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Volume 41 • Number 4 • April 2014
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in this issue UP FRONT
3
Tips for coping with IV saline shortage.
POLICY
10
“Bundling” and other reimbursement challenges.
CLINICAL
14
Newer CSTDs boost chemo prep safety.
TECHNOLOGY
22
A low-cost option for bringing sterile compounding in-house.
OPERATIONS & MGMT
37 38
Improving care transitions to nursing home facilities. Creating highperformance Rx teams.
Part 2 of a Two-Part series
Abx Stewardship Succeeds in All Shapes and Sizes
CDC: Poor Abx Prescribing In Hospitals Proving Deadly I
Small size is no excuse for not having an ASP, said Roy Guharoy, PharmD, MBA, the chief pharmacy officer and vice president for St. Louis-based Ascension Health, a nonprofit Catholic
n 1945, upon accepting his ssh hare of the Nobel Prize in Physiology or Mediiccine for the discovery and isolation of penicilllin, Alexander Fleming delivered an ominous w warning: If you use antibiotics too much, thee bad b bacteria could grow resistant and the d dru ug’s lifesaving power could diminish. The U.S. Centers for Diseaasee Control and Prevention (CDC) is amo on ng many organizations now confirmin ngg Fleming’s fears and issuing a prud deent call to action. “The more we use antibioticcss, the more fuel we provide to thee fire of resistance,” said Arjun Srin niivasan, MD, the associate direccttor for Healthcare Associated Infe fecction Prevention Programs in th hee CDC’s Division of Healthcarre Quality Promotion. In its March “Vital Signs”” report (http://1.usa.gov/NvLJ-sU), U the CDC underscored the importance of antibiotics in saving lives but noted a pandemic of poor prescribing practices that is putting patients at unnecessary risk for drug-resistant infections and deadly diarrhea. The paucity of new antibiotics in the development pipeline has further heightened the urgency for improved use of today’s drugs.
see STEWARDSHIP, P page 20
see CDC REPORT, T page 18
Orlando, Fla.—Antibiotic stewardship programs (ASPs) come in all shapes and sizes, but the successful ones usually share at least one trait: the ability to track the patient-care benefits that accrue from pharmacistcoordinated interventions. At the American Society of HealthSystem Pharmacists 2013 Midyear Clinical Meeting, ASP coordinators presented a wide range of such benefits, including a 39% decrease in Clostridium difficile infections, hundreds of thousands of dollars in cost avoidance and a nearly sixfold increase in the use of indicated broad-spectrum antimicrobial regimens.
Small Yet Successful
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EDUCATIONAL REVIEW
Medication Errors: A Year in Review See insert after page 40.
NOW AVAILABLE! Our brand new iPad app!
Cedars-Sinai Takes A Team Approach To Pain Treatment Atlanta—Better pain management does not necessarily require more drugs, an initiative at Cedars-Sinai Medical Center, in Hollywood, Calif., has demonstrated. The health system has improved patient satisfaction by fostering collaboration between patients and providers, having patients set their own treatment goals and expectations, balancing the needs of pain
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see TEAM APPROACH, page 36
Effective Pharmacy-Led Discharge Plans Share Some Common Traits
H
ospital leaders looking to build a successful pharmacist-coordinated discharge process could do a lot worse than to consider the examples of veterans who presented “best practices” for the discipline at the fall leadership and December meetings of the American Society of Health-System Pharmacists (ASHP). The successes included 31 hospital readmissions prevented annually, for a projected savings of $400,000; a 45% increase in enrollment in a hospital’s home prescription delivery service; and a 44% increase in
patient satisfaction about timely access to discharge medications. To have a shot at such positive outcomes, however, a hospital needs to make a smart start, according to Linda S. Tyler, PharmD, FASHP, the administrative director of pharmacy services at the University of Utah Hospital & Clinics, in Salt Lake City. A good first step, she told attendees of the leadership conference, is to ask, “What’s the ideal? Where are the gaps, and what’s preventing us from getting there?”
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Spotlight on Bleeding Management
see DISCHARGE, page 34
New Product Teva introduces Moxifloxacin HCl Tablets
Section b begins on p pa age 24
See page 12
PATIENT SAFETY. PharMEDium’s single highest priority.
PharMEDium.com | 1-800-523-7749 twitter.com/pharmedium © PharMEDium Services, LLC 2014 P10377
Up Front 3
Pharmacy Practice News • April 2014
Capsules
Clinicians Look for Ways To Ease Effects of Saline Shortage
A
shortage of IV sodium chloride solution has struck hospitals across the United States, forcing some clinicians to adopt conservative saline measures and/or to turn to alternative products. To ascertain the effect of the shortage, the American Society of Health-System Pharmacists (ASHP) surveyed U.S. pharmacy directors earlier this month. Of the pharmacists who responded, 76% reported that the shortage has affected their institutions. Among the pharmacists affected by the shortage, slightly more than half said conservation efforts have been sufficient to preserve supplies. Pharmacists who indicated their supply of saline was inadequate to fulfill patient needs, on the other hand, represented 29% of respondents. “While the survey does not point to patients being harmed as a result of the shortage, such a severe shortage of this widely used intravenous solution is extremely concerning,” said Paul W. Abramowitz, PharmD, ScD (Hon.), the chief executive officer of ASHP, in a Feb. 11 statement. The ASHP survey revealed that the shortage has had a wider influence on certain areas of care than others. An impact on surgery and perioperative care was reported by 64% of pharmacists, whereas 10% of respondents cited an impact on pediatric care. At St. Jude Children’s Research Hospital, in Memphis, Tenn., clinicians are “weathering the storm,” said William L. Greene, PharmD, St. Jude’s chief pharmaceutical officer. “Conservation efforts have focused on minimizing waste, especially at the bedside, where
surf
allowing longer hang times [up to 48 hours] of simple solutions reduces the need for replacement,” Dr. Greene said. Although changing IV bags at 24 hours is a common infection control method due to the perceived increase in risk of contamination over time, a 2009 study found no relationship between length of infusate use and bacterial colonization (J Clin Nurs 2009;18:3022-3028). Lactated Ringer’s solution, dextrose and other fluids may provide health care systems with alternatives to saline, which 64% of the ASHP survey population report using. But these are not always good substitutions for sodium chloride solution, Dr. Greene noted; certain medications compatible with saline are incompatible with dextrose, for example, including the antifungal agent caspofungin, as well as the antibiotics daptomycin and meropenem. The lack of saline also has started to put pressure on the supply of substitute options. “We’re beginning to see that it’s more difficult to obtain some of the alternative fluids,” Dr. Greene said, “but it’s not elevated to the point where anyone would call it a shortage.” The FDA, meanwhile, is pursuing the importation of sodium chloride, and other forms of saline may be available. Compounded saline or 0.45% sodium chloride solution, for example, could be used as alternatives to 0.9% saline, said Bona E. Benjamin, BS Pharm, the director of medication-use quality improvement at ASHP. For health care systems that choose to use compounded sodium chloride, purchasers should “make sure [saline] is compounded
APRIL 2014
watch
The five most-viewed articles last month on pharmacypracticenews.com:
‘We’re beginning to see that it’s more difficult to obtain some of the alternative fluids.’ —William L. Greene, PharmD by an ethical, licensed pharmacy that observes sterile standards,” she said. There are few details regarding why saline is in short supply. “Apparently, one manufacturer had some production problems, and that shifted demand to other providers,” Dr. Greene said. “This strain on supplies was accentuated when another manufacturer had a scheduled shutdown … for maintenance purposes. Production levels simply have not returned to levels which meet demand.” —Ben Guarino
1. It’s Time To Stop Fighting Specialty Pharmacy 2. Pharmacy Residents Show Their Worth in Geriatric Clinic 3. Amitriptyline “Arguably” Effective for Functional Dyspepsia 4. Telemedicine Shows Satisfaction and Safety 5. Medical Homes Get Spruce-Ups From Pharmacists Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.
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Volume 41 • Number 4 • April 2014 • pharmacypracticenews.com
ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY
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4 Up Front
Pharmacy Practice News • April 2014
Opinion
Is It Time To Put ‘RMP’ on Every Drug Label? Rashmikant Patel, PharmD Pharmacist
Seta Socheata San, PharmD Pharmacist Los Angeles County Rancho Los Amigos National Rehabilitation Center
M
edications can prevent, mitigate, and, in some cases, even cure a wide range of medical conditions. But each drug presents a unique set of challenges in achieving an acceptable benefit-to-risk ratio. One of the most vexing of those challenges is to adequately account for the degree to which renal and hepatic dysfunction may adversely affect drug metabolism. This is a particularly acute problem in elderly patients, who often have impaired renal and hepatic function and who may take many medications for multiple diseases. In such patients, elimination of a drug can be severely compromised, leading to potentially toxic adverse reactions, compromised patient outcomes and excessive health care costs. It, therefore, is critical to account for these variables in drug metabolism if we are to ensure successful outcomes. But elderly patients should not be our only concern. Pregnancy is another condition that can affect drug metabolism significantly and should be factored into the drug prescribing and management equation. The question is how do we systematically ensure that all of these factors are indeed considered by prescribers? We have developed a simple drug labeling tool that we feel can accomplish this important goal. Specifically, we are proposing that all drug labels carry the following information as an aid to prescribers: • R = Renal • M = Metabolism/hepatic function • P = Pregnancy The “RMP” label, as we call it, should be printed on all medication bottles, in much the same way that National Drug Codes (NDC) are listed. This will help ensure that patients with impaired renal or hepatic function are given appropriate doses, and it will provide a final check on whether a patient is pregnant and, thus, in need of dosing adjustments or if there is a contraindication to such use. Here are some additional considerations for why each of these individual labeling categories is needed:
R–Renal: The number of patients with chronic kidney disease (CKD) is increasing steadily, in part due to the aging population. This trend is likely to continue, in part related to advances in dialysis technique and medication development, both of which have resulted in increased survival and quality of life possible for patients with CKD. In 2002, the National Kidney Foundation issued guidelines for staging CKD.1 According to the guidelines, there are five stages: • Stage 1: Normal or slightly increased glomerular filtration rate (GFR) or some form of kidney damage (90 mL/min/1.73 m2 or higher) • Stage 2: Slightly decreased GFR (60 to 89 mL/min) • Stage 3: Moderately decreased GFR (30 to 59 mL/min) • Stage 4: Severely decreased GFR (15 to 29 mL/min) • Stage 5: Kidney failure (less than 15 mL/min; or dialysis) For purposes of the RMP code, R will be defined as: • R0: No renal adjustment is necessary for a given drug because it is not renally cleared • R1: Creatinine clearance (CrCl) is 60-75 mL/min; may or may not need dose adjustment • R2: CrCl is 30-59 mL/min; need dose adjustment • R3: CrCl is 20-29 mL/min; need dose adjustment • R4: CrCl is less than 20 mL/min; need dose adjustment M–Metabolism: Most drugs are eliminated from the body, at least in part, by being chemically altered (i.e., metabolized) to less lipid-soluble products that are excreted via the kidneys or liver. Cytochrome (CYP) P450 enzymes affect the metabolism of approximately 75% of all drugs, with the CYP3A subfamily accounting for half of this activity.2 Many drugs have been
Placing the RMP code on each medication bottle (similar to how the National Drug Code is listed) would provide clinicians easy access to information regarding a specific drug’s effects on renal and hepatic function, as well as safety in pregnancy. identified as inducers and/or inhibitors of CYP enzymes. Clinically significant interactions often can occur when CYP-affected drugs are used in combination—especially when one of the medications has a narrow therapeutic index, thus causing decreased or increased metabolism of the involved substrate.2 Thus, the metabolism of a drug is a very important factor to consider before a medication is prescribed; hence we have included it in our drug labeling tool. For purposes of the RMP code, M will be defined as: • M0: Drug is not metabolized by the liver
Examples of RMP Codes Carbamazepine R1M1 PD This drug induces hepatic enzymes that increase metabolissm of other drugs. It is excreted in the urine. Renal: Data not available Hepatic: Data not available Pregnancy: Category D
Lisinopril R3M0PC-D Renal:
This drug needs renal adjustment in patients with CrCl <30 mL/min Hepatic: No adjustments are needed Pregnancy: Category D in first and second trimesters
• M1: Data are not available • M2: Data are not available; may need dose adjustment • M3: The benefits of use may be acceptable despite risk (i.e., in lifethreatening situations or for serious diseases for which safer drugs cannot be used or are ineffective) • M4: Drug is contraindicated in liver diseases In addition to these numbered labeling designations, the M label also will have an arrow-up or arrow-down symbol to denote whether the drug is a metabolic inducer or inhibitor. This will allow clinicians to adjust medications or dosages, if necessary, in patients who are taking other medications that are affected by inducers or inhibitors. This action will help to avoid drug–drug interactions, reduce side effects and reduce the risk for subtherapeutic dosages. P–Pregnancy: g y Given the fact that medications are able to cross the placenta to some extent, there is a risk that drugs administered to parturients can harm the fetus. Indeed, the fetuss always must be kept in mind m as a potential uninttended recipient off a given drug. This is an imporT tant clinical issue because th he fetus does not
Up Front 5
Pharmacy Practice News • April 2014
Letters
What’s Really y Behind the Specialty Pharmacy Juggernaut? To the Editor: read the article, “It’s Time To Stop Fighting Specialty Pharmacy,” by Bonnie Kirschenbaum (February, page 26), and found it appalling that the author chose to have such a limited focus and apparently a lack of understanding of the implications associated with the current path that some insurance companies and manufacturers are taking in regard to specialty pharmacy. First, I would be interested in understanding Ms. Kirschenbaum’s thoughts of how the current path of specialty pharmacy will affect hospital revenue; after all, her standing column, “Reimbursement Matters,” implies that she is an expert on reimbursement issues, and yet she chose not to address that angle in her column. Second, I would be interested in the author’s views on who should determine which pharmacies/pharmacist can or cannot buy limiteddistribution drugs. It is my understanding that state boards of pharmacy have the authority to determine whether a specific pharmacy is licensed or not and which pharmacists are qualified to purchase, inventory and dispense drugs. It appears that this new approach—allowing manufacturers and insurance companies to make those decisions—is more in line with protecting the corporate entity rather than protecting public interest. I am also finding it difficult to understand how an insurance company can mandate where a patient gets his or her prescriptions filled when there are state laws that prohibit others from directing patients to specific pharmacies. I do agree with the author’s concern about patient care, but I think she totally misses the obvious differences between the motivation of health-system pharmacists (providers) and for-profit entities (manufacturers and insurance companies).
I
have fully formed organs and other body systems during many stages of pregnancy, and those systems can be adversely affected by certain drug regimens. For purposes of the RMP code, P will be defined using the following categories, based on FDA categories that have been published and adapted in various drug information resources3: • PA: Controlled studies in women do not demonstrate a risk to the fetus in the first trimester; there is no evidence of risk in later trimesters; and possibility of fetal harm appears remote. • PB: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than decreased fertility) that was not confirmed in controlled studies in women in the first trimester (and no evidence of risk in later trimesters). • PC: Animal reproduction studies have documented adverse effects on
The other obvious point that Ms. Kirschenbaum fails to address is that affordable care must begin with affordable drugs and equipment and that specialty pharmacy initiatives are more about protecting manufacturers’ investment in research and development than in ensuring that care is affordable and accessible. After all, what good is it to have specialty pharmaceuticals if no one can afford to pay for them? In addition, health-system pharmacists have been successfully delivering specialty care with complex drugs for years and are proficient in acquiring, storing, dispensing and monitoring sophisticated drug therapies (i.e., heparin, colony stimulating drugs, etc.). Wouldn’t it be more affordable and prudent to use existing delivery channels that work than to create limited-distribution channels that fragment the continuity of care and prevent providers from participating? Perhaps a more appropriate focus would have been to describe the merits of allowing qualified health-system pharmacists to participate in limited-distribution and specialty pharmacy supply channels similar to what is being proposed by the UHC Specialty Pharmacy Collaborative. I don’t know what motivated Ms. Kirschenbaum to write—and you to publish—such an unbalanced article, but it appears that you both are out of touch when it comes to this topic. Steven Ciullo, BPharm, MS, MPS Syracuse, NY Editor’s note: To Mr. Ciullo’s point regarding the UHC Specialty Pharmacy Collaborative, Pharmacy Practice News covered the initiative in a previous issue: “Specialty Pharm Carve-out May Be Eased by UHC Plan” (November
the fetus, but there are no adequate and well-controlled studies in women. A drug should be given only if the potential benefit justifies the potential risk to the fetus. • PD: There is positive evidence of human fetal risk based on adverse reaction data from studies in humans, but the potential benefits of use in pregnant women may be acceptable despite the risk (e.g., in a life-threatening situation or use is for a serious disease for which a safer drug cannot be used or is ineffective). • PX: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks of using the drug in pregnant women clearly outweigh potential benefits.
A Worthy Endeavor Placing the RMP code on each medication bottle (similar to how the National Drug Code is listed) would provide clinicians easy access to infor-
2013, page 1). In that same issue, we also explored some of the downsides to specialty pharmacy: “White Bagging of Specialty Drugs Draws Some Ire” (page 36). We feel these articles presented a balanced treatment of the topic in our reporting. It’s also worth pointing out that Ms. Kirschenbaum is a columnist, not a reporter, and thus is free—indeed encouraged—to inject her own views into her work.
