quantities for specific individuals. Two of the pharmacies were producing large quantities of such drugs and shipping them across state lines, Dr. Catizone reported. Asked who should be held accountable for the NECC violations that led to the nearly nationwide fungal meningitis outbreak, Dr. Catizone said that although it is easy to point fingers, “every single one of us was responsible for this tragedy. The regulatory system broke down, the pharmacy compounding system broke down, [and] the collaboration between FDA and the states broke down.” And he did not leave health-system pharmacy unscathed: Because facilities that purchased the steroids from NECC failed to exercise sufficient due diligence in vetting the vendor for safe manufacturing practices, “those transactions [also] broke down.”

Health Systems Get Failing Grade On Medication Safety

ealth systems scored a failing grade on key measures of medication safety preparedness, according to a Medication Self-Assessment Survey issued by the Institute for Safe Medication Practices (ISMP). Overall, respondents achieved an average score of only 64% on questions designed to assess whether practitioners receive sufficient orientation on medication use, undergo baseline and annual competency evaluation of knowledge and skills related to safe medication practices, and receive ongoing education on medication error prevention and the safe use of high-alert drugs, according to the survey results, which were reported first by PPN. Certain survey items yielded particularly low scores: In 34% of the respondents’ hospitals, new staff pharmacists undergoing orientation are not assigned to spend time in patient care units becoming familiar with drug-prescribing practices, unit stock storage conditions, medication administration procedures and patient education programs. Additionally, nearly 72% of respondents noted that newly hired nurses do not spend time in the pharmacy or with clinical pharmacists during orientation. Kyle Hultgren, PharmD, the managing director of the Center for Medication Safety Advancement at Purdue University, in West Lafayette, Ind., said these medication safety shortcomings can be addressed by establishing drug safety standards for all members of the care team. However, he stressed that those standards should not be created solely through a “top-down” approach. “It really should be a collaborative approach across the board,” Dr. Hultgren said.

A Breakthrough for Acute Promyelocytic Leukemia

chemotherapy-free regimen consisting of alltrans-retinoic acid (ATRA) and arsenic trioxide (ATO) should be considered the new standard of care for patients with non–high-risk, acute promyelocytic leukemia (APL), according to results of a study by researchers from Italy and Germany. Event-free survival at two years—the primary end point of the study—was 97.1% in patients treated with the ATRA/ATO chemotherapy-free regimen versus

85.6% in patients treated with ATRA plus chemotherapy ((P=0.02). Overall survival for the two groups was 98.7% and 91.1%, respectively ((P=0.02). Grade 3/4 thrombocytopenias occurring for more than 15 days was more frequent in the chemotherapy arm (69% vs. 45%; P≤0.0001), the investigators reported. Although the data was presented in December 2012 at the annual meeting of the American Society of Hematology, many oncology pharmacists first began fielding questions about the regimen in 2013, according to Cindy L. O’Bryant, PharmD, BCOP, an associate professor at the University of Colorado Skaggs School of Pharmacy, in Denver. Dr. O’Bryant said she stressed to her own colleagues that the new regimen “minimizes the long-term toxicities associated with anthracyclines. This is important in a cancer where cure rates are reaching 80%.” She noted, however, that the chemotherapy-free treatment is not without risks. “Concurrent medications will need to be screened to minimize QTc prolongation. More frequent monitoring of electrolytes, blood glucose, coagulation and hematologic toxicities also will need to be performed.”

Resistant Superbugs ‘A Public Health Crisis’

report in the March issue of Infection Control and Hospital Epidemiologyy (2013;34:259-268) found that the proportion of Klebsiella pneumoniae cases resistant to carbapenems increased from 0.1% in 2001 to 4.5% in 2010. The findings triggered alarm in the infectious disease (ID) community, which only intensified when the Centers for Disease Control and Prevention (CDC) issued its own report on rising rates of carbapenemresistant enterobacteriaceae (CRE). According to the report, in the past decade, hospitals have seen a fourfold increase in CRE, with most of that increase attributable to Klebsiella species ((MMWR 2013;62:1-6). Robert Rapp, PharmD, a professor of pharmacy and surgery emeritus at the University of Kentucky Medical Center, in Lexington,, said these findings g should be keeping ID pharmacissts up at night. In the past, he noted, K. K pneumoniae typically haad been treated with cephalosporins or caarbapenem antibiotics, but b the bacteria are becomiing increasingly resistantt to those medications.. Because alternative drugs such as colistiin, polymyxin B and tigeecycline are not always effective

Special Feature 29

Pharmacy Practice News • December 2013

alone, they have to be used in combination. “But there’s no real, solid data on the drugs of choice,” Dr. Rapp said. Thus, medical staff “are just kind of flying by the seat of their pants.” With no new antibiotics in the pipeline, “we really have a problem,” he stressed. “If you come down with one of these superbug infections, your chances of dying are high—probably 40% to 50%,” a figure echoed in the March CDC report. “Make no mistake,” said Dr. Rapp, “this is a public health crisis.”

In Canada, Echoes Of NECC Debacle?

ore than 1,200 oncology patients in five Canadian hospitals received diluted doses of gemcitabine and cyclophosphamide for a year or longer because labels on bags of premixed IV drug solutions prepared by an outsource compounding pharmacy did not make clear that the bags were intended for single individuals only, investigators reported.

Although the clinical effect on patients who received the lower doses of chemotherapy remained unclear, the disclosures triggered a storm of controversy in Canada—and raised concerns that U.S. hospitals are vulnerable to similar mishaps. Michael R. Cohen, RPh, MS, ScD, the president of the ISMP, said the Canadian underdosing issue highlighted the need for more rigorous universal standards for preparing, labeling and administering chemotherapy and other high-alert drugs. He noted that even in U.S. hospitals, there is “an inconsistency in the way

we make things in IV admixture areas” that “can lead to serious errors.”