Ms. Kirschenbaum responds: The past few columns have been written to address or bring to the table many bewildering issues that are facing hospital pharmacy practitioners and often putting them into unfamiliar and uncomfortable territory. Certainly there’s angst in the pharmacy when the hospital is moving ahead with new models, and specialty pharmacy is no exception. The tremendous expense of new drugs for the patient, the practice site and the payer’s concerns over cost control have ramped up discussions of how to handle this growing market force. However, rejecting change and clinging to past practices may not be the prudent thing to do in a health care environment that is charging ahead. There’s no question that the phrases “specialty pharmacy” or “white bagging” or “brown bagging” will stir up emotions and a myriad of comments and opinions. And yet some larger multi-facility organizations or teaching facilities have opted to establish a specialty pharmacy within their organizations to service their patients. Others have vetted specific specialty pharmacies with whom they work when necessary. Granted, still others have chosen not to play in this field at all or are dreading change. I’m not suggesting that any one of these responses is necessarily the “best” strategy for dealing with this market trend; that’s a decision each hospital or health system has to make on its own. But the reality is that specialty pharmacy, specialty pharmaceuticals and restricted drug distributions systems, play a major and ever-expanding role in the management of health care dollars spent on medications. The hospital pharmacy or ambulatory care practitioner needs to recognize this dizzying degree of change and decide how to play in the newly designed sandbox. Of course, it’s the patients and their needs that must come first!
mation regarding a specific drug’s effects on renal and hepatic function, as well as safety in pregnancy. This will help encourage prescribers to be more aware of their patients’ renal and hepatic function and take those factors into consideration when deciding on drug doses. This, in turn, will help to decrease adverse effects of the medications and, ultimately, reduce the number of emergency room visits and hospitalizations caused by drug toxicity. The RMP code also will play an important role in preventing worsening of renal and hepatic function. There are some challenges, however, in implementing RMP labeling. It likely will be difficult to establish RMP codes for each drug, in part because the process may need to be coordinated with the FDA—a process that may raise significant regulatory and logistical issues. Moreover, at this point, we are not able to calculate an exact dose for liver function; however, knowing what percentage of a drug is eliminated by the liver allows clinicians to adjust medication doses along with their clinical
experience. Becoming familiar with the various stages of liver disease4 and how they affect drug metabolism can help promote more responsible drug dosing and prescribing. Despite these challenges, we are confident that the considerable efforts required to get RMP labeling off the ground will pay off based on improved patient outcomes. In fact, this initiative literally can be a lifesaver.
References 1. National Kidney Foundation. KDOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 2002. http://www.kidney.org/professionals/KDOQI/guidelines_ckd. Accessed March 3, 2014. 2. Bachmann KA, Lewis JD, Fuller MA, Bonfiglio MF. Drug Interactions Handbook, 2nd ed. Hudson, Ohio: Lexi-Comp, Inc.;2004. 3. William DJ, Fuller MA, Goldman MP, et al. Drug Information Handbook, 22nd ed. Hudson, Ohio: Lexi-Comp, Inc.;2013. 4. American Liver Foundation. The progression of liver disease. http://www.liverfoundation. org/abouttheliver/info/progression. Accessed March 24, 2014.
6 Up Front
Pharmacy Practice News • April 2014
Opinion Impact of new sterile compounding law:
‘Survival of the Fittest’ for Outsourcing Facilities Rich Kruzynski, RPh, MBA President PharMEDium Services, LLC. Lake Forest, Ill.
T
he Drug Quality and Security Act (DQSA), signed into law on Nov. 27, 2013, has been a game-changer for the pharmacy compounding industry. My company, PharMEDium, had been an advocate for the new law and was the first entity to voluntarily register with the FDA in the newly created “outsourcing facility” category. As of Feb. 28, however, of the estimated 3,000 compounding pharmacies that make sterile injectable drugs, only 28, including all four of our locations, have registered, which raises a question about how many outsourcing facilities will ultimately register. The DQSA requirements for outsourcing facilities are challenging, but feasible, and we are pleased the law helps establish and strengthen FDA oversight by eliminating a patchwork of ambiguous federal jurisdiction and inconsistent state regulatory approaches, especially those related to licensing. The law itself and the subsequent FDA draft guidance for outsourcing facilities cover several aspects of the new category: registration, interim product reporting and labeling additions, all of which we are following. We also submitted letters to the agency during the draft guidance’s public comment period requesting several clarifications to help us better understand and follow the law’s requirements. As the FDA deliberates on the public comments from our company and other stakeholders, we firmly believe that in the long run the law will create greater clarity and certainty into the oversight of compounding facilities. This will result in a significant advance in the integrity of customized, compounded sterile preparations administered to millions of patients and will align all large-scale anticipatory compounding outsourcing facilities with the proper standards and requirements.
NECC Tragedy Spurs Action The impetus for the DQSA was the 2012 fungal meningitis outbreak attributed to the New England Compounding Center (NECC) that resulted in more than 750 cases of confirmed or probable fungal meningitis. A federal
investigation of outsourcing facilities followed, with the FDA and Congress determining that, in part, poor regulatory coordination and gaps in oversight may have contributed to the outbreak. The DQSA attempts to correct this situation by establishing a stronger federal oversight and enforcement role under the FDA. Most significantly for our company, the law created the outsourcing facility category under a new section 503B of the Food, Drug & Cosmetic (FD&C) Act to regulate our category. To be designated as an outsourcing facility, the entity, among other requirements, must register with the FDA. If an entity chooses not to register with the FDA, then it is technically not an outsourcing facility, and its operation will be regulated under a different section of the FD&C Act, 503A, which requires that it adhere to the requirements of a traditional state-regulated pharmacy. During a media briefing shortly after the DQSA’s passage, FDA Commissioner Margaret Hamburg, MD, urged hospitals to purchase from only FDA-registered outsourcing facilities, calling it “a critical step they can take to better ensure the health and safety of their patients.” Numerous questions remain, however, even after the law was passed, about how facilities that do not register, yet currently perform outsourcing, will be regulated. Hospitals that have partnered in the past for certain types of compounding (e.g., anticipatory non–patient-specific), may become increasingly concerned that their compounder has not chosen the 503B pathway.
Following cGMPs Is Important Piece of the Puzzle Although DQSA has certainly affected PharMEDium, many 503B outsourcing facility requirements are not new to our company. For example, PharMEDium has been registered and inspected by the FDA since its inception more than a decade ago. Moreover, as the law requires, we always have followed current Good Manufacturing Practices for pharmacy compounding. Other than registration, the FDA’s draft guidance includes several changes, including submitting a report to the agency identifying all drugs compounded by the facility during the previous six-month period. The legislation also requires additions to product labels, which we are in the process of completing. We did not have to start from scratch with the labeling because we already had incorporated the majority of the requirements into our internal labeling policies years ago.
One significant labeling change is the addition of text reading “This Is a Compounded Drug” to be added to all products, including IV containers or their packaging. We are exploring ways to give products a uniform visible representation to this requirement, which we believe will help ensure safety and transparency in the medication administration process. We also added the DQSA-required phrases in labeling of “Not for Resale” and “Hospital/Office Use Only” and incorporated the FDA’s Adverse Event Reporting website and phone number.
Encouraging Early Industry Response The health care industry’s reaction to the DQSA has been cautiously optimistic, with many experts observing that the law should have granted the FDA more oversight over outsourcing facilities: As it stands, registration as an outsourcing facility is voluntary. A “Perspective” article by Boston University School of Law Professor Kevin Outterson, JD, LLM, in the Jan. 9, 2014 edition of The New England Journal of Medicine (370:97-99) noted that the DQSA will be most effective at protecting patients’ safety if purchasers “demand that their sterile compounded drugs be sourced exclusively from outsourcing facilities regulated by the FDA.” Mr. Outterson, who was a member of the Massachusetts Special Commission on the Oversight of Compounding Pharmacies that convened after the NECC tragedy, also wrote that the decision to purchase from registered outsourcing facilities could be “included in accreditation standards and reimbursement contracts. Such a market-based response would force compounders to accede to their major customers’ demands and register with the FDA.” Hospital pharmacists, including one of our customers, Andrew J. Donnelly, PharmD, MBA, FASHP, the director of pharmacy services at the University of Illinois Hospital & Health Sciences System, in Chicago, have indicated their support for the increased federal oversight. Dr. Donnelly told us that he believes “it’s extremely important for hospitals and other health care providers to work with FDA-registered compounders as FDA has advised.” Not doing so, he said, could ultimately have patient safety, drug supply and compliance implications, which could affect accreditation or reimbursement from payors. Likewise, in a letter to hospitals and other purchasers issued shortly after the
bill’s passage, the FDA’s Dr. Hamburg echoed Dr. Donnelly’s comments by urging organizations to carefully consider the entity they select as their pharmacy outsourcing facility. “As a purchaser of compounded drugs, you can play an important role in improving the quality of compounded drugs by requiring compounding pharmacies that supply drugs to your facility to register as outsourcing facilities,” Dr. Hamburg wrote. “Once they register, you and the patients you serve can be assured that FDA will inspect these facilities on a risk-based schedule, hold them to cGMP [Current Good Manufacturing Practices] requirements, monitor the adverse-event reports they are required to submit to the agency and require appropriate labeling.” Nonetheless, many industry stakeholders still have several questions and concerns about enforcement and requirements under the law. “The addition of the outsourcing facility category will help promote the safety of products that health care providers and the public receive from compounding outsourcers,” said American Society of Health-System Pharmacists CEO Paul W. Abramowitz, PharmD, ScD (Hon.), FASHP, in a prepared press statement. “However, we were disappointed that the bill did not go further to require compounding outsourcing facilities to register with the FDA, and create clearer risk-based criteria to help the FDA identify outsourcers that are operating outside the scope of traditional pharmacy compounding.”
Building Confidence In the Category The DQSA will continue to pose challenges for outsourcing facilities as they try to interpret and meet all the requirements of the new law and forthcoming FDA final guidance. However, entities with a history of regulatory compliance that staff qualified personnel and that invest in state-of-the-art centers should be capable of adjusting to these changes. Not only will it instill confidence in the new outsourcing facility category, but it also might help prevent another national disaster like the devastating fungal meningitis outbreak. In the coming months, we look forward to contributing input to the FDA as it finalizes the DQSA guidelines. We also look forward to educating our hospital customers about this landmark legislation and how their choice of a registered outsourcing facility protects and enhances their continued commitment to superior patient safety and care. ■
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8 Policy
Pharmacy Practice News • April 2014
Formulary Management Part 2 of a Two-Part Series
With Biosimilars, More Questions Than Answers? A
s the anticipation of the influx of biosimilar medicines begins to gather momentum, health-system pharmacies need to join together to help formulate strategies for their arrival, according to Philip Johnson, MS, RPh, FASHP, the oncology director at Premier Inc. Speaking at the Institute for Safe Medication Practices’ recent webcast, “Biosimilars: The Safe Integration into the Medication Use Process,” Mr. Johnson said many questions remain to be resolved before the new biosimilars are approved for hospital formularies and oncologists and other clinicians become accustomed to using them. “How much risk are we willing to take?” he asked, “and how much restriction are we going to put on these products within our own institutions for our own patients? Until we get comfortable with them and understand them a little better,” Mr. Johnson said, “we just have to be vigilant.” The questions surrounding biosimilars should grow in urgency as more products move closer to approval. European countries already are far ahead of the United States in their acceptance of biologic alternatives. In this country, Mr. Johnson said, “We can expect that there is going to be a very rich pipeline,” particularly for oncology agents. “We know that there is going to be a significant attrition rate” as a host of new products wend their way through various trial phases, he said, “but with the pipeline we have, we can be assured that every year there are going to be new biologics and biosimilar drugs.” The willingness of health systems to substitute biosimilar products, he said, is likely to be eased by the adoption of wellestablished tools for evaluating alternatives to originator drugs. “We’ve been substituting biologic products for a long time, if you consider insulin, human growth hormone, the interferons and others,” Mr. Johnson told Pharmacy Practice News. The newer biologics and biosimilars, he added, represent a fresh opportunity for pharmacy and for oncology. “We just have to be ready for them and have our policies in place,” he said. These policies will vary from institution to institution, he said, but underlying them will be a fundamental reliance on hospitals’ pharmacy and therapeutics (P&T) committees and their formulary selection processes. He cited the guidance offered by the American Society of Health-System Pharmacists (ASHP) as an important tool for establishing effective practices ((Am J Health Syst Pharm 2008;65:1272-1283).
‘The precedent that we have is the hospital’s generic substitution and therapeutic interchange process. We should probably take that experience and apply it to the biosimilars.’ —Philip Johnson, MS, RPh, FASHP “According to ASHP, and I fully agree,” he said, “the precedent that we have is the hospital’s generic substitution and therapeutic interchange process. We should probably take that experience and apply it to the biosimilars.”
Practice Guidelines Sorely Needed Guided-use policies that include practice guidelines and off-label policies also will be important, Mr. Johnson said. These policies, he noted, “are more than just restrictions and more narrow than just across-the-board therapeutic indication policies,” he said. “There are very specific tools that need to be addressed by the institution,” including patient-specific use criteria. For example, he said, “what if the patient doesn’t qualify under the therapeutic indications of a drug, but nothing else has worked? The medical team discusses its use, they try it, it works and it can be documented. It may only work
for that patient,” he said. That is why “individual, personalized, patient-specific medication use is going to become more important and may at some point supersede therapeutic indications,” he noted, “if we’re able to get the proper genomic markers, so that we know that a specific patient will respond based on lab results, not necessarily on published indications.” The support of informatics technologies also will be critical, Mr. Johnson said, especially smart computer orderentry systems that can convey the drugs’ restrictions and dosing guidelines. “Electronic clinical pathways can help guide the selection of the appropriate drug as well as therapeutic alternatives. “And what are the label conventions within your own institution?” he asked webcast participants. “Certainly there are the label conventions on the product itself, but when you compound that drug and relabel it, how are you going to do that and how is it going to be Movement toward arrowhead involves: • Increasing data requirements for approval • Decreasing safety concerns
New biologic under full biologics license application
• Increased potential for therapeutic interchange
Interchangeable biosimilars Biosimilars
Figure. Three distinct biosimilar approval pathways: which market strategy will prevail?
documented in the electronic medical record so that people know that the drug has been substituted? Who has to be notified?” These are all questions, he said, that hopefully will be answered by informatics technology. “Will there be Risk Evaluation and Mitigation Strategies [REMS] and Elements to Assure Safe Use [ETASU]” for the new products? he asked. “There may or may not be. But there will certainly be cautions that we should all take that are REMS-like in nature.” Mr. Johnson said that payors also can be expected to play a key role in biosimilar decision making. For example, he said, “what if the payor says that three specific drugs are equivalent and we will only reimburse based on certain tests or on the cost of the less expensive drug? That is something that is yet to be determined, but I can tell you from talking to various payors that they are asking these same questions: How much risk can they take? How pharmacovigilant do they have to be before they can require or support a therapeutic indication and interchange?” “Our confidence level that these drugs are safe will be stronger if they undergo a full biologic approval process,” Mr. Johnson said, noting that the ultimate pathway for approval has yet to be determined (Figure). “The degree of confidence will probably be somewhat less with a biosimilar-based approval,” he added, but resistance to therapeutic interchange can be expected to ease as use of the products increases.
Therapeutic Interchange Is a Key Consideration James G. Stevenson, PharmD, FASHP, the director of pharmacy services for the University of Michigan Health System and the associate dean for clinical sciences at the University of Michigan College of Pharmacy, in Ann Arbor, said that although it is “highly unlikely” that any of the early biosimilars “are going to be considered interchangeable by the FDA,” health systems “will use the existing tools that we have, one of which is therapeutic equivalence,” to accomplish biosimilar substitution. “We already do this with many biologics, where the drugs are very similar but not exactly the same,” he said, “but we consider them through our formulary process and the medical staff to be therapeutic equivalents. So that allows us to automatically use the formulary process and make conversions. I believe that’s likely what we’ll see with some of the early biosimilars.” —Bruce Buckley
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10 Policy
Pharmacy Practice News • April 2014
Reimbursement Matters When reacting to CMS’ bundling and packaging changes ...
Are You Helping or Hindering Reimbursement? D
espite the flurry of reports that emerged during the debates over how the Centers for Medicare & Medicaid (CMS) would structure payments for 2014, many pharmacists were taken by surprise when confronted by the effect of the significant move to a hybrid model that combines a traditional fee-for-service approach with bundled payments. CMS’s rationale for the new payment strategy, as noted in the Federal Registerr (http://1.usa.gov/1bXBfKr), was to change hospital’s financial incentives and prod them to improve the quality of health care while cutting medical costs. Under the program, Medicare will reim-
burse hospitals at a fixed rate for all care related to an individual’s primary diagnosis, such as a patient’s need for knee replacement surgery. A hospital that delivers high-quality, cost-effective care will earn more revenue as a result of that care plan. Conversely, if the treatment results in complications, a higher rate of hospital readmissions or any other problems, the hospital will bear the cost of the additional treatments that result. Conceptually, it is vital that pharmacy understands how these bundles or packages are structured and how payment for them is determined. Simply put, the bundle or package is based on a compila-
• All non-separately payable drugs <$90/day in 2014 • Pass-through drugs • Clinic visit • Separately payable drugs • Drug administration • Accurately billed waste
Figure. What’s in your bundle? Anything missing? Source: B. Kirschenbaum
HCPCS Alert!
A
lthough for several years Healthcare Common Procedure Coding System (HCPCS) codes assigned to drugs and biologics trended with the concept of using a generic description, the advent of newer biologics and biosimilars has brought the assignment of brand-specific HCPCS codes into play. Not recognizing this and not incorporating this into your billing for drugs and biologics will drive a fatal blow to your reimbursement picture! Here are a few examples to keep in mind: Granix (tbo-filgrastim) was approved as a new biologic with its own labeled indications and not as a biosimiliar. Effective Jan. 1, 2014, the drug has its own HCPCS code (J1446) and its own billing-unit designation (5 mcg), as well as its own reimbursement rate and labeled indications. Using the HCPCS code, billing-unit designation and applying the reimbursement rate for filgrastim is not appropriate if you are using Granix. Continuing to use a miscellaneous code is not appropriate either and will result in zero reimbursement. A new CMS HCPCS code for Neupogen (filgrastim) was released in November 2013 by CMS as part of the HCPCS code-set updates that became effective Jan. 1, 2014. CMS assigned a new HCPCS code for Neupogen, J1442 injection, filgrastim 1 mcg. This new HCPCS code replaces both old Neupogen HCPCS codes of J1440 for 300 mcg and J1441 for 480 mcg. The new code has a billing unit designation of 1 mcg. It is critical to make sure billing-unit conversion is working in your systems! You must convert the dose administered into billing units to be billed: Neupogen 300 mcg = 300/1 = 300 billing units of 1 mcg (single-use vial) Neupogen 480 mcg = 480/1 = 480 billing units of 1 mcg (prefilled syringe). Key points to remember: Neupogen and Granix have different labeled indications, different HCPCS codes and different billing units assigned to them. Check your systems carefully to ensure that you’ve captured these Jan. 1, 2014 changes, to ensure maximum reimbursement. For more information, visit http://www.cms. gov/Medicare/Coding/HCPCSReleaseCodeSets/Alpha-Numeric-HCPCS.html.
tion of every drug and related materials that a facility has used for a certain procedure or treatment. Unfortunately, CMS determines the reimbursement based not only on the coding and specifics of what is submitted; the agency also takes into account historical claims data for that specific procedure in determining the dollar value of the reimbursement. This is where things can unravel quickly! If a facility has failed to present a complete picture of all products, tests and services used for a given procedure or drug regimen and, for example, underreports drug usage because of faulty billing unit conversions, then the reimbursement calculation for the bundle that emerges may very well be less than the costs of the services. Remember, this is not a water-underthe-bridge scenario: There is action that pharmacy departments can take now to ensure that they are helping ensure reimbursement to the fullest extent. At the top of the list should be remembering that all products must be accounted for by billing individually for them, regardless of reimbursement status. Why? Because it’s the only way to get an accurate picture of the cost of a procedure or clinic visit, and because other payors, including Medicaid, may continue to separately reimburse for products that Medicare doesn’t. Use of this diagram (Figure) helps prompt discussion with staff and fix the problems! Understanding how to unbundle the payment at the facility level is equally important. CMS makes one payment to the facility with the assumption that the facility will disburse the funds internally to the appropriate cost centers. Is this happening at your facility? Have you had this discussion with the C-suite?
2014 Bundles and Packages According to CMS, the agency expanded its packaged payment policies to encourage hospitals to furnish services efficiently and negotiate effectively with manufacturers and suppliers to reduce the purchase price of items and services or explore alternative group-purchasing arrangements. Promoting predictability and accuracy for services over time also is important. Payment for all packaged drugs is included in the services and procedures with which they are reported. As in past years, certain non–pass-through drugs are “policy packaged” in 2014; these include all diagnostic radiopharmaceuticals; all contrast agents; implantable biologics that are surgically inserted or implanted into the body through a surgical incision or natural orifice; and other drugs that are packaged because
“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
their per-day costs do not exceed a cost threshold that increased from $80 to $90 in 2014. New additions this year are drugs that function as supplies when used in a diagnostic test or procedure and drugs that function as supplies or devices in a surgical procedure. Although procedures described by add-on codes also are bundled, add-on codes for drug administration services and for calendar year 2014 add-on codes assigned to device-dependent ambulatory payment classifications (APCs) are exempted in 2014. I urge you to examine those drug administration fees very carefully: Are you using the right codes? Is your documentation up to snuff? Could reworking the electronic medication administration record help? Drugs that function as supplies when used in a diagnostic test or procedure. CMS will unconditionally package drugs, biologics and radiopharmaceuticals without pass-through status that function as supplies when used in a diagnostic test or procedure. This includes the currently packaged categories of contrast agents and diagnostic radiopharmaceuticals. CMS identified specific drugs that function as supplies when used in a diagnostic test or procedure that fall under this packaging policy, including stress agents and hexaminolevulinate HCl intravesical solution (Cysview, Photocure). Drugs that function as supplies when used in a surgical procedure. CMS will unconditionally package all drugs and biologics that function as supplies or devices in a surgical procedure. Skin substitute products and implantable biologic products fall within this category, although pass-through status will continue to be available to new skin substitutes that meet the pass-through criteria. Because of the significant difference in resource costs among skin substitute products, CMS divided them into two packaging groups to ensure adequate resource homogeneity among APC assignments. High-cost skin substitutes have payment amounts greater than $32 per square centimeter, are reported with Current Procedural Terminology (CPT)
•
see BUNDLING, page 12
12 Policy
Pharmacy Practice News • April 2014
Reimbursement Matters
BUNDLING continued from page 10
codes 15271 to 15278, plus the applicable skin substitute Healthcare Common Procedure Coding System (HCPCS) Q-code. Low-cost skin substitutes have payment amounts at or below $32 per square centimeter and are reported with the new set of HCPCS C-codes C5271 to C5278 and the applicable skin substitute HCPCS Q-code. Skin substitute products applied as either liquids or powders per milliliter or per milligram and employed in
procedures other than CPT codes 15271 to 15278 will not be classified as high- or low-cost but rather packaged into the surgical procedure in which they are used. Procedures described by add-on codes. Add-on reimbursement codes describe medical procedures that commonly are performed in addition to a primary procedure and that are generally supportive of, dependent on or adjunctive to the primary service (usually a surgical procedure). In 2014, according to CMS, the agency will unconditionally package the procedures described
by add-on codes with the exception of add-on codes for drug administration services and add-on codes assigned to device-dependent APCs.
What To Anticipate for 2015 Comprehensive APCs! These are a classification for the provision of a primary service and all adjunctive services provided to support the delivery of the primary service. CMS will create 29 comprehensive APCs for the 29 most costly device-dependent services. CMS delayed implementation until 2015 to give hos-
pitals more time to prepare and to give themselves more time to operationalize changes. But effective January 2015, CMS will make a single, all-inclusive prospective payment based on the cost of all individually reported codes packaged into a comprehensive APC including: • Drugs provided to the beneficiary as part of the delivery of the comprehensive service and pursuant to a physician order, regardless of the route of administration, except for drugs separately paid through a transitional pass-through payment • Devices: Implantable durable medical equipment • Implantable prosthetics • Durable medical equipment, prosthetics and orthotics when used as supplies in the delivery of the comprehensive service • Supplies used in support of these services • Outpatient department services reported by therapy HCPCS codes when those services occur within the perioperative period • Nott included: mammography services, ambulance services, brachytherapy seeds, and pass-through drugs and devices ■
Next Issue: Revenue cycle. End-to-end audits. We often hear these terms bandied about as being important, but do you really understand what they mean and why they’re important to you in the pharmacy? Don’t miss next month’s column, where I will explore the ins and outs of the revenue cycle and how the actions (or inactions) of pharmacy can have a profound impact on your health system’s bottom line.
Find us at the Intersection ctio on of Patient Safety and Pharmacy Efficiency Pharmacies juggle many critical tasks.Patient safety is top priority and operational efficiency is coded important too. Institutions seek to provide bar-coded medications, while minimizing packaging tasks to enable BCMA. American Health Packaging can support you at this ional ”key intersection” of patient safety and operational e industry efficiency. Our unit dose line is the largest in the industry, with continued growth to support your needs and many of our items are industry exclusives.
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Policy 13
Pharmacy Practice News • April 2014
Student’s Corner
NASP Offers Online Specialty Pharmacy Modules for Students
T
reported that they would recommend SPEC courses to other pharmacy students. In addition to Roosevelt University, Touro College of Pharmacy, in New York City; the University of Colorado Skaggs School of Pharmacy, in Aurora; and the University of Florida College of Pharmacy, in Gainesville, are incorporating the SPEC content into their curricula.
he National Association of Specialty Pharmacy (NASP) is teaming up with colleges of pharmacy around the country to incorporate online specialty pharmacy education into their curricula. NASP’s Specialty Pharma Education Center (SPEC) offers approximately 175 hours of specialty pharmacy content in 20 therapeutic categories including cystic fibrosis, hemophilia, hepatitis C,
—Sarah Tilyou
Table. Specialty Pharmacy Therapeutic Categories
SIMPLICITY
Cardiology Crohn’s disease Cystic fibrosis Gout Hereditary angioedema Hemophilia Hepatitis C HIV/AIDS Human growth hormone Immunoglobulins Infectious disease Infertility Macular degeneration Multiple sclerosis Oncology Hematologic cancers: acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin lymphoma Solid tumors: breast, colorectal, hepatocellular, lung, melanoma, ovarian, pancreatic, prostate, renal cell Pulmonary arterial hypertension Rheumatoid arthritis Transplantation
infectious diseases, multiple sclerosis, pulmonary arterial hypertension, rheumatoid arthritis, transplantation and various cancers (Table). Students from participating colleges can access the specialty pharmacy content through online courses. This past fall, 51 students from Roosevelt University College of Pharmacy, in Chicago, completed such online courses. “The SPEC education modules enabled students to develop skills in the specialty pharmacy area beyond what is available in the traditional curriculum,” said Matt Nelson, PharmD, an assistant professor of clinical sciences at Roosevelt University, who coordinates the program there. “We found SPEC to be a valuable teaching tool for elective course offerings in a hybrid approach.” Students participating in the program
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14 Clinical
Pharmacy Practice News • April 2014
Drug Preparation Part 2 of a Two-Part Series
New Devices Expand Safe Compounding Options T
he National Institute for Occupational Safety and Health (NIOSH) estimates that 8 million U.S. health care workers annually may be exposed to hazardous drugs (http://1.usa. gov/1icLRvc). Moreover, workplace exposures to hazardous drugs can cause both acute and chronic health effects such as skin rashes, adverse reproductive outcomes (including infertility, spontaneous abortion and congenital malformations), and possibly leukemia and other cancers, according to the Centers for Disease Control and Prevention (CDC; http://1.usa.gov/1ca5a5P). The extent of the health risk depends on how much exposure a worker has to the drugs and the substances’ toxicity, according to the federal data. To help protect hospital staff and patients from these risks, several companies have developed closed system transfer devices (CSTDs), which are defined by NIOSH as a drug-transfer device that mechanically prevents the entry of environmental contaminants into the drug preparation system and the escape of hazardous drug or vapor concentrations outside the system. San Diego-based CareFusion, which makes the Alaris System smart IV pumps and IV sets that are used by more than 50% of all U.S. acute care hospitals, according to the company, has created a new CSTD that, along with other products, make up the CareFusion Chemo Safety System. Because this system makes it possible for hospitals using CareFusion’s Alaris System to adopt a CSTD for hazardous drugs without needing to purchase additional components for nursing, it has the potential “to reduce costs and create workflow efficiencies, while protecting hospital workers and patients from exposure to hazardous drugs,” said Jeffrey Reinhardt, the company’s senior marketing manager of oncology and chemotherapy safety.
System can still use the Chemo Safety System, but they need to add one additional mating component, “much like many hospitals already do today with some of the older CSTDs,” he said, adding that the system is currently in use at more than 100 hospitals at press time.
Diana, ChemoClave and ChemoLock
The new SmartSite VialShield is part of the CareFusion Chemo Safety System and fits all common vial sizes (13, 20, and 28 mm).
adapters “because they didn’t fit well and were cumbersome. Now, they can’t take the adapter off because it’s bonded to the IV tubing, which is good. It’s safer,” she said. Dr. Proctor, who has used other CSTD systems, said when it is used properly, the Chemo Safety System “is as safe as any that I’ve used in the past.” She also said the system was flexible and worked well with her hospital’s existing equipment. “We didn’t have to buy many components [other than] the Texium Syringes, the SmartSite Vented Vial Adapter, VialShield and adapters for some old tubing on Alaris.” Going forward, Dr. Proctor added, Dallas VA most likely will use the Chemo Safety System as its “exclusive” CSTD. She noted further that the hospital currently is conducting wipe
One Hospital’s Experience With Chemo Safety System
Correction
Marsha Proctor, PharmD, an oncology pharmacist who supervises the IV room at the Dallas VA Medical Center, which averages 100 chemotherapy preparations per day, had been using the Chemo Safety System for about two months at press time. She described the system as “easy to use; easy to adapt; and with less components, it means less twisting so it’s easier on the body.” The CSTD that Dallas VA was using before the Chemo Safety System was “more difficult to use,” she said. As a result, nurses did not always use some
P
samples to confirm and document the system’s efficacy. Underscoring those research efforts, Mr. Reinhardt said clinical trials to document the effectiveness of the Chemo Safety System in reducing health care worker exposure to drugs are currently under way. He echoed Dr. Proctor’s point that the Chemo Safety System is flexible. For example, although hospitals do not need to have the Alaris System to adapt the CareFusion Chemo Safety System, those that already have the system in place (including SmartSite IV sets) only need to purchase the SmartSite VialShield and Texium components in the pharmacy “to create a closed system throughout the continuum of care from pharmacy to nursing,” he explained. Hospitals that do not have the Alaris
art 1 of this two-part series (“Are CSTDs at a Tipping Point in Nation’s Hospitals?” Pharmacy Practice News, 41[3]:16,19) misstated the ONB status of two closed system transfer devices (CSTDs). (An ONB is a product code granted by the FDA, designating that a CSTD is a device for transferring liquids to reduce hazardous drug exposures in specific workplace settings.) That status should have been described as follows: “Two CSTDs currently have an ONB designation: PhaSeal (BD) has an ONB designation for both compounding and administration while ChemoLock (ICU Medical) has an ONB designation for compounding.” The article also misstated the outcomes of a drug-waste study conducted at the University of Texas MD Anderson Cancer Center, in Houston. The article should have quoted Lucy Moyer, RPh, the director of pharmacy operations at MD Anderson, as follows: Before using PhaSeal for Drug Vial Optimization (DVO), “we were throwing away $463,000 of partial vials” in a typical month. “After we began using PhaSeal in our DVO program, we reduced [that] waste to $245,000—a 47% decrease.”
Introduced to the U.S. market at ASHP’s 2013 Midyear Clinical Meeting, and in use in Europe for a little over a year, the Diana Hazardous Drug Compounding System is “the world’s first user-controlled, automated sterile compounding system for the accurate, safe and efficient preparation of hazardous drugs,” according to ICU Medical, the device’s manufacturer. The company said it incorporated ChemoClave CSTD needle-free components into the system to protect technicians as they operate Diana. In addition to keeping clinicians safe from hazardous drug exposure during chemotherapy preparation, the microbiologically and mechanically closed Diana system also helps keep the drugs themselves safe from exposure to outside contaminants, according to ICU Medical. Besides its safety features, Diana “automates the compounding pro-
cess so it becomes more accurate and repeatable, and is now being used in four U.S.-based high-volume pharmacies,” according to Tom McCall, the vice president and chief marketing officer at ICU Medical. Diana’s workflow, he said, “lets pharmacists and technicians control the process better, creating traceability, helping pharmacists understand exactly what’s been done. The system provides premix verification to assure that what is about to be mixed matches the patient order, and then provides postmix validation and up to five separate labels that can be placed on the patient bag, in the logbook or on the patient order form for traceability.” A bar-code scanning option helps to reduce human input error, he added. Peninsula Regional Medical Center (PRMC) in Salisbury, Md., has been betatesting Diana for the past two years. “Nothing visibly leaks; the process is accurate and easy to use,” said Mary Enger, an oncology pharmacy technician at PRMC. “The most challenging part is activating the buttons on the Diana screen and switching vials.” Technicians who work with the Diana system inside a protective biological safety cabinet start the drug preparation process by scanning the bar code on the patient order, which
Clinical 15
Pharmacy Practice News • April 2014
Drug Preparation provides order traceability. They then scan the medication bar code to display the drug name and concentration on the screen. After entering the desired volume for transfer, the system pulls drugs from a single vial at a time. Diana has two channels for mixing, Mr. McCall noted: The first channel is for low-volume transfer and adding medication to patient IV bags and syringes, and the second is for highvolume transfers, reconstituting lyophilized drugs, adding diluents to patient IV bags or filling elastomeric pumps. The system is designed with a proprietary cassette that Ms. Enger said makes it impossible for Diana to push back into a vial that it has just pulled from. Because Diana functions as the compounding “workhorse,” Ms. Enger said, “it minimizes repetitive use of our hands, wrists and shoulders. Also, it consumes fewer syringes.” Further describing the process, Ms. Enger noted that the technician uses Diana’s scanner to scan the Aztec bar code on the pharmacy’s work label, which transfers the information to Diana. The technician then uses Diana’s scanner to scan the selected drug product. This is done, according to Mr. McCall, so that the drug name and concentration can be displayed on the system’s touch screen. After the technician enters the desired mix volume, he noted, Diana displays a verification screen that the technician compares against the patient order prior to mixing, to assure the drug and volume about to be mixed
A technician, h b behind h d a biological b l l safety f cabinet, b uses ICU Medical’s d l ChemoLock h k to secure a completely dry connection between a chemotherapy vial and a syringe that will later be used to inject the medication into a patient on the nursing floor.
matches what was ordered. The technician proceeds by admixing the drug and the diluent, Ms. Enger said. Diana prints three labels—one for each step—for traceability: The first label represents the volume drawn from the base fluid; the second label represents the volume of diluent added to the drug for mixing from the second channel; and the third label represents the drug name and concentration of the drug, including the volume added to the patient’s IV bag. Because the process is needleless, she pointed out, the potential for accidental needlesticks and leaks is eliminated. Currently, a PRMC medium-volume oncology pharmacy satellite compounds 30 to 50 IV bags daily, Ms. Enger noted, adding that 60% of the
bags are compounded using Diana.