Billion-Dollar Savings Projected From Biosimilars

ational drug spending could be cut by $250 billion between 2014 and 2024 if only 11 biosimilar versions

•

see YEAR IN REVIEW, page 30

FDA Inspections Take Toll On Compounders

s the fallout from the NECC crisis deepened, a barrage of continuing inspections by the FDA and state pharmacy boards uncovered numerous safety violations at compounding pharmacies that supply hospitals and practitioners across the country with batch quantities of customized sterile solutions. Most of the investigators’ on-site reports focused on incidents of failure to maintain optimal-quality conditions and procedures for safe sterile compounding, a reflection of lax adherence to standards set forth by U.S. Pharmacopeia (USP) Chapter <797>. But some inspections also uncovered evidence of product contamination, and several cases led to large-scale product recalls. On May 8, for example, the FDA announced concerns about a lack of sterility for drugs manufactured and distributed by The Compounding Shop of St. Petersburg, Fla., following inspections of the company’s manufacturing facilities. The FDA requested that the company withdraw all of its sterile products from the market, and that any existing products not be administered to patients. The inspection reports and recalls raised apprehension levels among hospitals that rely on outsourcers to fill at least part of their sterile compounding needs. “There is a legitimate heightened concern out there,” said Kasey Thompson, PharmD, the vice president of policy, planning and communications at the American Society of Health-System Pharmacists (ASHP). “We could say that as the months have passed, perhaps it has gotten worse.” Allen Vaida, PharmD, the executive vice president of the ISMP, agreed that the NECC crisis was making outsourcing a scary proposition. “We’ve been hearing ... that many hospital administrators are telling their directors of pharmacy, ‘No more outsourcing. We’re scared of this. We want you to do it all in-house.’ But many of these pharmacies may not be equipped to do it.”

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30 Special Feature

YEAR IN REVIEW continued from page 29

of current best-selling biologics are approved during those 10 years, Express Scripts forecasted (www.lab.expressscripts.com). The company’s vice president of research and analysis, Sharon Frazee, said the projection is based on an “uber-conservative” model and suggested the savings could even be higher. “There are 92 patent expiries coming up; we only included the 11 that we believe are certainly going to have competitor

Pharmacy Practice News • December 2013

biosimilars come to market,” Ms. Frazee said at the Express Scripts Outcomes Symposium in Orlando, Fla. Despite the billion-dollar savings projections, one pharmaceutical analyst struck a note of caution. “These [biosimilars] aren’t [easily manufactured] generic substitutes,” stressed Helen Sherman, PharmD, the vice president of clinical pharmacy consulting at Solid Benefit Guidance. “They will be a brand. But, in any case, despite all the press about biosimilars, I haven’t heard of one solid example indicating that there is a bio-

similar coming out anytime soon.”

Pharmacists Feeling Pain Over Harsh AMA Resolution

bluntly worded American Medical Association (AMA) resolution that was intended to curb a barrage of retail pharmacy phone calls to physicians

Read Pharmacy Practice News Anywhere, Anytime!

requesting addition-al information aboutt pain medication pre-scriptions triggered a backlash from phaarmacists, some of wh hom objected to the ressolution’s sharp tone as a departure from the mostly m collegial relationships that exist between the two professions. The AMA resolution stated that the group “deem[s] inappropriate inquiries from pharmacies to verify the medical rationale behind prescriptions, diagnoses and treatment plans to be an interference with the practice of medicine and unwarranted.” It also threatened that if the issue were not resolved, the AMA would “advocate for legislative and regulatory solutions to prohibit pharmacies and pharmacists from denying medically necessary and legitimate therapeutic treatments to patients.” Kasey Thompson, PharmD, the vice president of Policy, Planning and Communications for the ASHP, said the AMA resolution did not “really reflect the state of collaboration that exists today. If you talk with a vast majority of ASHP’s 42,000 members, you’ll hear story after story about how they work in an interdisciplinary team in the care of patients. It’s the health care delivery system of the 21st century; there’s more collaboration, not less, going on.”

‘Unthinkable’ Errors And Preparedness

oes your health system have a plan for responding to catastrophic medication errors that could trigger negative media coverage and lawsuits, in addition to the tragic consequences for patients? Put another way, are the nation’s hospital prepared for the “unthinkable,” as several speakers asked during a session on crisis management at the ASHP 2013 Summer Meeting. “Many health care systems think they have a crisis plan, but they don’t,” said Frank Federico, RPh, the executive director at the Institute for Healthcare Improvement (IHI), in Cambridge, Mass. “Often it’s only in someone’s head. It’s not written, not practiced, not tested.” “A plan must describe a well-defined process you can rely on in times of extraordinary stress,” added Elizabeth Ennis, MD, the chief medical officer of Baptist Health System, in Birmingham, Ala. “Without one, you decrease your ability to assess the crisis, intervene and resolve it.” Tips for boosting a hospital’s preparedness included having a standing crisis

Special Feature 31

Pharmacy Practice News • December 2013

management team on hand at all times, led by the organization’s chief executive, with each member given clear areas of responsibility. Ideally, the team also should include the hospital’s chief medical officer, chief nursing officer, chief public relations officer, legal counsel, a medical ethicist, a patient representative and a pastoral care counselor, according to a white paper on the topic authored by Dr. Federico (bit.ly/14VRdVL).

with impressive efficacy in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). (At press time, the FDA approved the drug for use in patients with MCL who have received at least one prior therapy. Pharmacyclics, Inc., will market the drug as Imbruvica.) The submission came on the heels of findings published in The New England Journal of Medicine showing a 71% clinical response rate in patients with difficult-to-treat CLL (2013;369:32-42). Some of the more common, manageable

Joblessness Crisis For Pharm Grads?

Hematology/Oncology Division at Columbia University Medical Center, in New York City. The emergence of ibrutinib “is a huge kudos for the field,” said Dr. Lamanna, who was not involved in research on the drug. “There is little doubt in most of our minds that ibrutinib will be used … as first-line therapy for CLL, with the potential of sparing some patients a number of treatments that otherwise might be too toxic.” —Compiled by David Bronstein

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y 2018, 20% of new pharmacy graduatees will enter a job market thatt has no positions for them m, according to Daniel L. Brown, PharmD, a professor of pharmacy practice at the Lloyd L. Gregory School of Pharmacy, in West Palm Beach, Fla. P In a commentary in thee American Journal of Pharmaceutical EducaP tion ((AJPE 2013;77:90; doi: 10.5688/ajpe77590), Dr. Brown wrote that the number of new PharmD graduates is expected to reach about 15,000 annually by 2018 (compared with 7,000 in 2001). However, the job market is not keeping pace, and by his estimate will accommodate only about 10,000 to 12,000 new pharmacists per year. Hence, by 2018, 3,000 graduates (20%) per year will not be able to find employment in their field. “I don’t believe there currently is a need for more pharmacists,” Dr. Brown told PPN. ““The pipeline we’ve already got is more than enough.” However, not all educators agreed with Dr. Brown’s bleak jobs forecast. In a commentary in the same issue of AJPE, Katherine Knapp, PhD, and Jon C. Schommer, PhD, asserted that “projections, even when based on the most solid evidence available, are not inescapable outcomes.” They outlined six scenarios under which Dr. Brown’s “looming joblessness” might not happen, including rising demand for all health care services as the economy improves, and increasing retirement in the large cohort of pharmacists trained in the 1970s.