A Second-Generation CSTD ICU Medical is now rolling out its second-generation CSTD, ChemoLock. To connect two components together using first-generation ChemoClave, technicians need to screw or twist them together, Mr. McCall explained. He describes ChemoLock as “faster, with an audible click-to-lock technology that makes it easy to tell when it is connected correctly. It’s very safe. You take it out of the bag, connect it to the end of [the] syringe and you’re ready to go. It provides safety without increasing preparation and administration time.” Nebraska Methodist Hospital, in Omaha, was one of the first hospitals to test ChemoLock. Firouzan “Fred”
Massoomi, PharmD, FASHP, the hospital’s pharmacy operations coordinator, said his staff likes the fact that the ChemoLock-to-user interface closes with a “push-and-lock” motion, which he said “is easier to use, easier to train personnel, and can minimize repetitive strain injuries.” To test whether ChemoLock creates a dry connection, “which is one facet of the NIOSH definition of a CSTD and what we strive for, we did a litmus test using three solutions—pH 4.0, pH 7.0 and pH 10—which we thought would mimic the spectrum of residuals that a chemo drug might leave if the connectors weren’t completely closed tightly. In 80 manipulations that we performed, it was a completely dry connection. In addition, we performed a wipe analysis evaluation with cyclophosphamide to validate containment.” ChemoLock, he added, “was easier to learn in comparison to the other devices on the market, and the new changes are a welcome enhancement to improving safety.” Both ChemoLock and ChemoClave are needle-free devices, which Dr. Massoomi said eliminates the potential for occasional failures of devices using encased needles. “Devices do fail and we’ve had needles pop out of enclosures from other systems,” he said. “So the potential is there for a needle-stick injury.” —Liz Parks Look for continuing coverage on CSTDs in future issues.
Cardiovascular Disease
Hypertension, Stroke Associated With High-Sodium Drugs
D
rugs that contain high levels of sodium, such as dissolvable “fizzy tablets,” are associated with increased risks for hypertension, stroke and overall mortality, according to a new study by British researchers. “The increased sodium is doing what is biologically plausible—increasing your stroke risk,” said Thomas MacDonald, MB, ChB, a professor of clinical pharmacology and pharmacoepidemiology at the University of Dundee, United Kingdom, and an author of the study ((Br Med J 2013. doi: 10.1136/bmj.f6954). With a retrospective look at drug prescriptions and cardiovascular events, the report included data from more than 1.2 million patients taken from a nationwide U.K. database. The investigators compared patients with prescriptions for two or more soluble, dispersible or effervescent drug formulations with those who had prescriptions for the equivalent nonor low-sodium versions of drugs. Prescriptions for multiple sodiumcontaining drugs were associated with
increased odds of overall verall mortality (odds ratio, 1.2 28; 95% confidence interval [CI], 1.231.33). Similarly, the odds of having a nonfatal stroke (odds ratio, ti 11.22; 22 95% CI CI, 1.16-1.29) or hypertension (odds ratio, 7.18; 95% CI, 6.74-7.65) also were raised in the group with prescriptions for high-sodium drugs. “From an outpatient standpoint, this is the first article I’ve seen in a long time that addresses this very important issue,” said Robert L. Page, PharmD, MSPH, BCPS, an associate professor of clinical pharmacy at the University of Colorado School of Pharmacy, in Aurora, who was not involved with the research. On an inpatient basis, “people understand [that] the content of sodium in drugs could possibly exacerbate existing problems,” he said, but for outpatients, providers often neglect sodium content. Low consumption of sodium-containing drugs is unlikely to have a large health
impact. “If yyou have a hangover and the next n morning you take a big Alka-Seltzer, that might not be an issue,” Dr. MacDonald said. He’s more concerned, H however, with chronic use. h Taking eight tablets of effervescent acetaminophen per day—the maximum dose—delivers more than the daily 2.3-g recommendation for sodium intake. With respect to prescription drugs, “sodium content is not easily found information,” Dr. Page said. To determine the amount of sodium in certain drug formulations, the study authors contacted several pharmaceutical manufacturers. They reported sodium content as high as 430 mg per 500-mg tablet of soluble acetaminophen. “When you add that to your normal diet,” Dr. MacDonald said, “you’re taking a lot of extra sodium.” Although soluble tablets can be beneficial for people who have difficulty with swallowing, such as patients with
esophageal cancer, Dr. MacDonald said that this does not outweigh the risk for the majority of patients. Barring modified-release medication, he said, “for most indications, it is possible to get liquid forms or grind up the tablets,” obviating the need for dissolvable drugs.
‘Association, not Causation’ Because the report used information from a database, researchers “cannot control for a large number of variables,” Dr. Page said. “The study shows association, not causation.” Still, he said, it brings attention to a problem many providers don’t assess when prescribing medication. Dr. MacDonald said he would like to see a reduction in the use of salt-laden tablets, and he called on “the pharmaceutical industry to produce fizzy tablets that don’t contain sodium.” —Ben Guarino Drs. MacDonald and Page reported no relevant financial conflicts of interest.
In the treatment of CIDP...
SEIZE THE DATA, SEIZE THE DAY Patients with CIDP treated with GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) once every 3 weeks for 6 months experienced SIGNIFICANT IMPROVEMENT IN:
Disability scores1
Grip strength1
Quality of life2
Important Safety Information GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) is indicated for the treatment of primary humoral immunodeficiency disease (PIDD), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Thrombosis may occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IVIG) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIG products containing sucrose. GAMUNEX-C does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable. GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity. Severe hypersensitivity reactions may occur with IVIG products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment. Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG treatment, including GAMUNEX-C. There have been reports of noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]), hemolytic anemia, and aseptic meningitis in patients administered with IVIG, including GAMUNEX-C. The high-dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern. Because GAMUNEX-C is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, and, theoretically, the CreutzfeldtJakob disease (CJD) agent. Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMUNEX-C and at appropriate intervals thereafter. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis. If signs and/or symptoms of hemolysis are present after an infusion of GAMUNEX-C, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum. After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. In clinical studies, the most common adverse reactions with GAMUNEX-C were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection-site reaction, nausea, pharyngitis, and urticaria with intravenous use (in PIDD) and infusion-site reactions, headache, fatigue, arthralgia and pyrexia with subcutaneous use (in PIDD); and headache, vomiting, fever, nausea, back pain, and rash (in ITP). The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in 1 subject (in PIDD), and myocarditis in 1 subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP). Please see brief summary of GAMUNEX-C full Prescribing Information on adjacent page. References: 1. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 2008;7:136-144. 2. Merkies ISJ, Bril V, Dalakas MC, et al. Health-related quality-of-life improvements in CIDP with immune globulin IV 10%: the ICE Study. Neurology. 2009;72(15):1337-1344. © 2014 Grifols
All rights reserved.
March 2014
GX71-0314
GAMUNEXÂŽ-C
C ?6+8685:+/4+3/' =/:. 8+9;2:'4: ).'4-+9 /4 9+8;3 </9)59/:? '4* +2+):852?:+ /3('2'4)+9 3'? 5));8 /4 6':/+4:9 8+)+/</4- # :.+8'6? Immune Globulin Injection (Human) 10% Caprylate/Chromatography Purified C !.853(59/9 .'9 5));88+* /4 6':/+4:9 8+)+/</4- # :.+8'6? 54/:58 6':/+4:9 =/:. 145=4 8/91 ,'):589 ,58 :.853(59/9 )549/*+8 HIGHLIGHTS OF PRESCRIBING INFORMATION ('9+2/4+ '99+993+4: 5, (255* </9)59/:? ,58 :.59+ ': 8/91 5, .?6+8 </9)59/:? These highlights do not include all the information needed to use GAMUNEXÂŽ-C safely and effectively. See full prescribing C 9+6:/) +4/4-/:/9 ?4*853+ .'9 (++4 8+658:+* =/:. information for GAMUNEX-C. " $ '4* 5:.+8 # :8+':3+4:9 +96+)/'22? =/:. ./-. *59+9 58 8'6/* /4,;9/54 GAMUNEX-C, [Immune Globulin Injection (Human) 10% Caprylate/Chromatography Purified] C +352?:/) '4+3/' )'4 *+<+256 9;(9+7;+4: :5 # :.+8'6? *;+ :5 +4.'4)+* 9+7;+9:8':/54 54/:58 6':/+4:9 ,58 .+352?9/9 '4* Initial U.S. Approval: 2003 .+352?:/) '4+3/' WARNING: THROMBOSIS, RENAL DYSFUNCTION C 54/:58 6':/+4:9 ,58 6;2354'8? '*<+89+ 8+'):/549 :8'49,;9/54 and ACUTE RENAL FAILURE 8+2':+* ');:+ 2;4- /40;8? %! & See full prescribing information for complete boxed warning. C #52;3+ 5<+825'* E $3=:8-:>4> 8,y occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.
E := ;,?409?> at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. E "09,7 /Csfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. E "09,7 /Csfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMUNEX-C does not contain sucrose. E := ;,?409?> at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.
C " $ /9 3'*+ ,853 .;3'4 62'93' '4* 3'? )54:'/4 /4,+):/5;9 '-+4:9 + - </8;9+9 '4* :.+58+:/)'22? :.+ 8+;:@,+2*: '15( */9+'9+ '-+4: C " $ /9 45: '6685<+* ,58 9;();:'4+5;9 ;9+ /4 ! 6':/+4:9 ;+ :5 ' 65:+4:/'2 8/91 5, .+3':53' ,583':/54 *5 45: '*3/4/9:+8 " $ 9;();:'4+5;92? /4 6':/+4:9 =/:. ! C '99/<+ :8'49,+8 5, '4:/(5*/+9 3'? )54,5;4* 9+8525-/) :+9:/4- ----------------------------ADVERSE REACTIONS ---------------------------+8/5;9 '*<+89+ 8+'):/549 =./). 5));88+* /4 :.+ )2/4/)'2 :8/'29 =+8+ '4 +>')+8(':/54 5, ';:5/33;4+ 6;8+ 8+* )+22 '62'9/' /4 54+ 9;(0+): '4* 6;2354'8? +3(52/93 /4 54+ 9;(0+): =/:. ' ./9:58? 5, !.+ 359: )53354 '*<+89+ 8+'):/549 5(9+8<+* /4 âą&#x2013; 6':/+4:9 =+8+ PI 4tra<enous +'*').+ )5;-. /40+):/54 9/:+ 8+'):/54 4';9+' 6.'8?4-/:/9 '4* ;8:/)'8/' ;();:'4+5;9 4,;9/54 9/:+ 8+'):/549 .+'*').+ ,':/-;+ '8:.8'2-/' '4* 6?8+>/' ITP +'*').+ <53/:/4- ,+<+8 4';9+' (')1 6'/4 '4* 8'9. CIDP +'*').+ ,+<+8 )./229 .?6+8:+49/54 8'9. 4';9+' '4* '9:.+4/'
To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 or GAMUNEX-C is an immune globulin injection (human) 10% liquid www.fda.gov/medwatch. indicated for treatment of: ----------------------------DRUG INTERACTIONS ---------------------------C 8/3'8? ;358'2 33;45*+A)/+4)? C !.+ 6'99/<+ :8'49,+8 5, '4:/(5*/+9 3'? :8'49/+4:2? /4:+8,+8+ =/:. C */56':./) !.853(5)?:56+4/) ;86;8' ! :.+ 8+96549+ :5 2/<+ </8'2 <'))/4+9 9;). '9 3+'92+9 3;369 '4* C .854/) 4B'33':58? +3?+2/4':/4- 52?4+;856':.? 8;(+22' --------------------------INDICATIONS AND USAGE -------------------------
----------------------------CONTRAINDICATIONS ----------------------------
---------------------USE IN SPECIFIC POPULATIONS ---------------------
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----------------------WARNINGS AND PRECAUTIONS---------------------C - *+A)/+4: 6':/+4:9 =/:. '4:/(5*/+9 '-'/49: - '8+ ': -8+':+8 8/91 5, *+<+256/4- 9+<+8+ .?6+89+49/:/</:? '4* '4'6.?2'):/) 8+'):/549 '<+ +6/4+6.8/4+ '<'/2'(2+ /33+*/':+2? :5 :8+': '4? ');:+ 9+<+8+ .?6+89+49/:/</:? 8+'):/549 C 54/:58 8+4'2 ,;4):/54 /4)2;*/4- (255* ;8+' 4/:85-+4 9+8;3 8/,529 !.+8'6+;:/)9 4) )8+':/4/4+ '4* ;8/4+ 5;:6;: /4 6':/+4:9 ': 8/91 5, *+<+256/4- ');:+ +9+'8). !8/'4-2+ '81 " 8+4'2 ,'/2;8+ " /)+49+ 5
3036427/3036428-BS Revised: 9/2013
18 Clinical
Pharmacy Practice News • April 2014
Infectious Disease
CDC REPORT continued from page 1
The CDC implored hospitals nationwide to respond to this public health crisis with strong antimicrobial stewardship programs (ASPs). At the core of that effort, the CDC noted, are pharmacists. “They are true leaders in this area,” said Dr. Srinivasan, senior author of the new report. “We’re excited to partner even more with the pharmacy community to help expand the impact and work of clinical pharmacists in stewardship.”
The first red flag uncovered by Dr. Srinivasan’s team in their survey (http://1.usa. gov/1phPWMB) was the high frequency of antibiotic prescribing. Of patients at 323 hospitals in the MarketScan Hospital Drug Database in 2010, 55.7% received antibiotics during their hospitalizations. Further analyses suggested that this rate poses an unnecessary risk to public health, as well as to a hospital’s bottom-line. Antibiotic prescribing could be improved in about 40% of the most common prescribing scenarios, according to data from the CDC’s Emerging Infec-
tions Program on 11,282 patients at 183 hospitals in 2011. (See box for more on this program.) Antibiotics to treat urinary tract infections and vancomycin often were given to patients without proper diagnostic testing or beyond the time at which they should have been discontinued, according to the CDC data. The CDC also found that about onefourth of Clostridium difficile infections could be prevented if use of broad-spectrum antibiotics was cut by 30%, based on 19 hospitals reporting to the National Healthcare Safety Network (NHSN).
“Healthy bacteria get wiped out and that allows C. difficile to really flourish,” Dr. Srinivasan explained. Great variability in prescribing practices also was evident in the NHSN. Doctors in some hospitals prescribed three times as many antibiotics as doctors in similar departments at other centers. “Whenever you see variations that are that significant, it suggests there may be room for improvement,” Dr. Srinivasan said. It is not yet clear which hospitals in the databases had ASPs, he noted. In fact, no statistics exist on the overall prevalence of such programs in the United States.
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Ronald Polk, PharmD, FIDSA, FSHEA, a research professor in the Department of Pharmacotherapy and Outcomes Science at the Virginia Commonwealth University School of Pharmacy, in Richmond, said the CDC’s findings of large and unexplained variability in antibiotic use across hospitals matches well with his own experience in monitoring a consortium of academic medical center hospitals. He said he has also found that most academic institutions do run formal ASPs. “It’s less common when you get into nonacademic hospitals,” noted Dr. Polk, who has worked extensively with ASPs over the past decade. “All hospitals ought to be engaged in antimicrobial stewardship, and pharmacists are a key element of that team,” he added. Dorothy McCoy, PharmD, BCPS, an infectious disease pharmacist at Hackensack University Medical Center and a clinical associate professor at Rutgers University, New Brunswick, both in New Jersey, highlighted the important effects ASP pharmacists can have on antibiotic prescribing—beginning the moment an order is placed. ASP pharmacists may, for example, call a prescribing physician to address the required approval for a restricted-use antibiotic, she said, initiating a second-thought process for the doctor: “Do I really need to use this antibiotic? Is this the most appropriate one to use right now?” Pharmacists also can play the lead role in reassessment after the first 48 hours of treatment, Dr. Srinivasan said. During this “antibiotic time out,” he noted, they might round with clinical team to determine if the therapy is still needed, if it is, in fact, the right therapy and if it has been prescribed at the correct dose and for the optimal duration. As part of their ASP, Dr. McCoy’s team, which includes Arpi Kuyumjian, PharmD, and Rani Sebti, MD, lead a range of further efforts to bolster antibiotic-resistance awareness and proper prescribing— from an ASP screensaver on all of the hospital’s computers and an information table in the cafeteria during the CDC’s Get Smart About Antibiotics Week, to an annual investigation into the hospital’s use of one specific drug. Most recently,
Clinical 19
Pharmacy Practice News • April 2014
Infectious Disease Dr. McCoy noted, the use of daptomycin (Cubicin, Cubist) fell under their scrutiny. “We saw an increase in how much we were spending on the drug, which is a restricted agent at our hospital,” she noted. “We wanted to take a closer look to make sure it was being used appropriately and for the indications that we had in our hospital’s guidelines.” As it turned out, daptomycin was being used appropriately for the indication of interest: skin and skin structure infections. Still, the team continues to keep a close eye on when and how doctors prescribe the restricted agent, she stressed. In some cases, the collaboration of the ASP with infection control and the microbiology laboratory has reduced the use of various antibiotics and, thereby, leveled off rates of resistant organisms, Dr. McCoy pointed out. The improvements also have provided another welcome perk for the hospital. “We’re spending less money every year on antibiotics,” she said. The CDC’s latest release lists seven elements that hospital ASPs should adopt, at a minimum, including these types of strong educational programs and oversight for evaluating, tracking and reporting prescriptions and resistance patterns. Also among their core recommendations is to appoint a pharmacist leader as the drug expert. Just how an individual institution’s ASP will look, and the roles played by its pharmacists, will depend on the types of patients, available resources and expertise, noted the CDC. Dr. Polk agreed that ASP strategies will vary between hospitals. Yet teaming up with other hospitals, he added, can maximize each program’s individual effect. “Stewardship programs are now talking to other stewardship programs,” he said. One key benefit of a consortium, such as the approximately 100 academic medical centers affiliated with the University HealthSystem Consortium that Dr. Polk and his colleagues have been working with for more than 10 years, is the ability of a hospital to benchmark its antibiotic use against other hospitals. For example, his research has shown that in 2009, antibiotic use at Tufts Medical Center, in Boston, was
CDC Also Eyes HAIs As Target for Improvement
A
nother CDC survey, released on March 27, gives an updated view of the overall problem of health careassociated infections (HAIs) (http:// www.nejm.org/doi/full/10.1056/ NEJMoa1306801#t=articleResults). This survey, based on data from the CDC’s Emerging Infections Program indicates that 722,000 patients had an HAI in 2011, that 1 in 25 hospital patients has at least one HAI, and that 75,000 patients with HAI died during their hospitalizations. Look for more on the survey in our next issue.
roughly 20% lower than at similar centers, after adjusting for differences in patient mix. The ASP medical directors, Shira Doron, MD, and Gretchen Volpe, MD, and the ASP pharmacist, Kirthana Beaulac, PharmD, continue to monitor usage to assure its appropriateness. “Hospitals with higher rates of adjusted usage compared with their peers then have strong incentive ... to evaluate and reduce their use where appropriate,” Dr. Polk said. Of course, antibiotic overuse and misuse is not confined to hospitals. “We know there is a definite need and certain-
ly room for improvement in both human and animal sectors,” Dr. Srinivasan said. “Making those improvements will work hand in glove to improve resistance.” The benefits of better stewardship of antibiotics, whether for humans, livestock or farmed fish, Dr. Polk added, could extend beyond just lowering risks for drug-resistant infections. “There is emerging evidence that antibiotic exposure in children may be linked to altering gastrointestinal bacteria, which may predispose them to a variety of things we would never have thought were linked,
such as obesity,” he said. Still, concerns over a possible return to the “preantibiotic era,” a time when many infections may be untreatable, are far from new. “This has not caught us by surprise,” Dr. Polk said, referring back to Alexander Fleming’s warnings in the 1940s. “But now we’ve gotten to the point where the problem is looming so great that action has to be taken.” —Lynne Peeples None of the sources reported relevant financial conflicts of interest.
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20 Clinical
Pharmacy Practice News • April 2014
Infectious Disease
STEWARDSHIP
100
continued from page 1
Massive Stewardship Program Yields Impressive Achievements When pharmacists at Select Specialty Hospitals set out to create an ASP in 2009, they had to contend with a daunting challenge: devise a program that meets the complex needs of longterm, acute care patients who need to be seen at 86 facilities sprawled over 26 states (poster 5-046). “Our patients typically spend short amounts of time on ventilation in other acute care facilities before being admitted to one of our facilities, and they often have been on long-term antibiotics and tend to have lots of multidrug-
80
Reductions (%)
health system (poster 5-106). Dr. Guharoy and Mohamed Fakih, MD, the medical director of infection prevention and control at St. John Hospital and Medical Center, an Ascension Health hospital in Detroit, examined antimicrobial utilization at 69 Ascension hospitals. They found that smaller institutions used nearly five times as many broad-spectrum antimicrobials as larger hospitals. “It is essential that every hospital, regardless of size or resources, develop a multidisciplinary antimicrobial stewardship management team to ensure broad-spectrum antimicrobials in particular are used judiciously and that the alarming rates of multidrug resistance are addressed,” Dr. Guharoy said. His analysis included data from more than 9 million patient-days between 2009 and 2011, and nearly 5 million daily defined doses of broad-spectrum antibiotics, including quinolones, carbapenems, piperacillin/tazobactam, streptogramins, tetracycline, macrolides, lipopeptides, oxazolidinones and third- and fourth-generation cephalosporins. Also included were doses of antifungals, such as azoles, polyenes and echinocandins. Dr. Guharoy divided hospitals into those with less than or more than 50,000 patient-days per year. He found that 34% of patients treated at the smaller hospitals received at least one broad-spectrum antimicrobial daily compared with 7.1% of patients in hospitals with more than 50,000 patientdays annually ((P=0.009). The findings, he said, have prompted Ascension to provide more oversight on the antimicrobial use at individual hospitals. “Until now, Ascension hospitals have been able to decide whether or not to implement an ASP, but that process is now changing,” he said. “We are working with pharmacists and clinicians to develop system-wide internal guidelines for antimicrobial use.”
69 60
40
20
0
39 33 19
CLABSI Clostridium SystemSystemdifficile wide wide infections antifungal antibiotic use use
Figure. Improved outcomes from an ASP at Select Specialty Hospital— Orlando South. ASP, antibiotic stewardship program; CLABSI, central line–associated bloodstream infections
resistant infections,” said Christopher Jones, PharmD, CPh, the senior director of pharmacy at Select Specialty Hospital—Orlando South, in Edgewood, Fla. Together with a team of pharmacists, nurses and physicians (the latter group including, but not limited to, infectious disease physicians), Dr. Jones built a system-wide ASP based on four “pillars.” The first three pillars included administering antibiotics according to the patient’s general condition; ensuring that treatment closely adheres to national guidelines, such as those issued by organizations like the Infectious Diseases Society of America; removing central and catheter lines promptly and converting patients from IV to oral medications when possible. The fourth pillar is to be selective about which sites to culture, Dr. Jones said. “Because our patients have been in hospitals for a long time, they are typically colonized in multiple areas, but many of these colonies do not represent true infections,” he explained, citing sputum and wounds as two sites that might not require culturing. To implement these pillars, pharmacists join in rounds and determine when central and catheter lines can be removed. During additional rounding with an infectious disease specialist, patients whose antibiotics can be deescalated are identified. Dr. Jones said that by 2011, two years after all 86 Select hospitals implemented the ASP, system-wide antibiotic use dropped by 19% and antifungal use fell by 33% compared with the year before implementation. There was an accompanying 39% decrease in C. difficile infections, an 8% reduction in multiple drug–resistant organisms and a 65% reduction in the number of central line–associated bloodstream
infections (Figure). As for the cost savings associated with the improved outcomes, the hospital chose not to share those figures. But the team said the significantly reduced rates of antibiotic use should give an indication of the cost savings achieved as a result of the ASP initiative.
CPOEs Present Unique Challenges and Opportunities For Stewardship Pharmacists at Sunrise Hospital and Medical Center, in Las Vegas, had just begun implementing a newly created ASP in August 2012, when their institution switched to an electronic medical records (EMR) system and a computerized prescriber order entry (CPOE) system (poster 5-111). The change led to opportunities as well as challenges, according to Kim Ly, PharmD, BCPS, the clinical pharmacy specialist in critical care/infectious diseases and the antimicrobial stewardship clinical lead. “Whereas we had been writing down recommendations in the patients’ charts prior to the switch, with the new systems in place, interventions require contacting physicians by phone or in person, which makes that part of the process more time-consuming,” Dr. Ly said. However, she added, once a physician was contacted, “changes could be made immediately.” Scattering clinical pharmacists throughout the hospital also helped overcome the potentially time-consuming process of tracking down physicians with the new CPOE and EMR systems in place, Dr. Ly noted. Additionally, face-to-face meetings have offered a chance for greater pharmacist–physician collaboration on a patient’s treatment plan, she added. Despite the adaptations and a slightly more time-consuming communication process that has come with the EMR and CPOE systems, Dr. Ly said the ASP has been a success. Between September 2012, when data collection for the program officially began, and April 2013, the ASP team reviewed 11,222 patient charts and conducted 1,055 interventions, 89% of which were accepted by physicians (Table). Dr. Ly said antibiotic use dropped 8%
over the eight-month period that was reviewed, and drug spending decreased by $232,589 from the period before the ASP. The interventions helped avoid an additional $91,571 in costs related to equipment for drug administration, such as lines, fluids and diluents. “It would be ideal if our CPOE system had some kind of messaging functionality between the physicians and the pharmacists for certain recommendations that may not be urgent enough to warrant a phone call,” Dr. Ly said. “We have reached out nationally to see how other facilities have integrated their ASP with CPOE and EMR, but other facilities seem to face similar challenges.”
Probiotics Reduce Incidence, Severity and Costs of CDAD Administering probiotics with antibiotics can cut the total costs of C. dificile-associated diarrhea (CDAD) management by as much as 90%, Bich Ngoc Hoang, MS, a PharmD candidate (2014) at the School of Pharmacy, Bouvé College of Health Sciences at Northeastern University, in Boston, found (poster 3-168). Ms. Hoang’s findings add a financial element to a body of clinical knowledge showing that probiotics reduce
Table. Summary of ASP Interventionsa
a
Number of patients reviewed
11,222
Number of interventions made
1,055
Number of interventions accepted
939
Number of antibiotics de-escalated/streamlined
78
Number of antibiotics discontinued
708
Average number of days on antibiotics before discontinuation
7.46
Number of drug modifications
172
Number of IV to oral interventions
405
Acceptance rate
89%
Sunrise Hospital and Medical Cente Center, er, Las Vegas
Clinical 21
Pharmacy Practice News • April 2014
Infectious Disease
Experimental Biochemical Approach Targets MRSA Toxicity
A
new treatment for methicillinresistant Staphylococcus aureus (MRSA) infection, under investigation by researchers at the University of Bath, in the United Kingdom, aims to weaken rather than kill infectious bacteria. By exposing MRSA to oxacillin, scientists can induce the microbes to overexpress genes for resistance, which, in turn, decreases their ability to produce toxic proteins. In their study, Ruth Massey, PhD, a lecturer in the department of biology and biochemistry at the University of Bath and her colleagues grew several strains of community-associated MRSA in vitro and exposed the bacteria to subinhibitory concentrations (0.5 mcg/mL) of oxacillin. When T-cells were exposed to MRSA that had been treated with
oxacillin for 15 minutes, 47.7% of the cells survived; without oxacillin, only 17.7% of T-cells survived (P ( <0.001; Antimicrob Agents Chemother 2013. doi: 10.1128/AAC.01618-13). According to the investigators, oxacillin ramped up the expression of proteins that confer antibiotic resistance in MRSA, and, in general, repressed the secretion of toxic molecules such as phenol-soluble modulins and delta toxins. “The only concern we have at the moment is [that] although some of the really important toxins are downregulated, there is one that is upregulated,” Dr. Massey said. Future approaches in this vein may need to tailor antimicrobial agents to ensure that the drugs do not cause upregulation of cyotoxins in patients, she noted.
This research “serves as a reminder that antimicrobials being used for any purpose still have profound effects on the bacteria they come into contact with, even those that appear to be resistant to the drug,” said Erika Ernst, PharmD, the past president of the Society of Infectious Diseases Pharmacists (SIDP) and an associate professor at the University of Iowa College of Pharmacy, in Iowa City, who was not involved with the report. “SIDP supports research into new ways to treat resistant infections,” Dr. Ernst added. “I think practical and clinical applications of this type of research are probably a ways off, however.” Dr. Massey acknowledged that at this time, “we’re a long way from putting [this treatment] into a patient.” Despite
this, she stressed that early in vivo trials have been promising. In those studies, MRSA induced to have high resistance was less virulent in mice; the animals retained more weight and had a longer time to death than those exposed to less resistant MRSA strains. In the meantime, Dr. Massey believes there are opportunities to adopt more clever approaches to resistant microbes. “We use a sledgehammer at the moment and we need to start being a bit more subtle,” she said. “We need to be using [antimicrobials] more selectively, making sure we’re keeping drugs for the people who really need them.” —Ben Guarino Drs. Ernst and Massey reported no relevant financial conflicts of interest.
FMT Stands Up to Antibiotics in Cost-Effectiveness Model
F
ecal microbiota transplant (FMT) has been rapidly gaining ground as a treatment for recurrent Clostridium difficile infection (CDI), showing in one study after another to be safe and often more effective than conventional therapies. A new study by Boston researchers supports the cost-effectiveness of this procedure as well. The growing incidence of CDI and the high cost of drugs used to treat it has resulted in soaring health care costs related to management of the infection. CDI has become particularly more difficult to manage since the emergence of the 027 strain, which has resulted in lower cure rates and increased resistance to treatments. Additionally, the rate of recurrence is growing: As many as one-third of patients experience a recurrence after an initial infection, and up to twothirds of those patients experience further recurrent infections. “All of this has resulted in a high
economic burden of over $1 billion annually,” said Gauree G. Konijeti, MD, MPH, a fellow in gastroenterology and hepatology at Massachusetts General Hospital and Harvard Medical School, both in Boston. Presenting the results at the American College of Gastroenterology 2013 Annual Scientific Meeting, Dr. Konijeti said that at Massachusetts General, “we manage an initial infection with metronidazole or vancomycin, and recurrences with either of these two antibiotics or fidaxomicin. FMT also has emerged as a highly effective therapy because of high cure rates and low rates of recurrence.” Given that background, Dr. Konijeti and her colleagues constructed a decision-analytic model to compare the cost-effectiveness of four treatments for recurrent CDI: metronidazole, vancomycin, fidaxomicin and FMT. The model used a patient cohort with a median age of 65 years with mild to
moderate CDI. In the primary analysis, FMT administered via colonoscopy was the most cost-effective strategy, showing an incremental cost-effectiveness ratio (i.e., the additional cost per additional unit of effectiveness gained) of approximately $38,000. “FMT also dominated metronidazole and fidaxomicin, which means that it was both more effective and less costly than either of those two antibiotics,” Dr. Konijeti said. The researchers also looked at the cost of FMT delivered via duodenal infusion and enema, but they found both strategies to be cost-prohibitive, mainly because of lower one-time infusion cure rates. They acknowledged that if cure rates with these techniques could be brought up to 89%, these two delivery strategies would be preferable to treatment with antibiotics as well. Sensitivity analyses revealed that FMT via colonoscopy would remain
the preferred strategy if the CDI recurrence rate following the procedure were lower than about 10%; for recurrence rates higher than 10%, the preferred strategy would be vancomycin. Vancomycin was the most costeffective initial treatment in situations where FMT was not available. In this scenario, competing antibiotic therapies with an efficacy similar to fidaxomicin would need to cost less than about $1,500 to be considered cost-effective. “In summary, a strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of CDI appeared cost-effective at conventional willingness-to-pay thresholds,” Dr. Konijeti said. “Guidelines should consider earlier use of FMT in the treatment of CDI, and future studies should incorporate FMT for comparative effectiveness,” she concluded. —Monica J. Smith
the incidence, severity and duration of CDAD. “Our results serve as a strong foundation supporting the use of probiotics in the prevention of CDAD, which payors do not pay for,” she said. Ms. Hoang’s team conducted their cost analysis based on two sets of data. The first was a randomized, doubleblind, controlled trial of a probiotic (BioK+2, Bio-K Plus International, Inc.) for CDAD prophylaxis ((Am J Gastroenterol 2010;105:1636-1641). In that study, 255 inpatients were administered penicillin, cephalosporin or clindamycin for a variety of infections and were ran-
domized to receive 100 or 50 billion colony-forming units (CFUs) daily of the active bacteria, or a placebo. All patients received the usual care if they developed CDAD despite active or placebo prophylaxis. Prophylaxis was initiated within 36 hours of the first dose of an eight-day course of antibiotics, and continued for five days following antibiotic cessation. Ms. Hoang said that study’s findings showed that 1.2% of the highdose probiotic group developed CDAD compared with 9.4% of the low-dose group and 23.8% of those who received a placebo ((P<0.05).
The second set of data Ms. Hoang’s team based their analysis on was a single-center cohort study that found nonsurgical inpatient stays to be 41% more expensive when patients develop CDAD (Clin Infect Dis 2008;46:497504). “Combining both data sets, we found that administering high-dose probiotics was the most cost-effective CDAD prevention and treatment strategy,” she reported. Specifically, the cost for each additional day of health averaged $14.38 per patient in the high-dose clinical study group compared with $55.91 and $160.84 for each additional day
of health in the low-dose and placebo groups, respectively. Ms. Hoang noted one study limitation is that the data her team relied on could have been flawed in some way that her team is not aware of. “Additionally, the [[Am J Gastroenteroll] study we utilized was conducted in China, so we advise caution when generalizing these results to the North American population until further studies are conducted.” —David Wild None of the sources reported any relevant financial conflicts of interest.
22 Technology
Pharmacy Practice News • April 2014
Compounding
A Clean, Well-Ventilated Place for Rent QleanSpace offers ‘turnkey,’ low-cost option for bringing sterile compounding in-house
W
ithin just a few months of the introduction of a new unique turnkey cleanroom system that facilities can rent rather than build themselves, 10 compounding pharmacies in the United States—the majority in hospitals—are in various stages of installing or working with the system, called QleanSpace. By mid-March, less than one month after its launch at the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting, the company that makes QleanSpace, Swedish-based QleanAir Scandinavia, had received more than 80 inquiries, according to QleanAir’s chief executive officer Dan Pitulia. A U.S. subsidiary, QleanAir Scandinavia, Inc, just opened in Columbus, Ohio. The first company to install a QleanSpace room in the United States, Krs Global Bio Technology Inc, in Boca Raton, Fla., a high-volume privately held third-party compounding company, signed a lease for the ASHP show sample unit right on the floor at ASHP. “I was extremely impressed with the technology,” said Rick Roscetti, the chief executive officer and president of Krs Global. So impressed that just two weeks after the unit was installed in early January, Mr. Roscetti signed a lease for another unit, this one at 600 square feet, “four times larger” than the traditional cleanroom it will replace in one of his two facilities. “I liked it that much,” he said. Mr. Roscetti said he plans to lease a third QleanSpace unit (approximately 600 square feet) to be used for nonhazardous drug compounding that will be installed in a new facility that Krs Global is opening this spring, and he also plans to lease a fourth, possibly 600-square foot QleanSpace, in the fall. “I like the service. I like the flexibility and ease, and most importantly, I don’t have to worry about the cleanrooms’ upkeep or its compliance to regulations because QleanAir manages and monitors everything for me as part of the monthly leasing fee,” he said, adding that as part if its commitment to patient safety, Krs Global voluntarily registered with the FDA as part of the newly passed compounding legislation. QleanSpace can be purchased if a hospital is sure it wants to operate a cleanroom over the long term, but if a hospital wants to have a cleanroom now, but possibly outsource some or all compounding in three, four, five or even six years, QleanSpace is “a very attractive option,” said Gregory Burger, MS, RPh, the senior director of hospital and health system services for Minneapolis-based Visante, Inc., a medications management consulting company.