adverse effects (AEs) included grade 1/2 diarrhea (47%), grade 1/2 fatigue (28%) and grade 1/2 upper respiratory tract infections (33%). More severe AEs included pneumonia (12%), neutropenia (15%) and hypertension (5%). Six patients (7%) had to drop out of the 85-patient study due to AEs, the investigators reported. The results elicited nearly unanimous enthusiasm from the hematology/oncology community, including Nicole Lamanna, MD, an associate clinical professor of medicine in the

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Van der Linden P, Douchamps J, Schmitt C, Forget D. Ready-to-use injection preparations versus conventional reconstituted admixtures: economic evaluation in a real-life setting. Pharmacoeconomics. 2002;20(8):529-536. 2 Fanikos J. Premixed products improve safe medication practices. Pharmacy Practice News. 2011;38:56-57. 3 Maki DG, Rosenthal VD, Salomao R, Franzetti F, Rangel-Frausto MS. Impact of switching from an open to a closed infusion system on rates of central line-associated bloodstream infection: A meta-analysis of time-sequence cohort studies in 4 countries. Infect Control Hosp Epidemiol. 2011;32(1):50-58. All trademarks herein are the property of Sagent Pharmaceuticals, Inc. ©2013 Sagent Pharmaceuticals, Inc. Printed in USA 1666 PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc.

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32 Technology

Pharmacy Practice News • December 2013

Compliance

INTO THE CLOUD

‘I think this service is the first crest of a bigger wave of advanced medication adherence solutions.’

continued from page 1

of pharmacy benefit manager (PBM) feeds and other cloud-based technologies to flag patients who are most prone to not taking their medications as prescribed. Dennis Sexton, the principal and CEO of MCS Carelink, said the engine driving the service is a software program called Remedia. “The program stratifies nonadherence risk and identifies those patients who account for the highest amount of health care spending due to

—Myke R. Green, BS Pharm, PharmD, BCOP frequent readmissions.” Remedia uses daily PBM feeds to select outpatients with a higher-than-average number of emergency department visits and admissions and also scans the data for predictors of nonadherence such as multiple comorbidities, use of complex medication regimens, visits to multiple

providers and the need for frequent monitoring. The program also looks at whether patients are reaching their treatment goals for diabetes, cholesterol and hypertension. “Other risk stratification software exists, but they use data that’s sometimes up to 90 days old and is no longer

in Your Inbox

relevant,” Mr. Sexton said. “Remedia goes far beyond other software in both level of detail and breadth of capability.” The next steps in MCS Carelink’s three-part medication management process include performing medication reconciliation, using hospital discharge plans, and finding out “what’s in patients’ home medicine cabinets,” he noted. “This last source is often missed and it is so important because the three sources [often] don’t match. Sending a pharmacist into a patient’s home would definitely accomplish the mission of finding out what’s there, but it’s a costly approach.” Instead, MCS Carelink asks patients or their caregivers or family members to capture cell phone images of any pill bottles they find at home and to upload them to a secure cloud-based service called Medalogic. Pharmacists can then access the images through a secure Web portal and, pulling in the PBM data and hospital discharge regimen, they ensure there are no contraindicated, duplicative or expired medications.

A Plethora of Pillboxes ... to receive the monthly e-newsletter from

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

Once the medication reconciliation stage is complete, MCS Carelink will recommend a pillbox best suited to the patient’s nonadherence risk level. For example, those with complex regimens might use smart pillboxes that are prefilled weekly at the pharmacy or by a caregiver. These devices remind patients when to take their medication and also can alert pharmacists, family members or other caregivers of missed doses. Those with stable and simpler regimens may only need a conventional pill organizer, Mr. Sexton said. “What we’re hearing from pharmacists is that they need different interventions for different levels of patients,” he said. “Because we’re unaffiliated with any particular pillbox manufacturer and we follow the latest developments in pillbox technology, we can suggest the most appropriate solution for the patient.” Asked to give details on the projected cost of the program components, Mr. Sexton said that most of the costs are related to the Remedia and Medalogic licensing fees, which will be quoted to customers “based on which features they want.” Thus, “estimates are only released on a case-by-case basis.” As for the pillboxes, pricing can range from $35/month to hundreds a month, based on the risk level of the patient, he added. Ernest R. Anderson Jr., MS, RPh, who is a consultant located in Brockton, Mass., and who works with MCS Carelink, said health systems also should expect to incur some costs from adding staff hours for data and pill bottle image review. However, those costs—and in fact, the entire cost of the MCS Carelink program, he noted—are minimal compared with

Technology 33

Pharmacy Practice News • December 2013

Compliance the potential gains. “It’s a small price to pay for making sure patients are adherent,” Mr. Anderson said, especially given the positive impact that improved drug compliance can have on 30-day hospital readmission rates. In fact, the payment reductions that the Centers for Medicare & Medicaid Services (CMS) can levy against hospitals that fail to stay under the 30-day readmissions ceiling established by CMS “can quickly add up,” he said. “Is drug compliance the only factor you have to consider in staying under that ceiling? Of course not, but it’s certainly a big piece of the puzzle.” Mr. Sexton noted that the potential cost savings from the MCS Carelink initiative also can accrue from the entire patient care continuum, including emergency room visits, total hospital stay, physician office visits, home health care visits, lab tests, imaging studies, etc.

‘What we’re hearing from pharmacists is that they really need different [medication adherence] interventions for different levels of patients.’ —Dennis Sexton As for the timeline for introducing the service, “I estimate [launch by] the second or third quarter of 2014, on a paid customer basis by certain early adopters, for all components,” Mr. Sexton said.

Oncology Pharmacist’s Take Myke Green, PharmD, BCOP, who is an oncology clinical pharmacy specialist at the University of Arizona Medical Center, in Tucson, said that he sees value in the approach taken by the MCS Carelink service, in part because it addresses a downside to current medication adherence efforts by health systems—that is, the siloed approach that many hospitals take. “We are part of a 14-hospital consortium, and although we do share notes on what works for us in improving adherence, we’re all sort of creating our own different homegrown approaches,” Dr. Green said. “There’s really no cohesive strategy for tackling this problem.” He added that robust strategies for addressing medication adherence are sorely needed, especially in the oncology arena. “Patients not only have to take their oral chemotherapy agents properly, they also need to take other supportive medications, such as antimicrobials,

antiemetics and pain relievers, with a high degree of adherence in order for the overall therapy to be successful, and this pharmacotherapy regimen can be very complex,” he said. “I think this service is the first crest of a bigger wave of advanced medication adherence solutions.” —David Wild Mr. Sexton reported that he is principal and CEO of MCS Carelink. Mr. Anderson reported that he is a consultant with MCS Carelink. Dr. Green reported no relevant ﬁnancial conﬂicts of interest.