Mr. Pitulia said, are done to ensure compliance with ISO standards.
‘Peace of Mind’
QleanAir Scandinavia displayed a fully operational ISO class 5 cleanroom at its U.S. launch at the 2013 ASHP Midyear Clinical Meeting.
As a rental and a turnkey approach, QleanSpace has no up-front costs, Mr. Burger noted. A pharmacy doing compounding by leasing the unit does not have to worry about upkeep or pay additional “à la carte fees” for maintenance, electronic monitoring, parts, filters, testing etc., he added. QleanSpace has another unique feature: It is designed with a self-contained air-filtering system that can operate without a connection to a hospital’s heating, ventilation and air conditioning (HVAC) system. “All a hospital needs is electricity,” Mr. Pitulia said. “They just plug it in and it runs.” QleanSpace can be connected to a hospital’s HVAC if a client wants that setup, but the self-contained filtering system, both Mr. Burger and Mr. Pitulia explained, gives a hospital “complete flexibility.” The hospital can choose to “install, expand, move or reinstall the room, without having to provide outside ventilation,” Mr. Burger said.
Temperature Another Benefit QleanSpace executives pointed out another environmental benefit to the new cleanroom. Traditional cleanrooms, Mr. Pitulia noted, can become “very warm,” especially when there is additional equipment like laminar air flows putting off heat. QleanSpace, in contrast, when used for compounding nonhazardous drugs, is an open environment with the room itself serving as a hood, “with air filtration washing over the work surface.” Hooded laminar air-flow units, also known as biologic safety cabinets, will need to be placed in the room and QleanSpace rooms will need ventilation to the outside if clinicians will be working with hazardous medications such as chemotherapy drugs, the company noted. Mr. Burger described the filtration
devices, ISO Class 5 (Class 100) air filtration, high-efficiency particulate air or ultra-low penetration air fan/ filter modules that are attached on the outside of QleanSpace’s walls, as “very slim, taking up no space inside the cleanroom and very energy-efficient.” He further noted that “for a retrofit, it becomes very attractive because you don’t have to find additional space for HVAC equipment.” There are three main physical components to QleanSpace: the filters, one or two anterooms and the cleanroom area itself. Air from outside is drawn in and through the filters into QleanSpace’s anteroom(s) (where technicians garb up) and then flows into the clean space area. There are enough filtration devices and air force to create a pressure gradient that moves the air in a continuous cycle, Mr. Burger explained. Air pressure moves the air through the filters into the clean room area at ISO 5 and then the pressure circulates the air out through the anterooms where the ISO Class decreases to ISO 7, “keeping the cleanroom space area as clean as possible, going from less clean to more clean coming in and back to less clean going out.” Software continuously monitors in real time four key metrics: the level of airborne particles, pressure levels, temperature and humidity. The results are displayed on a screen that can be read by staff from within or outside the room, and because the data are logged into a computer, it can be reviewed at any time or whenever a hospital needs to document that its cleanroom environment has been maintained in compliance with regulations. Warning signals are issued at preset levels when the cleanroom rating limits are approached. Regular audit tests,
In describing what he liked about QleanSpace, Mr. Roscetti said, “It goes the whole nine yards. It’s computerized. It monitors all the parameters daily in real time, particle counts, temperatures, humidity and pressure. It’s clean, compact, easy to expand and easy to operate, and QleanAir takes care of the maintenance. They come in every three months and certify it. They change the filters. If any repairs are needed, they take care of it. I can focus on just running my business. It gives me peace of mind.” Mr. Roscetti described QleanAir’s management and staff as “very helpful to work and collaborate with.” He noted that QleanAir is developing an application for his iPhone that will make it possible for the QleanSpace software to send alerts directly to his smartphone. Savings come from a variety of sources. Mr. Roscetti estimates a savings of approximately $8,000 a year just by not having to hire a third party to test the rooms to ensure compliance. And because he had been considering buying a large traditional cleanroom for about $125,000 and a smaller one for $70,000, he feels the leasing option was just right for him. “I didn’t have to make large outlays up front.” Mr. Burger noted that hospitals considering buying a cleanroom “are probably looking at an initial outlay of a couple of hundred thousand dollars at a minimum on up to $1 million for a hard [traditional brick and mortar] room. Some hospitals could save up to $30,000 a year in maintenance fees alone. So, for many hospitals, there are strong financial incentives for opting for a QleanSpace cleanroom.” Rental fees are $25 per square foot a month, which includes installation, monitoring and parts replacement as needed. If hospitals lock in for longer rental periods, for example, three years rather than six months, the fees can be discounted, depending on the length of the rental. Mr. Pitulia said the wait for an installation would be approximately six weeks, and that an average install could be done in one or two days. The smallest installation, he added, would be 30 square feet, but the space can be expanded easily. If a hospital needs multiple rooms for different types of compounding or for redundancy, he said, they can “install QleanSpace areas side by side for no additional cost.” —Liz Parks
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24 Spotlight on Bleeding Management n nt
Pharmacy Practice News • April 2014
New meta-analysis confirms earlier data: t ta:
Novel Anticoagulants Best Warfarin on Two Counts F
or more than half a century, physicians treating patients with atrial fibrillation had a single anticoagulant available to reduce the risk for stroke: warfarin. Within the past five years, a flurry of novel anticoagulants has completely changed the playing field. In rapid succession, dabigatran (Pradaxa, Boehringer Ingelheim; 2010), rivaroxaban (Xarelto, Janssen; 2012) and apixaban (Eliquis, Bristol-Myers Squibb; 2013) were approved for this indication, and Daiichi Sankyo’s edoxaban (Savaysa) appears poised to be the fourth such drug. However, despite strong evidence from four of the largest clinical trials ever to be conducted in medicine (between 14,000 and 21,000 patients each), clinicians have been somewhat wary of the new agents, especially for patients who have done well on warfarin. “The uptake of these new agents has been relatively modest,” according to Christian Ruff, MD, MPH, a cardiologist at Brigham and Women’s Hospital, in Boston, and co-principal investigator of the ENGAGE AF-TIMI 48 trial of edoxaban. Estimates vary, but it is thought that between 30% and 50% of patients with atrial fibrillation who are eligible for anticoagulation do not receive it because of a perceived risk for bleeding. Even among patients who are prescribed anticoagulant therapy, about half do not take it or are not doing so effectively. Now, a new meta-analysis conducted by Dr. Ruff and his colleagues at Brigham and Women’s Hospital may change that.
‘Because they have a much shorter half-life, missing a dose with one of these drugs leaves the patient relatively unprotected from stroke. Pharmacist– physician communication is critical to make sure patients are taking these drugs as prescribed.’ —Christian Ruff, MD, MPH
Published in Lancet (doi:10.1016/S01406736(13)62343-0), the analysis found that all four of the novel drugs are as effective as warfarin, if not more so, and they offer much better safety profiles. The pooled results showed a significant reduction in stroke or systemic embolism (relative risk [RR], 0.81;
95% confidence interval [CI], 0.73-0.91; P<0.0001), primarily due to a reduction in hemorrhagic stroke (RR, 0.49; 95% CI, 0.38-0.64; P<0.0001). Intracranial hemorrhage also was reduced (RR, 0.48; 95% CI, 0.39-0.59; P<0.0001), although there was an increase in gastrointestinal (GI) bleeding (RR, 1.25;
95% CI, 1.01-1.55; P<0.04). The new drugs also reduced all-cause mortality compared with warfarin (RR, 0.90; 95% CI, 0.85-0.95; P<0.0003). “There are differences from trial to trial, but patients live longer when they take these drugs compared to warfarin,” said Dr. Ruff. “Warfarin reduces mortality by over 20%, and you get another 10% with these new agents.” Although there is nothing particularly surprising in the findings of the metasurp anaalysis, it’s helpful to have the stronger pooled data, said Edith Nutescu, PhaarmD, FCCP, a clinical professor of phaarmacy practice at the University of Illin nois at Chicago. “It’s nice to see that the results of the four major trials hold up in a large meta-analysis, as well as havving better answers to some of the queestion marks, such as GI bleeding.” Dr. Nutescu told Pharmacy Practice D New ws that the meta-analysis also offers insiights on the use of the low-dose opttions with apixaban and edoxaban. ““These can be used in more frail patients, such as the elderly and renally impaired,” she said. “In these patients, we see that the lowdose versions of these drugs are no more effective than warfarin, but they are no worse and there is a safety advantage. It’s one more option for our toolbox: In patients at a higher risk of complications, we can use lower doses and not pay on the efficacy side.” The large pool of data allowed for a deeper dive into data on vulnerable subgroups, such as elderly patients, patients
•
see META-ANALYSIS, page 32
Reversing Novel Anticoagulants: No Easy Answers
N
ovel anticoagulants such as dabigatran, rivaroxaban and apixaban have several advantages over warfarin: They have fewer drug–drug interactions, require less frequent monitoring, offer standardized dosing and, according to a new meta-analysis, are at least as effective as warfarin while reducing all-cause mortality and the risk for life-threatening bleeding (see story, above). But warfarin has one thing that these other agents do not: a specific antidote in the event of a major bleeding complication. To address this problem, pharmacists from the Clement J. Zablocki Veterans Affairs Medical Center, in Milwaukee, developed reversal protocols for the novel anticoagulants. In a presentation
‘I don’t think there’s a single right answer or a right protocol. It’s using the evidence that’s available and customizing it to the institution’s resources.’ —Daisy Peterson, PharmD, BCPS at the American Society of Health-System Pharmacists 2013 Midyear Clinical Meeting, they discussed the challenges of creating and keeping up such protocols, given the paucity of the current evidence on the subject. “With the evolution of these novel agents, James Sebastian, MD, our physician champion for anticoagulation, felt that it was essential that we be prepared before a bleeding event occurs,”
Jennifer Koch, PharmD, BCPS, CGP, a clinical pharmacy specialist involved with the project, told Pharmacy Practice News. “So he brought together a group of clinical pharmacy specialists to review the literature.” They did not find much. “We started in the fall of 2012, when dabigatran [Pradaxa, Boehringer Ingelheim] and rivaroxaban [Xarelto, Bayer] were on the market and four-factor [prothrom-
bin complex concentrate (PCC), Kcentra, CSL Behring] had not yet been approved in the U.S.,” said Daisy Peterson, PharmD, BCPS, a clinical pharmacy specialist in primary care at the VA medical center. “At that time, the evidence for reversal using concentrated clotting factor products was limited to one study with healthy humans, and the rest were mainly lab and animal studies.” The working group sent a request to anticoagulation listservs to see what other hospitals were using, and found that only a handful had created protocols. “So we created our protocols based on the very limited literature we had available,” Dr. Peterson said. For major bleeding, the protocols for
•
see REVERSING, page 33
Spotlight Sp p on Bleeding Management 25
Pharmacy Practice News • April 2014
Antithrombin Deficiency Ups Risk for Recurrent VTE P
atients who have inherited antithrombin (AT) deficiencies face an increased risk for recurrent episodes of venous thromboembolism (VTE), according to a recent study by Italian researchers. The study’s findings aree important because AT deficiency preesents continued risk for recurrence of o VTE, said Nancy Shapiro, PharmD, a cllinical associate professor in the Dep partment of Pharmacy Practice at the University U of Illinois, Chicago, who was not n involved with the research. Inherited AT deficiency, allthough rare with an estimated frequencyy of 0.02% of the general population, can n pose up to a 10-fold increase in risk forr VTE. Normal AT concentrations rangge from 80% to 120%, corresponding to a reference range of approximately 17 to o 39 mg/dL. During a 10-year study period, clinicians at the Federico II University Hospital, in Naples, Italy, en nrolled 823 patients with a previous ep pisode of VTE. They separated the paatients into three categories by AT conc centration: no AT deficiency ncy
(>80%), mild AT deficiency (70%-80%) and overt AT deficiency (<70%). Of these, 37 patients had overt AT deficiency, 43 had mild AT deficiency and 743 had normal AT levels (Circulation 2014;129:497-503). 2014;129:497 503). Observing the total study population, the investigators found that VTE recurred in 253 patients, for a rate of 3.53% per patient-year. The researchers further divided the patients who experienced a recurrent VTE into two groups: patients with provoked VTE (n=502), who had an additional risk factor such as undergoing surgery within three months before the
thromboembolism, experiencing trauma or fracture, or traveling long distances; and patients with unprovoked VTE (n=321), who had no other risk factors besides AT deficiency.
German Team Evaluates Adverse Outcomes Of AT Deficiency During Pregnancy
A
ntithrombin (AT) deficiency, although affecting only a small percentage of pregnant wo omen, may result in adverse outcomes, such as premature birth and early miscarriage. In a rettrospective analysis of more than 1,000 women with pregnancy-associated venous thromboem mbolism (VTE) or complications, German researchers screened for inherited or acquired thrombophiilia and found seven patients with AT deficiency. Of the seven women evaluated, there were 18 pregnancies, 11 resulting in healthy newborns, o one premature infant, two late-pregnancy losses and four miscarriages ( 2014;93:385-392). More than h half of the pregnancies occurred before the patients’ diagnoses of inherited AT deficiency; consequently, tthe patients were untreated during those pregnancies. In five pregnancies, patients received AT replacemen nt and lowmolecular-weight heparin (LMWH), and in three cases, patients received only LMWH. When clin nicians administered both AT replacement therapy and LMWH, the researchers found the lowest number of p pregnancy complications and the best neonatal outcomes. Study author Bettina Toth, MD, of the Department of Gynecological Endocrinology and Fe ertility Disorders at the Ruprecht-Karls University, in Heidelberg, Germany, told Pharmacy Practice News that cliinicians should aim to differentiate patients with preexisting VTE from patients without any thrombosis, to mitig gate the effects of AT deficiency among pregnant women. But screening isn’t routinely practiced unless a patient has a history of miscarriage, intrauterin ne growth retardation or other pregnancy complications, according to Nancy Shapiro, PharmD, a clinical a associate professor in the Department of Pharmacy Practice at the University of Illinois, Chicago, who was not involved with the study. She also noted that because the study was not prospective, “you can’t globally recommend [AT replacement or LMWH treatment] at this point.” William Dager, PharmD, a clinical professor of pharmacy at the University of California, San Frrancisco, agreed, noting that AT replacement therapy during pregnancy is not standard, and it is ex xpensive. The population in this study, he said, is too small to result in a convincing best approach. Dr. Shapiro, who said she has followed roughly 200 to 300 pregnant women who have neede ed anticoagulation therapy, called this a “very difficult population to manage.” It’s a “considerable challenge” for pregnant patients to receive injections, “let alone come in and have infusions” du uring their entire pregnancies. What is more common, Dr. Shapiro said, is for clinicians to try to m manage AT deficiencies closer to the delivery period. Additionally, Dr. Dager said, for identified AT-deficient patients, “it’s important to have anticoa agulation management for six weeks post pregnancy.” To minimize the risk for complications, Dr. Toth suggested that pharmacists should work to treat patients together with hematologists and general practitioners. —B.G.
The investigators found that patients with AT deficiency had a higher rate of recurrence compared with patients with normal AT levels. Specifically, in the unprovoked group, patients with mild AT deficiency were 3.9 times more likely to have a VTE recurrence than those with normal AT levels (95% confidence interval [CI], 2.25-6.77) and patients with overt AT deficiency were 5.93 times more likely (95% CI, 3.38-10.39). Given these findings, the study authors recommended that clinicians consider screening patients for thrombophilia following the initial VTE events. Dr. Shapiro pointed out, however, that the applicability of screening might be limited because of the rarity of the condition, as well as the cost of the screening assay—which she called significant, at “hundreds of dollars per test.” She suggested that if ultrasounds reveal residual clots, D-dimer levels and other risk factors, “you need to consider the individual clinical risk for recurrence,” by evaluating a patient’s age, weight, and their history of cancer and of smoking. Because of the low frequency of the inherited condition, no universal guidelines for screening or treating patients have been established, but the investigators suggested using the rate of 5% recurrence per patient-year as a cutoff to determine whether patients should consider long-term anticoagulation therapies. Matteo Nicola Dario Di Minno, MD, a researcher in the Department of Clinical and Experimental Medicine at Federico II University and an author of the study, told Reuters Health that patients with unprovoked VTE might consider a regimen of a lifelong oral anticoagulant, “although,” he acknowledged that the results “should be confirmed in further studies.” William Dager, PharmD, a clinical professor of pharmacy at the University of California, San Francisco, who was not involved with the research, said that an unnecessary increased risk for bleeding might result from lifelong anticoagulation that is based on testing instead of symptomatic events. At this point, Dr. Shapiro suggested that clinicians should continue to administer anticoagulation therapies, such as warfarin or other vitamin K antagonists, to appropriate patients “unless their risk of bleeding becomes too high.” She said that a balance should be struck between a patient’s individual risk for bleeding and his or her benefit from continuing therapy. —Ben Guarino
Drs. Shapiro, Dager and Toth reported no relevant financial conflicts of interest. Drs. Dager and Shapiro 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
12
2G3450
360 mg/200 mL
1.8 mg/mL
43066-360-20
10
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
30 Spotlight on Bleeding Management nt
Pharmacy Practice News • April 2014
Pharmacists Boost IVIG Rx Outcomes in CIDP
W
hen pharmacists are involved in managing immunoglobulin therapy for patients with chronic inflammatory demyelinating polyneuropathy (CIDP), these patients are more likely to have better outcomes, according to a recent pilot study. The study examined whether intervention by specialty-trained pharmacists with disease-specific expertise and evidence-based dosing recommendations
can improve outcomes for patients with CIDP, an autoimmune disorder affecting the peripheral nerves that results in progressive weakening of upper and lower extremities. To optimize the use of intravenous immunoglobulin (IVIG) for patients with CIDP, investigators from Accredo Health Group, in St. Louis, developed a therapy management program to guide patient assessment and selection of an appropriate dosing regimen.