Rationale, Reversal, and Recovery of Neuromuscular Blockade Part 1: Framing the Issues Case Study Harold is a 74-year-old man undergoing a video-assisted right upper lobectomy for stage I non-small cell lung cancer. Current Symptoms • Dyspnea • Coughing with hemoptysis • Chest pain Vital Signs • Height: 177.8 cm (70”) • Weight: 65 kg (143 lb) Signi¿cant Medical History • Hypertension • Chronic obstructive pulmonary disease (moderate) Current Medications • Metoprolol succinate ER 50 mg/d • Tiotropium bromide inhalation powder Laboratory Results • 2-cm lesion in right upper lobe revealed on chest computed tomography (CT) scan; malignancy con¿rmed with needle biopsy • No abnormal bronchopulmonary or mediastinal lymph nodes; brain CT, isotopic bone scan, abdominal ultrasonography negative for distant metastases • Forced expiratory volume in the ¿rst second: 43.6% of predicted value (1.44 L) • Carbon monoxide diffusing capacity: 71.7% of predicted values (20.19 mL/min/mmHg) • Cardiac ultrasonography: normal pulmonary artery pressure (22 mm Hg) At induction, Harold receives propofol 1.5 mg/kg and rocuronium 0.6 mg/kg. During the procedure, movement of the diaphragm interferes with surgery. This activity is jointly sponsored by Global Education Group and Applied Clinical Education. Supported by an educational grant from Merck.

Applied Clinical Education is pleased to introduce a new interactive 3-part CME series featuring challenging cases in neuromuscular blockade. Each activity will present a clinical scenario that you face in your daily practice. After reading the introduction to the case, consider the challenge questions, and then visit www.CMEZone.com/nmb1 to ¿nd out how your answers stack up against those of our multidisciplinary faculty panel. Access the activities on your desktop, laptop, or tablet to explore the issues surrounding safe, effective, neuromuscular blockade and reversal via a unique multimedia learning experience and earn 1.0 AMA PRA Category 1 Credit.™ Participate in the coming months as well to complete the whole series and earn a total of 3.0 AMA PRA Category 1 Credits.™ This activity’s distinguished faculty Jon Gould, MD Glenn S. Murphy, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Clinical Professor, Anesthesiology University of Chicago Pritzker School of Medicine Director Cardiac Anesthesia and Clinical Research NorthShore University HealthSystem Evanston, Illinois

Challenge Questions 1. What would you do next? 2. What potential postoperative risks does this patient face?

Access this activity at www.cmezone.com/nmb1

34 Technology

Pharmacy Practice News • December 2013

Automation

SMARTER PUMPS continued from page 1

occasionally programmed short, continuous infusions as high as 90,000 units per hour—doses that Dr. Balliu called “way too high.” That’s where the hard limits, which cannot be overriden, came in—specifically, a low hard limit of 200 units per hour and a high hard limit of 3,000 units per hour. If clinicians need to administer larger doses of heparin, she said, they must now select a separate setting with a hard limit range of 3,001 to 4,500 units per hour. Removing soft limits not only diminished the potential for IV drug administration errors, Dr. Balliu said, it also can reduce alert fatigue. Whenever clinicians exceed soft limits, the pumps generate alerts—and if alerts become too commonplace, they may not be treated as if they are clinically important, she explained. “Our goal is to improve the significance of the alert received,” Dr. Balliu added. “The medication files that generate the highest number of alerts are being modified to decrease [those] alerts.” When smart pumps were first introduced at the Cleveland Clinic in 2010, soft limits were overridden about 28% of the time, according to Dr. Balliu. Over the next few years, lower soft

Figure 1. IV Pump Safety Day communication process.

limits were eliminated for medications that require patient monitoring, such as norepinephrine. Now, clinicians at the health system override only about 6% of soft limits, she reported. Moreover, fewer overrides result in fewer alarms, which appears to have decreased alert fatigue. A July 2013 survey of more than 900 health care providers at the Cleveland Clinic found that 89% of users consider smart pump alerts to be clinically significant. “Of course,” Dr. Balliu said, “there’s still room for improvement.” But hard limits aren’t always the answer, said Susan J. Skledar, RPh, MPH, a professor of pharmacy and therapeutics at the University of Pittsburgh. “Your instinct is to have lots and lots of hard

stops, but you have to be choosy when using them,” she told Pharmacy Practice News. “What we don’t want to do is set up barriers to interventions.” If practitioners encounter too-frequent hard stops, Ms. Skledar said, they may choose to bypass the pumps’ guardrails completely. “If the library of smart pump limits is confusing, or it does not match practice, it can be very frustrating for nurses,” added Cynthia Niccolai, PharmD, a clinical pharmacist at the University of Pittsburgh Medical Center.

From Server to Pump To Practice At a large health care system such as Indiana University Health (IUH), which consists of 19 hospitals through-

Key Points 1. IV Pump Safety Day is the third Wednesday of the month. 2. Tier 1 contacts are the facility individuals to whom the Alaris pump library update coordinator sends the pump library notice. Tier 1 contacts include facility leadership and the pump safety point person for the facility. 3. Tier 2 contacts are those individuals on the tier 1 contact’s distribution list and include managers, directors, associate administrators and the unit/area pump safety champions. 4. Tier 3 contacts include the unit/area staff. 5. On Friday after the Wednesday pump library update, the Alaris pump library update coordinator sends the saturation report to tier 1 contacts. Facility staff then work to optimize saturation. 6. On the Wednesday following the pump library update, the Alaris pump library update coordinator sends the saturation report to tier 1 contacts. Facility staff then work to optimize saturation.