Presenting the study results at the American Society of Health-System Pharmacists 2013 Midyear Clinical Meeting, the investigators reported that physicians accepted recommended dose changes about half the time and that patients whose physicians accepted those recommendations were more likely to have an improved disability score than patients whose physicians’ declined the recommendations (63% vs. 25%, respectively).
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“There’s no clear standard guidance for IVIG dosing for CIDP, so there’s a wide variation in how the drug is prescribed,” said Lesley D’Albini, PharmD, BCPS, the lead researcher on the study, and a senior clinical practice manager at Accredo. For example, sometimes, obese patients are dosed according to their actual body weight, and other times according to their ideal body weight. “We wanted to show that specialist pharmacists with disease specific expertise ... can apply [their] knowledge to appropriate dosing, so patients get better outcomes and it costs less money [for] payors.” The study sample included 722 patients treated according to the CIDP Optimal Regimen Evaluation (CORE) therapy management program, an evidence-based, five-step algorithmic loop: dose assessment, initial patient assessment, physician engagement, patient reassessment and physician re-engagement. Researchers performed a retrospective review of CORE program records for patients receiving at least one dose of IVIG for CIDP from Jan. 1, 2010 to Feb. 25, 2013. The investigators concluded that the CORE program effectively evaluates IVIG therapy and it uncovered a tendency toward underdosing of IVIG. During the study, Accredo recommended dose increases 90% of the time. The findings raise questions for some experts. “It’s important to note the potential conflict of interest here,” said Eric M. Tichy, PharmD, BCPS, a senior clinical specialist in solid organ transplant at Yale-New Haven Hospital, in Connecticut. “Accredo may benefit financially from dispensing larger doses of IVIG for CIDP. However, the study shows improved outcomes, and, ultimately, getting the patient better without causing harm is everyone’s goal.” Responding to Dr. Tichy’s comment, Dr. D’Albini said, “Our purpose is not to automatically recommend a higher dose. If a patient’s disability score is 0, we recommend titrating back and eventually discontinuing IVIG. But we won’t see that until the program is running for about two years. At that point, we estimate up to onethird of patients will go into remission.” Dr. D’Albini, who is continuing to enroll patients in the program and is evaluating additional interventions to adjust (reduce or increase) the dosing regimen as clinically appropriate, is expecting to publish the additional findings in a couple of years. “The biggest takeaway from the study is that I hope it makes pharmacists feel more empowered to make changes in the dosing of IVIG for CIDP,” said Dr. D’Albini. “Especially when there are clinically significant reasons to do so.” —Dana Hawkins-Simons
Supported by an educational grant from Dr. Tichy reported no relevant financial conflicts of interest.
Spotlight Sp p on Bleeding Management 31
Pharmacy Practice News • April 2014
IVIG Stewardship Program Improves IVIG Dosing, Lowers Costs Orlando, Fla.—Intravenous immunoglobulin (IVIG), with its anti-inflammatory and immunomodulatory effects, continues to show a clinical benefit for a growing number of disease states. In a study presented at the American Society of Health-System Pharmacists 2013 Midyear Clinical Meeting, investigators concluded that an IVIG stewardship program helps ensure guideline compliance for appropriateness of indication and dose. “The purpose of an IVIG prescribing guideline is transparency,” said lead researcher Megan Rocchio, PharmD, BCPS, a clinical pharmacy specialist at Brigham and Women’s Hospital (BWH), in Boston. “The results of the study reaffirmed that we as an institution are doing a good job dosing IVIG. A detailed prescribing guideline assists both prescribers and pharmacists in ordering and approving appropriate doses for patients.” BWH has an extensive institution-specific prescribing guideline that outlines indications for use of IVIG, as delineated by the Pharmacy and Therapeutics Committee. In October 2010, a pharmacist-driven stewardship program was implemented to ensure the hospital was following its own prescribing guideline, with respect to indications, order frequency, dosing weight and grams dispensed. IVIG utilization data were collected from January through August 2013 for 194 patients on the indications for IVIG, the number of patients actually receiving the medication, the appropriateness of orders based on indication and dosing adherence, the number of orders discontinued due to guideline nonadherence, and the number of grams dispensed based on ideal body weight (IBW; the appropriate weight considering the patient’s height, sex and age) as opposed to theoretical grams potentially dispensed based on actual body weight. (Because IVIG does not penetrate into fat, BWH and some other institutions dose based on IBW rather than actual body weight. Using smaller amounts of the drug cuts costs—especially when figuring doses for obese patients. Some institutions dose based on adjusted body weight [ABW], which is a number that lies somewhere between IBW and actual body weight.) The BWH investigators found that 11,706 g were dispensed; about 2,684 g of IVIG was averted based on IBW dosing, and 650 g was averted based on noncompliant indications. Nine IVIG orders were evaluated but denied based on noncompliance with the guideline. On average, about 14 g were averted per case, resulting in a 19% theoretical reduction in the amount of IVIG dispensed. The top indications were hypogammaglobulinemia associated with bone marrow transplantation or oncologic disease, idiopathic thrombocytopenic purpura
and acute organ rejection. “I always say IVIG is like liquid gold,” said Eric M. Tichy, PharmD, BCPS, a senior clinical specialist in solid organ transplant at Yale-New Haven Hospital, in Connecticut. “If you have a pharmacist dedicated to IVIG stewardship at your medical center, you could save a lot of money. You could even pay a pharmacist’s salary with the money you’d save each year by establishing a stewardship pro-
gram.” He added: “If we have stewardship over antibiotics, then we should also have it over antibody therapies.” Could the study results change practice? Dr. Tichy thinks so. “The whole concept of antibody stewardship is gaining traction. IVIG is a precious resource, and it’s important that we use it responsibly.” He added that hospitals still not using ABW or IBW when figuring patient doses might make the change after they
high in botic risk is When throm thrombin deficiency ti hereditary an
see from the study how they could save money by switching to the lower doses. And that’s exactly what the BWH team had in mind. “We’re sharing our practices to help other institutions who may be looking to implement an IVIG guideline,” said Dr. Rocchio. “That’s our overall goal.” —Dana Hawkins-Simons Drs. Rocchio and Tichy reported no relevant financial conflicts of interest.
To learn more, visit www.thrombate.com
FELY PROCEED SA
Thrombate III® (antithrombin III [human])—proven effective for patients with hereditary antithrombin (AT) deficiency during surgery, childbirth, and in the prevention and treatment of thromboembolism1 Thrombate III provides predictable amounts of AT to replace what is normally present in the body t AT concentrate purified from human plasma and pasteurized to inactivate viruses, with no confirmed cases of virus transmission t In clinical studies, no cases of thrombotic complications during surgical and obstetrical procedures were reported
Easy to administer1
Convenient to store and reconstitute1
t One dosing formula t Bolus intravenous infusion (not continuous infusion) t Pregnancy category B
t 500 IU vials with sterile water for injection t Filter and transfer needles provided t Room temperature storage
Important Safety Information Thrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia. The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk. No cases of transmission of viral disease or CJD have ever been identified for Thrombate III. Please see brief summary of Thrombate III complete Prescribing Information on adjacent page. Reference: 1. Thrombate III® (antithrombin III [human]) [prescribing information]. Research Triangle Park, NC: Grifols Inc; 2012. © 2013 Grifols Inc.
All rights reserved.
February 2013
TH05-0113
32 Spotlight on Bleeding Management n nt
META-ANALYSIS
Low doses off some off these th h new drugs d are ‘one ‘ more option for our toolbox: In patients at a higher risk of complications, we can use lower doses and not pay on the efficacy side.’
continued from page 24
with a history of myocardial infarction, and individuals with kidney dysfunction. “Physicians worry that although the results of the trials are impressive, they don’t necessarily apply to more complex patients in the real world,” said Dr. Ruff. “But when we combined the data, we were able to see that the efficacy of these drugs in reducing stroke is consistent, even in patients at very high risk of having a stroke, and, most importantly, that the risk
Pharmacy Practice News • April 2014
—Edith Nutescu, PharmD, FCCP of bleeding is substantially less across subgroups. That was something that the individual trials couldn’t answer definitively because these vulnerable patients were relatively underrepresented.”
THROMBATE
III®
Antithrombin III (Human) BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
FOR INTRAVENOUS USE ONLY DESCRIPTION Antithrombin III (Human), THROMBATE IIIw is a sterile, nonpyrogenic, stable, lyophilized preparation of purified human antithrombin III (ATIII). THROMBATE III is prepared from pooled units of human plasma from normal donors by modifications and refinements of the cold ethanol method of Cohn. When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0–7.5, a sodium content of 110–210 mEq/L, a chloride content of 110–210 mEq/L, an alanine content of 0.075–0.125 M, and a heparin content of not more than 0.1 IU heparin/IU ATIII. THROMBATE III contains no preservative and must be administered by the intravenous route. Each vial of THROMBATE III contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation. The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm. The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. CLINICAL PHARMACOLOGY Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on ATIII. ATIII is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine proteases by ATIII proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect in vivo of heparin is mediated by ATIII, heparin is ineffective in the absence or near absence of ATIII. The prevalence of the hereditary deficiency of ATIII is estimated to be one per 500 to 5000 in the general population. The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with ATIII levels of 40%–60% of normal. These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary ATIII deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deficiency have been reported. In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism. Greater than 85% of individuals with hereditary ATIII deficiency have had at least one thrombotic episode by the age of 50 years. In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of ATIII, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals. In clinical studies of THROMBATE III conducted in 10 asymptomatic subjects with hereditary deficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administered based on immunologic ATIII assays, and 1.4% per unit per kg administered based on functional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of ATIII. These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days. In clinical studies of THROMBATE III, none of the 13 patients with hereditary ATIII deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures. Eight patients with hereditary ATIII deficiency were treated therapeutically with THROMBATE III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE III reversed heparin resistance in two patients with hereditary ATIII deficiency being treated for thrombosis or thromboembolism. During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving THROMBATE III became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for ⱖ 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B. INDICATIONS AND USAGE THROMBATE III is indicated for the treatment of patients with hereditary antithrombin III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.
Pharmacists will play an important role in helping their institutions adapt to these novel agents, Dr. Ruff said. One key challenge will be the development of reversal protocols for major bleeding
Subjects with ATIII deficiency should be informed about the risk of thrombosis in connection with pregnancy and surgery and about the inheritance of the disease. The diagnosis of hereditary antithrombin III (ATIII) deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency. ATIII in plasma may be measured by amidolytic assays using synthetic chromogenic substrates, by clotting assays, or by immunoassays. The latter does not detect all hereditary ATIII deficiencies. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.) Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation. CONTRAINDICATIONS None known. WARNINGS Because THROMBATE III is made from human plasma, it may carry a risk of transmitting infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for THROMBATE III. Inform patients that THROMBATE III is made from human plasma and may contain infectious agents that can cause disease. While the risk that THROMBATE III can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics Inc. [1-800-520-2807]. The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. PRECAUTIONS General 1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution. 2. Administer only by the intravenous route. 3. THROMBATE III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions. 4. Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in sharps container after single use. Discard all equipment including any reconstituted THROMBATE III product in accordance with biohazard procedures. The diagnosis of hereditary ATIII deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency. Laboratory Tests It is recommended that ATIII plasma levels be monitored during the treatment period. Functional levels of ATIII in plasma may be measured by amidolytic assays using chromogenic substrates or by clotting assays. Drug Interactions The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to THROMBATE III. It is not known whether THROMBATE III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.) Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation. ADVERSE REACTIONS In clinical studies involving THROMBATE III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were dizziness (8), chest discomfort (3), nausea (3), dysgeusia (3), chills (2), pain (cramps) (2), dyspnoea (1), chest pain (1), vision blurred (1), intestinal dilatation (1), urticaria (1), pyrexia (1), and wound secretion and hematoma (1). If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate. CAUTION & only U.S. federal law prohibits dispensing without prescription.
Grifols Therapeutics Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1871
events since, unlike warfarin, none of the new agents yet has a specific antidote (see page 24). Another issue with these new anticoagulants is cost and availability. And cost is a big factor contributing to nonadherence. Although they are cost-effective overall because of their ability to reduce serious events and hospitalizations, the out-of-pocket cost to the patient is obviously more, given that warfarin has been available generically for a long time. However, Dr. Ruff said, “All of these drugs have plans available from the manufacturers to help patients get them more affordably. Pharmacists have an important part to play in making sure that the patients are able to get the coupons and cost reductions that allow them to take this chronic therapy indefinitely.” With warfarin, international normalized ratio values can quickly tell a clinician whether or not the patient is compliant with therapy. But with the new drugs, more active pharmacist involvement will be needed to ensure medication adherence. “Because they have a much shorter half-life, missing a dose with one of these drugs leaves the patient relatively unprotected from stroke,” Dr. Ruff said. “Pharmacist–physician communication is critical to make sure patients are taking these drugs as prescribed.” While the intensive monitoring required for warfarin is not needed for the newer anticoagulants, that doesn’t mean they can simply be prescribed and forgotten. “These are still anticoagulants, and vigilance is still required,” Dr. Nutescu said. “In the trials, of course, there was very close follow-up. We need to see whether the same efficacy and safety benefits accrue in the large observational trials without this kind of monitoring.” Warfarin isn’t going to be displaced anytime soon, Dr. Ruff pointed out. “None of these drugs are approved for patients with very severe kidney diseases, or who are on dialysis. And for patients with a mechanical heart valve, it’s very dangerous and contraindicated to use the new agents. The vast majority of patients with [atrial fibrillation] are eligible for one of the new agents, but for patients like these, warfarin remains the only available anticoagulant.” —Gina Shaw Dr. Ruff reported doing research for Daiichi Sankyo and consulting/advisory board for Daiichi Sankyo, Bristol-Myers Squibb, and Boehringer Ingelheim. Dr. Nutescu reported no relevant financial conflicts of interest.
08941115-BS
Spotlight Sp p on Bleeding Management 33
Pharmacy Practice News • April 2014
REVERSING continued from page 24
all three anticoagulants recommend fluid replacement, hemodynamic support, blood and platelet transfusion, and activated charcoal administration at standard doses if the last anticoagulant dose was taken within the last two hours for dabigatran, six hours for apixaban [Eliquis, Bristol-Myers Squibb] and eight hours for rivaroxaban. Because dabigatran has low plasma protein binding, the reversal protocol for that drug also includes an option for hemodialysis. This is not an option with rivaroxaban or apixaban because they are highly protein-bound. If all these standard measures fail and life-threatening bleeding develops, the protocols then recommend consideration of concentrated clotting factor products. Noting that the strength of the evidence for these last recommendations “is weak and limited, they said the agents are used as a last resort.” For rivaroxaban and apixaban, threefactor PCC (Profilnine, Grifols) may be considered to help with clot formation at the site of bleeding. For dabigatran, the protocol recommends three-factor PCC or recombinant activated Factor VII (NovoSeven, NovoNordisk). Dr. Koch said the protocol is under revision to include recombinant activated Factor VII as part of the regimen with three-factor PCC. “Right now, for dabigatran it’s one or the other, and with rivaroxaban and apixaban it’s just three-factor PCC. We plan to update the protocol to include a small amount of Factor VII concurrently with the three-factor PCC for all three [anticoagulants], and we will likely switch to four-factor PCC when current stock of three-factor PCC stock is exhausted or expires.” The development of these protocols is as much art as it is science, Dr. Peterson said. “As more evidence develops, I don’t think there’s a single right answer or a right protocol. It’s using the evidence that’s available and customizing it to the institution’s resources.” It is a very complicated situation, agreed Michael Gulseth, PharmD, BCPS, FASHP, the program director for anticoagulation services at Sanford USD Medical Center, in Sioux Falls, S.D., and the president and lead consultant at Michael P. Gulseth Anticoagulation Consulting, Inc. “The literature is changing so quickly, and we still don’t have great evidence or guidance on not just the question of how you reverse different agents, but also on what dose you use. I often read recommendations on dosing from real experts, and I’m not sure I agree with them.” To make matters even more challenging, the agents used in an emergency
situation come me with ith their th i own risks. risks i k “Your antidote may be worse than your poison,” Dr. Gulseth said. “That’s one of my biggest concerns. I have one physician who wants hard and fast protocols—order sets you can pick in an instant—and I’m struggling with how much we can standardize this.” Nonetheless, he added, developing a protocol is “absolutely the right thing to do. But you have to be very careful to update your guidelines as new literature becomes available, and turn that around rather rapidly.”
Staying St i on ttop off th the literature as it comes in is a key charge for the Zablocki VA working group. “The time and resources it takes to do in-depth literature searches are an issue,” Dr. Koch pointed out. “It evolves pretty quickly. And there will be antidotes at some point, and that will change the whole thing again. It’s such a moving target. But I’m proud of being proactive. Too often, we wait until something happens.” They haven’t needed to use the protocol yet, he noted, but “if an instance comes up, we can guide
ERROR PREVENTION
the provider to give the best care we have available.” —Gina Shaw Drs. Koch, Peterson and Gulseth reported no relevant financial conflicts of interest.
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PATIENT SAFETY
34 Operations & Management
Pharmacy Practice News • April 2014
Continuity of Care ‘If you don’t start [the discharge planning] process when the patient walks in the door, it’s going to be a lot harder when he or she leaves.’