Figure 2. Communication flow for IV Pump Safety Day.

out Indiana, putting new limits into practice is no small task, in part because each pump must load dosing updates from a database on the hospital server. “We have had errors reported when patients are transferred between [IUH] facilities, due to different pump hardware and software versions, different data sets, different dosing units, different drug concentrations,” said Jennifer Reddan, PharmD, the director of the Center for Medication Management at IUH, during the ISMP seminar. “And we’ve also had errors reported due to the length of time it takes to capture and upload pump data set changes.” Many delays occurred as a result of care team members misunderstanding the way updates work—not all practitioners realized that smart pumps must be manually updated, Dr. Reddan noted. For the Alaris CareFusion pumps used at IUH, she said, loading updates requires a six-step process that involves turning each pump off and on. If a pump is administering medication to a patient, then that pump cannot be updated at that time. Dr. Reddan suggested discreetly flagging these pumps in a way that does not cause patient concern but informs clinicians that the machines are awaiting a new data set. To ensure system-wide compliance, the IUH designated the third Wednesday of each month as “Pump Safety Day.” On this day, the hospital pharmacy manager releases a new data set over the server and posts reminders to the hospital intranet informing clinicians to update pumps. Several additional steps are taken to ensure that details of programming updates are communicated to key members of the care team (Figures 1 and 2). In August 2013, one week after a Pump Safety Day, 77.1% of pumps had the new data set loaded. Before the institution of Pump Safety Day, similar compliance rates would have taken about six weeks to achieve. Establishing a multidisciplinary smart pump group is a key way hospitals can improve the setting and implementation of limits, Dr. Reddan said. “Working closely with the nursing staff and the bedside nurses helps tremendously,” she said, because pharmacists don’t always have the same perspective. “You really need those voices in your group.” “Smart pumps are primarily nursing tools to enhance medication safety at the bedside,” Dr. Niccolai said. To maximize a pump’s effectiveness, she added, “the pharmacist should build a drug library promoting [bedside] safety while not burdening the nurse with numerous unnecessary alerts.” —Ben Guarino Drs. Balliu, Niccolai and Reddan and Ms. Skledar reported no relevant ﬁnancial conﬂicts of interest.

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Pain, Sedation, and Delirium In the ICU: The Pharmacistâ&#x20AC;&#x2122;s Role DAVID J. GAGNON, PHARMD Postgraduate Year 2 Pharmacy Resident, Critical Care

GILLES L. FRASER, PHARMD, FCCM Clinical Specialist, Critical Care Maine Medical Center Portland, Maine

he American College of Critical Care Medicine and the Society of Critical Care Medicine recently published updated clinical practice guidelines for the management of pain, agitation, and delirium (PAD) in critically ill adult

patients.1 The new guidelines were formulated using robust methods and included practice advancements that occurred since the last iteration of the guidelines in 2002.2 The purpose of this review is to examine the role of pharmacists in managing PAD in the ICU and to help translate best evidence into clinical practice.

PAD Guidelines In 2006, a task force of experts was recruited to develop the PAD guidelines. Four subcommittees comprehensively examined the literature regarding analgesia, sedation, delirium, and outcomes in the ICU. Important clinical management questions were formulated and served as the basis for the 54 recommendations and statements that were published this year.3 Recommendations and statements were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method.4-6 The GRADE method enabled the experts to objectively, systematically, and transparently evaluate the literature and make recommendations based on the quality and strength of evidence. Consequently, the guidelines lack statements based solely on expert opinion. Despite the rigorous methods used to develop the PAD guidelines, limited data exist suggesting that guidelines improve outcomes.7 This is surprising and may be due in part to incomplete or inconsistent implementation.

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

Many practitioners, including pharmacists, think that practice guidelines define the standard of care; rather, they should be regarded as representative of best practice. Clinical decisions always should be made within the context of patient condition, local practice norms, and resource availability. These realistic and balanced expectations will facilitate the adaptation and implementation of guidelines on a local level. Successful efforts designed to change clinical practice consistently employ a multifaceted, interdisciplinary team approach. Pharmacists have been an instrumental part of the interdisciplinary ICU team since the 1980s.8 The financial impact, clinical expertise, and scholarly activities they offer an ICU team are well documented.9-11 The proposed duties and responsibilities of pharmacists in the ICU, which can be categorized as fundamental, desirable, and optimal, include guideline implementation and utilization (Table 1).12-15 It is imperative that pharmacists become familiar with all aspects of PAD management and how they can help

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alleviate the burden of PAD in critically ill patients. The first step is to appreciate the utility of systematic assessments of PAD with tools that have been tested for reliability and validity. Incorporating these tools into daily clinical practice will facilitate rational preventive and treatment interventions. Recommendations regarding pharmacotherapy made in the PAD guidelines are summarized in Table 2 and will be further explored below.

Pain and Discomfort IMPORTANCE Despite 2 decades of focused attention, pain continues to be the most traumatic experience reported by patients after ICU stays. Approximately 50% of medical, surgical, and trauma patients experience pain at rest, and untreated procedural pain (eg, during turning, suctioning, or wound dressing) remains a common issue.16,17 In addition to our inherent promise to provide humane care for our most vulnerable patient population, we should be mindful that unrelieved pain has clinical ramifications. The stress response from pain produces unwanted physiologic consequences including sleep impairment, hyperglycemia, inadequate tissue perfusion, vasoconstriction, impaired wound healing, and an increased risk for infection.18,19 It also has been linked to post-traumatic stress disorder (PTSD) in those discharged from the ICU.20

ASSESSMENT The PAD guidelines recommend that pain should be assessed 4 or more times per nursing shift, and additionally as needed. Recent data suggest that a systematic evaluation of pain can reduce the frequency of moderate to severe pain (by nearly 50%), the need for sedative-hypnotic agents, and ICU and hospital length of stay (LOS).21 The numerical rating scale (NRS) is considered the gold standard for pain assessment in communicative patients.22 For those who cannot self-report but have intact motor function, the use of the Behavioral Pain Scale (BPS) or Critical Care Pain Observation Tool (CPOT) is recommended. Both the BPS and CPOT have been tested for reliability and validity and assess facial expression, body movements or muscle tension, and compliance with the ventilator.23,24 Tachycardia and increasing blood pressure should not be used for pain assessment because fluctuations in vital signs are not specific to pain.25 They can, however, be used as a cue to conduct more formal pain evaluations with the valid and reliable pain assessment tools. This issue represents an important gap in clinical practice that pharmacists can help rectify, considering that less than 40% of nurses routinely perform such assessments.21

MANAGEMENT Pharmacists should play a prominent role in the treatment and prevention of pain. Pain should be addressed pharmacologically or nonpharmacologically within 30 minutes of identification and reassessed with the NRS, CPOT, or BPS. The preemptive treatment of pain before

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potentially painful procedures is imperative and also should include both pharmacologic and nonpharmacologic modalities. Nonpharmacologic options are attractive because they are analgesic-sparing, low-cost, and devoid of adverse effects. Unfortunately, nonpharmacologic treatments have been poorly studied in ICU patients.26 A recent review of nurses and patients found that music therapy, simple massage, and family presence may offer relief.27 If these measures are not effective, pharmacologic therapy is necessary. The PAD guidelines highlight the differences in the management of non-neuropathic and neuropathic pain. For non-neuropathic pain, all IV opioids appear to be efficacious when they are titrated to a desired pain intensity score. Neuropathic pain treatment should involve the enteral administration of gabapentin or carbamazepine in addition to IV opioids. The value of adjunctive pain medications including acetaminophen should not be underestimated. Pharmacists are encouraged to review other authoritative sources for information about the practical application of analgesics in the ICU.26,28 Analgosedation, an analgesic-first approach for comfort and sedation, is advocated in the guidelines. Analgosedation, typically with a short-acting IV opioid, can obviate the need for sedatives, control pain that may be difficult to assess, and may improve outcomes.29,30 It also is likely that analgosedation facilitates earlier patient mobilization, which can reduce the incidence of delirium and facilitate ICU discharge.31 Pharmacists should be alert for the adverse effects of opioids (eg, respiratory depression or reduced gastrointestinal motility) when employing analgosedation and offer remedial strategies, such as patient-specific titration and effective bowel regimens. It is not uncommon for patients to develop tolerance or hyperalgesia when treated with opioids in the ICU.32,33 During these situations, pharmacists can suggest rotating opioids (eg, switching from fentanyl to hydromorphone), which has been successful in cancer patients.34,35 Transitioning from IV fentanyl to enteral methadone also is feasible and has been shown to facilitate ventilator weaning and ICU discharge.36,37 Overall, the management of pain and analgesia should be guided by routine evaluations with valid and reliable scales. Pain medications should be used if there are indicators of pain at rest, as part of analgosedation and before all potentially painful procedures. Analgesics should be titrated to patient-specific needs to ensure the delivery of compassionate care.

Agitation and Sedation IMPORTANCE Prospective cohort studies have identified agitation as an independent risk factor associated with more frequent sedative and opioid administration, longer ICU LOS, greater time on a ventilator, more nosocomial infections, and unplanned medical device removal.38,39 The identification and treatment of possible underlying etiologies such as pain, delirium, hypoxia, and substance

Table 1. Duties of Pharmacists in an ICU Fundamental

Desirable

Optimal

Prospective drug therapy evaluation for allergies, dose, indication, and interactions

Regular rounding to provide drug therapy information to staff and patients

Assist physicians in speaking with families about clinical decision making

Provide pharmacokinetic monitoring

Complete medication reconciliation

Deliver accredited education sessions (grand rounds or continuing education)

Provide drug information and IV compatibility information

Participate on the advanced cardiac life support team and respond to all codes

Develop residencies or fellowships in critical care pharmacy

Provide drug therapyâ&#x20AC;&#x201C;related education

Provide didactic lectures on pharmacology and therapeutics

Educate the community or lay persons about critical care pharmacy

Act as a liaison to educate team on policies, guidelines, and pathways

Train pharmacy students, residents, and fellows

Evaluate the effect of guideline implementation

Implement policies, protocols, and procedures

Participate in critical care pharmacotherapy research

Secure funds for conducting research

Identify how drug costs can be minimized

Participate on committees or work groups

Publish research in peer-reviewed medical journals

withdrawal form the basis for ICU agitation management. Ideally, traditional sedatives should be reserved for refractory cases or when analgosedation has failed.

ASSESSMENT The PAD guidelines strongly recommend that agitation and sedation be routinely assessed 4 or more times per nursing shift, and additionally as needed. Data suggest that systematically evaluating for agitation can reduce its incidence by 33%.40 As with pain and delirium, the assessment of agitation and sedation should be done using valid and reliable scales. The PAD guidelines recommend the Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS), which have been tested for reliability and validity.41,42 A recent psychometric evaluation of these scales further demonstrated their equivalence.43 Despite this, the RASS and the SAS may have clinically important inherent differences related to the evaluation of wakefulness. Wakefulness (the ability to purposefully perform 3 of the following: open eyes, maintain eye contact, squeeze hand, stick out tongue, and wiggle toes) as a sedation goal should be achieved at least once per day.1 Targeting wakefulness may reduce time on the ventilator, ICU LOS, and the development of delusional memories or PTSD.44-48 These improvements may be due to less accumulation of sedatives and their active metabolites, enhanced patient participation in care, and the attainment of more accurate pain and delirium assessments. Intrinsic to the use of the SAS is an assessment of wakefulness, especially at a SAS of 3, which indicates that a patient has responded to verbal stimuli or gentle

shaking and obeyed simple commands.49,50 RASS assessments for sedation depth, on the other hand, are predicated entirely on eye opening, eye contact, and body movement.41 The implications of these differences are most pronounced when wakefulness is the sedation goal.

MANAGEMENT Provision of adequate analgesia, reorientation to the surrounding environment, and maintenance of a normal sleepâ&#x20AC;&#x201C;wake cycle should be optimized before sedatives are administered. When indicated, benzodiazepines, propofol, and dexmedetomidine are the most frequently used sedatives in the ICU.51 The PAD guidelines emphasize that the way sedatives are used is as important as the choice of agent. Daily sedation interruption or targeted sedation strategies can promote patient wakefulness. Sedation protocols often are developed to assist providers in reaching these goals. One study confirmed that about 30% of institutions do not use sedation protocols.52 Another study found that daily sedation interruption was not used in 40% of ICU patients.53 A way to improve adherence is to use a daily, pharmacistenforced sedation protocol. Such a protocol has been shown to reduce ICU and hospital LOS, as well as the number of days spent with mechanical ventilation.54 One of the more intriguing statements made in the guidelines is that non-benzodiazepines (propofol or dexmedetomidine) may be preferred sedatives because benzodiazepines are associated with worse clinical outcomes (eg, increasing ICU LOS by 0.5 to 1.6 days and time on the ventilator by 1.9 days) when compared with propofol or dexmedetomidine.1,55 These differences in

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Table 2. Recommendations in the PAD Guidelines Pertaining to Pharmacotherapy

Recommendationa

Pain and analgesia

Preemptive analgesia and/or nonpharmacologic interventions should be administered to alleviate pain during chest tube removal

+1C

For invasive and potentially harmful procedures in adult ICU patients, preemptive analgesics and/or nonpharmacologic therapy should be used

+2C

IV opioids should be considered first-line drugs for the treatment of non-neuropathic pain in adult ICU patients

+1C

All IV opioids are equally effective when titrated to similar pain scores

Nonopioid analgesics should be considered to decrease the amount of opioids administered and to decrease opioid-induced adverse effects

+2C

Enterally administered gabapentin or carbamazepine should be considered in addition to IV opioids for neuropathic pain

+1A

Non-benzodiazepine sedatives may be preferred over benzodiazepines to improve clinical outcomes in mechanically ventilated patients

+2B

Sedative medications should be titrated to maintain lighter rather than deeper levels of sedation, unless clinically contraindicated

+1B

The use of haloperidol or atypical antipsychotics to prevent delirium is not recommended

-2C

No evidence has been published to show treatment with haloperidol reduces duration of delirium in the ICU

No evidence

Atypical antipsychotics (quetiapine) may reduce the duration of delirium in the ICU

Administration of rivastigmine to reduce duration of delirium is not recommended

-1B

Use of antipsychotics in patients at significant risk for torsades de pointes is not recommended

-2C

Delirium unrelated to alcohol or benzodiazepine withdrawal should be treated with continuous IV dexmedetomidine to reduce the duration of delirium

+2B

Use of analgesia-first (analgosedation) sedation in mechanically ventilated ICU patients is recommended

+2B

Agitation and sedation

Delirium

Improving outcomes a

Quality of Evidence And/or Strength Of Recommendation

Guideline Section

This recommendation should not supplant clinical judgment of the provider.

outcomes are likely related to the sluggish pharmacodynamic profile of the benzodiazepines, which limits their ability to be easily titrated to effect. Despite these data, it is important for pharmacists to continue to recommend the use of benzodiazepines when appropriate. Given their amnestic, anxiolytic, and anticonvulsant properties, the benzodiazepines can be used to treat alcohol and sedative withdrawal syndromes, and intractable seizures, or as a part of a sedative regimen when neuromuscular blockers are used.51 Intermittent boluses can offer an effective way of calming an acutely agitated patient or for transferring patients to different areas of the hospital for procedures.

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Propofol is characterized by a rapid onset and offset, titratability, and a relatively low cost, making it an attractive agent for sedation. It is preferred over the benzodiazepines because it is associated with a shorter ICU LOS and has not been implicated in the development of delirium.55 When compared with patients treated with dexmedetomidine, propofol-treated patients have similar clinical outcomes with respect to duration of mechanical ventilation, ICU or hospital LOS, frequency of hypotension or bradycardia, and mortality.56 Propofol may be best used when deep sedation is necessary (eg, during therapeutic hypothermia or complex mechanical ventilation), when frequent neurologic

assessment is necessary (eg, strokes or traumatic brain injury), when movement could be harmful (eg, open surgical sites or wounds), or when γ-N-aminobutyric acid (GABA) activity is desired (eg, status epilepticus). Pharmacists should advocate for concomitant analgesia when propofol is used because it has no analgesic activity. Patients also should be monitored for hemodynamic derangement, hypertriglyceridemia, and propofol-related infusion syndrome, which can be fatal.57-59 Dexmedetomidine is a central α2-receptor agonist with unique attributes, including sedative, sympatholytic, and analgesic-sparing properties.60 This agent produces a light level of sedation, which allows patients to interact with their environment. It is not deliriogenic and does not induce respiratory depression.56,61,62 Dexmedetomidine may be most useful in patients who require frequent neurologic assessments, have developed delirium unrelated to alcohol or benzodiazepine withdrawal, are not intubated but require sedation, or are being weaned from mechanical ventilation. Pharmacists should monitor for adverse effects, which may include hypotension or bradycardia.60 Dexmedetomidine is underused for a number of reasons, including its cost (can exceed $1,000 per day), limited FDA approval with respect to dose and duration of use, and propensity to cause hemodynamic alterations.63 Pharmacists can rely on data from several trials that have shown that doses up to 1.5 mcg/kg per hour and extended durations of therapy (>24 hours) are both safe and effective.62,64 Pharmacists can counterbalance the expense of central α2-receptor agonist therapy by transitioning selected patients who have responded well to dexmedetomidine and who have stable dosing requirements to enteral clonidine.65 In summary, the management of sedation and agitation is guided by 3 principles: systematic evaluations using valid and reliable assessment tools, the identification and achievement of comfort and wakefulness as therapeutic goals, and the use of sedatives that can be readily titrated to patient needs and effect.

Delirium IMPORTANCE Delirium may manifest in up to 80% of mechanically ventilated critically ill patients and may be responsible for up to $16 billion in annual health care costs.1,66,67 Delirium is associated with increases in mortality, ICU and hospital LOS, cost of care, and long-term cognitive impairment.68-71 A recent trial confirmed that a longer duration of in-hospital delirium is associated with worse cognitive and executive function scores 3 and 12 months after discharge.72 Despite these data, we remain in the discovery phase of understanding the pathophysiology, appropriate assessment, and management of delirium.

ASSESSMENT Delirium assessment is strongly recommended in the PAD guidelines using validated scoring tools

(Confusion-Assessment Method for the ICU [CAM-ICU] and the Intensive Care Delirium Screening Checklist [ICDSC]) during every nursing shift and as needed. The CAM-ICU evaluates 4 domains, requiring 3 of the 4 to be present to identify delirium.73 The ICDSC assesses 8 domains, with a score of 4 or more indicating the presence of delirium.74 It is important to emphasize that domains affected by sedative use are not counted when delirium scores are tabulated using the ICDSC but they are counted when using the CAM-ICU. Recent data suggest that the timing of delirium assessments in relation to the degree of sedation is important. Studies have shown that there is up to a 30% reduction in the number of patients labeled as “delirious” if patients are allowed to awaken before evaluation with the CAM-ICU.75-78 These data indicate that delirium screening may be confounded by sedation and that pharmacists should encourage delirium assessment with the CAM-ICU during interruptions of sedation to reduce overdiagnosis of delirium. The clinical implications of sedation-associated confounding of delirium assessments recently were evaluated. A study found that coma or positive CAM-ICU assessments were 10 times more likely to be reported before sedation interruption than after.79 The investigators followed study patients for 1 year and reported that patients with delirium that resolved after sedation was interrupted had nearly identical outcomes to those patients who never had delirium. These data are intriguing and suggest that sedation-related positive CAM-ICU assessments do not portend poor clinical outcomes.

MANAGEMENT Delirium management should begin with identification and treatment of the underlying etiology (eg, pain, central nervous system and metabolic disorders, infections, drugs, etc). Patients at risk for ICU delirium include those with dementia, a history of hypertension or alcohol abuse, or a high severity of illness.80 Pharmacists can evaluate for use of deliriogenic medications such as the benzodiazepines, anticholinergics, cephalosporins, macrolides, or fluoroquinolones.81,82 Nonpharmacologic interventions can be attempted, but supportive data are limited in the ICU population. The use of environmental, acoustic, and visual stimulation (eg, wall clocks, glasses, or music) has been examined.83 Promoting the sleep–wake cycle by minimizing overhead pages and dimming hallway lights during the night as well as opening window blinds and preventing napping during the day may confer some benefit.84 Ultimately, early physical and occupational therapy (ie, early mobilization) has shown the most promising results including improved clinical outcomes.31 Improved outcomes may be due to lightened sedation, less delirium assessment confounding by sedatives, and avoidance of sedation-related prolonged mechanical ventilation and ICU stay. Traditional pharmacologic treatment of delirium has focused on the use of antipsychotics.52 This practice is

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based largely on a few studies that have found modest improvements in clinical outcomes, such as number of days spent with delirium, but have failed to show improvements in mortality or long-term cognitive function.85-87 The PAD guidelines concluded that there are limited data to support the use of antipsychotics to treat delirium and offered no formal recommendation. Pharmacologic prevention of delirium with antipsychotics has been a topic of current research. A study completed after the publication of the guidelines found that IV prophylactic haloperidol had no effect on the duration of delirium or coma or other clinical outcomes.88 These data support the stance within the guidelines that no recommendation could be offered for the prevention of delirium with antipsychotics, including haloperidol. The overall approach to delirium should start with an assessment during wakefulness with a valid and reliable tool. If delirium is detected, identification and removal of the underlying cause should ensue. Early mobilization should be encouraged in all capable patients because it is the only strategy proven to improve outcomes. Medication therapy with antipsychotics or a central α2-receptor agonist (dexmedetomidine or clonidine) should be used only when necessary. Ultimately, there are no drugs that will reverse delirium once it is present.

Pharmacists can further contribute during the gap analysis by providing drug use evaluations, assessments of prescribing trends, and chart reviews. An interdisciplinary approach to implementing the guidelines is encouraged. Practice leaders and key stakeholders should be identified. Representation should be diverse, with members from departments that are involved with direct patient care, have administrative responsibilities, and can speak on behalf of patients and their families.51 Pharmacists should be recognized as a crucial member of this integrated implementation team. Finally, pharmacists can offer interdisciplinary education and continuous quality improvement (CQI) strategies. Real-time reminders, direct feedback during rounds, and guidance at the bedside are effective ways to educate other providers. Implementation of order sets, protocols, or pathways and care bundles are exemplary ways to promote CQI. With these tools in place, pharmacists will have the data necessary to evaluate their institution’s commitment to managing PAD. Established metrics include percentage of time patients are assessed for PAD, percentage of time patients are optimally sedated, and percentage of compliance with institution-specific protocols, among others.1,51 The result of combining education with CQI will be more desirable outcomes and improved quality of care.

Best Evidence to Clinical Practice Implementing guideline-based recommendations at the bedside is both an art and a science. The PAD guidelines leave room for variation in clinical practice and patient condition. Thus, it may be of benefit to describe how pharmacists can incorporate the PAD guidelines outside of pharmacotherapeutic recommendations. Since the conception of the first set of guidelines in 1971, authors of guidelines have sought to improve quality of care by reducing practice variations and expediting the implementation of practice advancements.7,89 The use of guidelines depends on the quality of the evidence on which they are based, actual and perceived barriers to implementation, and strategies used for integration.90 Overall, the barriers to guideline incorporation are predominantly behavioral, organizational, and economical.91 The literature is replete with studies that have examined implementation strategies.89-94 Recently, a plan–do–study–act design was used to describe the implementation of an early mobilization protocol at 3 medical centers.95,96 Structured approaches that focus on systems and interdisciplinary collaboration to make largescale changes also have been used.97 Pharmacists are encouraged to visit the Institute for Healthcare Improvement website for additional implementation techniques.98 It is important to gain insight into a health care system’s current approach to PAD before implementing the guidelines’ recommendations. A gap analysis, or a comparison of current practices with what is recommended, can assist in the development of a priority list for change.99 Discrepancies are likely to exist in pain and delirium assessment, the use of benzodiazepines and the declaration of goals of care during rounds.

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Conclusion The 2013 PAD guidelines represent a significant advancement in methods and presentation of recommendations compared with the previous iteration. Critical care team members should routinely evaluate PAD patients using valid and reliable scales, optimizing pain management and titrating sedatives to wakefulness except in patients who require deeper sedation. The benzodiazepines should be avoided as primary sedatives but can still be used in intermittent boluses when indicated. There are no effective pharmacologic treatments for delirium, but early mobilization appears to be beneficial. Pharmacists are able to facilitate implementation of the PAD guidelines by developing protocols and order sets and providing real-time reminders and direct feedback to providers. As part of CQI efforts, they also can collect data to assess established metrics. Pharmacists should embrace the introduction of each new clinical practice guideline as an opportunity to help improve clinical outcomes.

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18. Akça O, et al. Postoperative pain and subcutaneous oxygen tension. Lancet. 1999;354(9172):41-42. 19. Peterson PK, et al. Stress and pathogenesis of infectious disease. Rev Infect Dis. 1991;13(4):710-720. 20. Schelling G, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med. 1998;26(4):651-659. 21. Joffe AM, et al. Evaluation and treatment of pain in critically ill adults. Semin Respir Crit Care Med. 2013;34(2):189-200. 22. Chanques G, et al. The measurement of pain in intensive care unit: comparison of 5 self-report intensity scales. Pain. 2010;151(3):711-721. 23. Gélinas C, Johnston C. Pain assessment in the critically ill ventilated adult: validation of the Critical-Care Pain Observation Tool and physiologic indicators. Clin J Pain. 2007;23(6):497-505. 24. Payen JF, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001;29(12):2258-2263. 25. Gélinas C, Arbour C. Behavioral and physiologic indicators during a nociceptive procedure in conscious and unconscious mechanically ventilated adults: similar or different? J Crit Care. 2009;24(4):628.e7-628.e17. 26. Erstad BL, et al. Pain management principles in the critically ill. Chest. 2009;135(4):1075-1086. 27. Gélinas C, et al. Patients and ICU nurses’ perspectives of nonpharmacological interventions for pain management. Nurs Crit Care. 2013;18(6):307-318. 28. Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Crit Care Clin. 2009;25(3):431-449. 29. Strøm T, et al. A protocol of no sedation for critically ill patients

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