DISCHARGE continued from page 1
“It’s really easy to jump to the outcome and not think through the processes that need to change first,” Dr. Tyler said. Take time to assess the unmet needs, walk through the modifications required to address them, stay flexible and be proactive in keeping tabs on how the organization’s needs may fluctuate, she said. Many of the best programs, including those featured in the ASHP-American
—Joseph L. Cesarz, PharmD Pharmacists Association report, “Medication Management in Care Transitions: Best Practices” (http://bit.ly/MqvXPm), stress strong communication between the inpatient and outpatient pharmacy
teams, Dr. Tyler noted. The University of Utah developed a unified thrombosis prevention discharge planning protocol that includes an inpatient anticoagulation pharmacy specialist
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
who arranges follow-up appointments for patients with the outpatient thrombosis clinic. These outpatient pharmacists then follow up with patients by phone to make sure they keep their scheduled appointments and contact them to reschedule if they miss an appointment. Discharge services at the University of Utah were developed based on an adverse event in which a patient left the hospital without filling his clopidogrel prescription and had serious complications. “We really focus on managing those transitions so we can prevent adverse outcomes,” Dr. Tyler said. Coordination between the inpatient and outpatient “arms” is critical in that regard, she added. The process was expanded throughout the hospital following successful pilot projects in a handful of units, including cardiology. Primary responsibility for discharge medication reconciliations in most of the units belongs to the ambulatory pharmacy staff because this group has the most thorough knowledge of insurance and prior authorizations. “Over time, we’ve developed staff that specialize in discharge pharmacy,” Dr. Tyler said.
The Ins and Outs Of Care Continuity Making sure outpatient pharmacists have access to inpatient information is emerging as another best practice, she said. This access is a feature of a model presented by Rhode Island Hospital, Providence, at the ASHP 2013 Midyear Clinical Meeting. The hospital created an integrated outpatient retail pharmacy and dedicated a clinical pharmacist specialist to serving as a liaison between the inpatient and outpatient pharmacy teams. A fully integrated computer system at the retail pharmacy gives the dispensing pharmacists access to medication histories, lab values, drug allergies and physician notes. The system also allows the dedicated pharmacist specialist to identify patients at risk for readmission and plan appropriate interventions. Since the program’s inception in July 2013, 200 patients have been seen and consulted on, reported Sergio V. Petrillo, PharmD, a clinical pharmacist specialist at Rhode Island Hospital. Most of these patients had targeted disease states of heart failure (HF), diabetes mellitus, acute myocardial infarction, chronic obstructive pulmonary disease (COPD) and/or pneumonia. Approximately half of the consultations resulted in contact with the prescriber regarding medication-related problems. Dr. Petrillo and his colleagues are currently analyzing data to assess the effect of the program. In the meantime, “we are continuing to develop ways in which patients are referred to our service,” he said. The highly complex “Rubik’s cube”
Operations & Management 35
Pharmacy Practice News • April 2014
Continuity of Care of medication discharge planning requires pharmacists to start working on the puzzle at the time of admission, according to Dr. Tyler’s co-presenter at the ASHP leadership meeting, Joseph L. Cesarz, PharmD, the manager of ambulatory pharmacy services at the University of Wisconsin Hospital and Clinics, in Madison. With discharge planning, “our challenge as pharmacists and pharmacy leaders is to develop ways to get the information to patients at discharge, or shortly after discharge, so they’re as self-sufficient with their medications as possible. If you don’t start that process when the patient walks in the door, it’s going to be a lot harder when he or she leaves,” he said. In the comprehensive discharge service designed and implemented by Dr. Cesarz and his colleagues, pharmacy technicians meet with patients at admission to verify prescription insurance, promote the retail pharmacy and enroll patients into a “discharge express” service that delivers medications to the bedside at discharge. They also troubleshoot medication affordability issues and enroll patients into appropriate prescription assistance programs as needed. Dr. Tyler pointed to the consistent thoroughness of initial medication reconciliations within 24 hours of admission as key to the success of the pharmacist-driven discharge process at her institution. The pharmacists review admission medications and new orders, resolve problems, update medication reconciliation, document immunizations and print a medication list for the patient. The process also includes the services of pharmacy technicians, who offer patients the option of having discharge medications delivered to their room and arrange the deliveries. Available weekdays from 8 a.m. to 4:30 p.m., the service captures an estimated 60% to 70% of discharges, Dr. Tyler said. Patients being discharged to rehabilitation facilities were not initially included in the protocol because “they have longer hospitalizations, and the pharmacists have a huge opportunity to work with these patients,” she said. However, these patients were quickly added when a look at the data revealed they had about twice as many discharge prescriptions as the average on all of the units, and that their prescriptions were significantly more expensive. Challenges have included obtaining buy-in for the process from the nurses, many of whom were preparing patients to leave before the pharmacists could see them, and from the physicians, who perceived that the pharmacists were delaying discharges. To address these issues, pharmacy staff presented data showing that their involvement did not slow the discharge process. “It also became clear that
‘We’ve had a large spike in multidisciplinary team members, including physicians, social workers and case managers, consulting with us inside and outside the program.’ —Derick G. Miranda, PharmD, BCPS pharmacists were catching many issues that could cause great harm to patients if … not addressed before they left the hospital,” Dr. Tyler said. It’s essential for pharmacists and pharmacy technicians to play a key role in the discharge process because medication-related errors are a leading cause of readmissions and serious events, Dr. Cesarz said.
What a Difference a Day Makes The involvement of a clinical pharmacist in medication reconciliations and patient education within 24 hours of admission and on the day of discharge, and in daily patient education sessions, significantly reduced 30-day readmissions in patients with COPD, HF or both, according to six-month data presented at the ASHP meeting. A pharmacist also called patients within three to seven days of discharge to answer questions, address medication-related problems and triage them to their physicians if they were experiencing significant symptoms or medication side effects. The study found 30-day readmission rates of 21.4% in an intervention group of 234 patients compared with 28.2% in a historical nonintervention population of 730 (relative risk, 0.76; 95% confidence interval [CI], 0.58-0.99; P=0.039). The interventions would prevent approximately 31 readmissions per year, with a potential cost savings of $400,000, said Derick G. Miranda, PharmD, BCPS, of Truman Medical
Centers, in Kansas City, Mo. On the day of discharge, patients were asked to “teach back” what they had learned to enable the pharmacist to assess their understanding of their medications and their ability to monitor their symptoms at home. “Looking at our data, we found a large gap between what patients understood they were supposed to be doing and what health care providers expected the patient to be doing at home per our documentation,” Dr. Miranda said. “We made a role for pharmacy to not only provide education, but also to assess the patient’s understanding throughout his or her stay.” Using a prepared checklist, the pharmacist also made a follow-up call to patients at home to assess whether they had obtained their medications and were experiencing symptoms or medication side effects. When problems occurred, the pharmacist documented the issue in the patient’s electronic medical record, forwarded it to the physician and transferred the patient to the clinic by phone to speak immediately with a clinic team member. One-year data for the study, currently being analyzed, suggest that all-cause readmissions continue to decrease among patients with HF, COPD or both, he noted. Dr. Miranda and his colleagues are currently exploring how best to expand the program—potentially by focusing on other diseases, specific units or readmission risk factors, such as lack of access
Tips for Managing Change
A
t the ASHP fall leadership conference, Joseph L. Cesarz, PharmD, the manager of ambulatory pharmacy services at the University of Wisconsin Hospital and Clinics, in Madison, reviewed principles of change management that can help pharmacists plan and win support for a pharmacy-driven discharge planning service. This information is contained in the focused learning module on transformational change in the ASHP Foundation’s Leadership Resource Center (www.ashpfoundation.org/lrc). Establish urgency: Understand the unmet needs the change will address. Build a guiding interdisciplinary team and seek out political support. Frame a vision and strategy: A good first step is to prepare an “elevator” speech—a concise summary of your proposed process and how it will improve patient discharge—and be ready to share it with stakeholders. Know your audience(s) and how those stakeholders will be affected. Navigate bumps in the road to change: Be flexible and don’t lose sight of the ultimate goal. Take a systems approach. Focus on short-term wins: Demonstrate data-driven results and share those results with stakeholders. Make the change stick: Change is not episodic. Follow up and continue to adapt and troubleshoot to achieve change that lasts. —S.B
to medications or number of medications the patient is receiving at home. According to Dr. Miranda, the biggest challenge in designing the program was identifying exactly where pharmacy could fill gaps in the discharge process. “We had smaller [educational] components in place, but it was the consistency that was the concern. We superimposed our program on those efforts,” he said. Since the program’s implementation, “we’ve had a large spike in multidisciplinary team members, including physicians, social workers and case managers, consulting with us inside and outside the program. The various teams want us to start seeing their patients because they have so much faith in the program.”
The Metrics of Success At the University of Utah, the pharmacy team makes corrections and adjustments on discharge orders for virtually 100% of oncology patients, according to Dr. Tyler. She and her team also have found overall readmissions at the hospital to be 39% higher among cardiology patients discharged on weekends. The only difference between the weekday and weekend processes was the absence of a pharmacist on weekends to perform discharge medication reconciliations. The finding has led to the addition of weekend services and a pharmacist in the cardiology clinic. Dr. Tyler stressed the importance of solid metrics to demonstrate the value of discharge planning initiatives over time. Dr. Cesarz and his colleagues at the University of Wisconsin have been able to show an increase in annual net revenue of $1.24 million and an increase in the outpatient pharmacy discharge capture rate from 55.8% to 65% with their comprehensive discharge program. Enrollment in the hospital’s prescription home delivery service has risen 45%, and patient satisfaction regarding timely access to discharge medications has risen 44%. The University of Utah has seen discharge prescription captures rise from 27% to 80%, along with increases in Press Ganey scores on “opportunity to talk to a pharmacist” (from 70.6% to 82.4%) and “satisfaction with wait time for medications” (from 73.1% to 84.2%). Thirty-day readmissions for cardiology patients have decreased by 28% to 38%, and compliance with standards for chronic HF and acute myocardial infarction patients for discharge instructions and angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists for left ventricular systolic dysfunction have risen from 74% to 100% and 87.5% to 100%, respectively. —Susan Birk Drs. Cesarz, Tyler, Miranda and Petrillo reported no relevant financial conflicts of interest.
36 Operations & Management
Pharmacy Practice News • April 2014
Pain Medicine
TEAM APPROACH
have, which can mean more falls and longer hospital stays, for example.” As part of the new initiative, the medical center also added “patient care boards” to patients’ bedsides (Figure 2). These whiteboards are where pain scores are plotted, patients’ pain medications are listed, and patients and providers write down the day’s treatment goals. “The board gives the patient care team a sense of where [the patient’s] pain is at, and that helps them set reasonable expectations for pain management together with the patient,” Dr. Anand said. An additional part of the new approach is a “comfort guide” that includes a directory of nonpharmacologic pain management options available to patients at the medical center. “The comfort guide lets patients know that we believe managing their pain is about more than just drug treatment,” said Dr. Anand, pointing to spiritual services, pet therapy and music therapy as some examples of other treatments that Cedars-Sinai offers. Sandra Sani, PharmD, a clinical pharmacist at Cedars-Sinai who helped develop the new program, said nurses provide patients with explanations of some basic pharmacologic concepts, such as routes of administration, peak concentration and duration of action. “In the past, patients would sometimes wait too long before asking for another dose because they weren’t sure when to, and so their pain would increase dramatically,” said Dr. Sani. “Now they know how long the drug effect lasts and when it peaks and when their next dose is due, so the medication is administered on schedule and their pain control is much more consistent.” To assess patient satisfaction with the new approach, Dr. Anand’s team
continued from page 1
management with physical functioning and encouraging use of nonpharmacologic pain treatments. “Incorporating pain management tools specifically to engage patients in their own care and set realistic expectations for pain management, as this program has done, has the potential to significantly affect how patients perceive and experience pain,” commented Jeffrey Fudin, PharmD, BS, the director of the PGY2 pharmacy pain residency at Stratton Veterans Affairs Medical Center, in Albany, N.Y., who was not involved in the program. Before the new initiative, providers at Cedars-Sinai had been doing “a really great job at reacting to patients’ pain,” said Kapil Anand, MD, an assistant professor in the medical center’s Department of Anesthesia and Pain Management, who helped spearhead the initiative. “But we needed to become proactive, to anticipate [patients’] pain and how it might impact their functioning, and to partner with them and develop plans they could take ownership of,” said Dr. Anand, who shared details of the initiative at the 2013 University HealthSystem Consortium annual meeting (abstract F17). The first step toward a more proactive approach was to correlate pain severity and pain management with physical functioning, Dr. Anand said. His team did so by adding behaviorspecific statements to the Wong-Baker Facial Grimace Scale, a commonly used visual analog pain scale (Figure 1). “The new scale reminds patients and staff that pain is not a solitary thing, that it is tied to functioning,” Dr. Anand explained. “The more a patient is medicated, the less mobility they tend to
0
Verbal Descriptor Scale
No pain
1
2
Mild pain
3
4
5
Moderate pain
6
Severe pain
Figure 2. Pain engagement: patient care board. Source: Cedars-Sinai Medical Center
‘The comfort guide lets patients know that we believe managing their pain is about more than just drug treatment.’ —Kapil Anand, MD asked approximately 2,000 surgical and nonsurgical patients to respond to two items from the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) questionnaire. The respondents included roughly equal numbers of patients treated before and after the intervention was implemented in May 2012. Prior to the intervention, patients felt that “hospital staff always did everything they could to help with my pain,”
7
8
9
Very severe pain
10
Worst pain possible
Wong-Baker Facial Grimace Scale
0
1-3
4-6
7-9
10
No pain
You feel some pain or discomfort but you can still complete most activities.
The pain makes it difficult to concentrate and may interfere with your ability to do certain normal activities, such as reading, watching TV, having a phone conversation, etc.
The pain is quite intense and is causing you to avoid or limit physical activity. Cannot concentrate on anything except pain.
Worst pain imaginable.
77% of the time, on average. According to Dr. Anand, that percentage rose to 82% one year following implementation of the program. Before the intervention, respondents indicated their “pain was always controlled,” 62% of the time, on average; that percentage increased to 66% after the program was rolled out. Improvements of any magnitude in pain management are desperately needed, Dr. Fudin emphasized. “A large number of emergency room visits are pain-related, and a significant number of those are because of uncontrolled pain at the time of discharge,” he said, referring to data from the National Hospital Ambulatory Medical Care Survey: 2009 Emergency Department Summary Tables (www.cdc.gov/nchs/ data/ahcd/nhamcs_emergency/2009_ ed_web_tables.pdf ). Dr. Fudin pointed to a study conducted in 2003 that included a national sample of 250 hospitalized surgical patients and found that 88% of the patients reported moderate to extreme pain at the time of hospital discharge ((Anesth Analg 2003;97:534-540). “Unfortunately,” he said, “things have not improved significantly since then.”
Figure 1. Pain and function assessment tool.a a
This tool is intended to help patient care providers assess pain according to individual patient needs. Explain and use 0-10 scale for patient self-assessment. Use the faces or behavioral observations to interpret expressed pain when patient cannot communicate his or her pain intensity.
Source: Cedars-Sinai Medical Center
—David Wild Drs. Fudin, Anand and Sani reported no relevant financial conflicts of interest.
Operations & Management 37
Pharmacy Practice News • April 2014
Care Transitions
Program Cuts Readmissions for Nursing Home Patients
‘We’ve known for a long time that pharmacists can add value [in care transitions]. Absent a pharmacist, we see problems. We have to partner with SNFs; otherwise, we’re at risk.’ —Edward Szandzik, RPh
50
40
Incidence, %
Orlando, Fla.—A care transitions process that integrates a pharmacist into the care team for patients discharged to skilled nursing facilities (SNFs) underscores the value of interdisciplinary collaboration and direct communication between team members in preventing medication errors, adverse events and readmissions, according to a presentation at the American Society of Health-System Pharmacists’ Midyear Clinical Meeting. Seven months into the program, in which a pharmacist was integrated into the Enhanced Care Program (ECP) for SNF patients, readmissions decreased from 17% before pharmacist involvement to 12%, said Caroline Nguyen, PharmD, a care transitions pharmacist at CedarsSinai Medical Center, in Los Angeles. Cedars-Sinai added the pharmacy component to the program in response to requests for “one clean medication list for patients” from local SNFs to which the hospital discharges patients. (The team initially consisted of nurse practitioners, a medical director, a nurse educator and administrative support). “They were having difficulty reconciling the medications between multiple sources. Pharmacy was asked to help improve the process,” Dr. Nguyen said. The care transitions pharmacist oversees the medication reconciliation process and ensures the accuracy and appropriateness of the medication list. This includes an evaluation of the patient’s home, inpatient and discharge medication lists; a review of the patient’s hospital stay and labs; and a comparison of the discharge medication list with the SNF medication administration record (MAR). A specialized medication reconciliation pharmacy technician provides support to the care transitions pharmacist. The pharmacist communicates drugrelated problems directly to the nurse practitioners and serves as a resource for medication-related questions and concerns. “The nurse practitioners have really appreciated having that second set of eyes on their patients’ medications,” along with ready access to a pharmacist to consult with about medication interactions, polypharmacy, geriatric medication management and side effects, she said. The comprehensiveness and quality of the medication reconciliation and the pharmacist’s ownership of the medication list were critical to pharmacy’s successful integration into the team, Dr. Nguyen said. “It’s another example of the value of having pharmacists doing medication reconciliations. Post-discharge medication reconciliation is more than a comparison of two medication lists.” From January through July 2013, Dr.
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17 11 8
10
0
Incorrect doses/ Recommendation dose to discontinue adjustments therapy
Medication omissions
Recommendations to initiate therapy
Therapeutic duplications
Other
Figure. Drug–related issues that emerged during medication reconciliation. Nguyen identified drug-related problems and made recommendations including correcting doses/dose adjustments (26%), made recommendations to discontinue therapy (19%), uncovered medication omissions (19%), made recommendations to initiate therapy (11%), uncovered therapeutic duplications (8%) and other (17%). She used a modified version of the validated National Coordinating Council for Medication Error Reporting and Prevention Index for Categorizing Medication Errors to divide the drug-related problems into the following categories: low capacity for harm, serious/significant, and life-threatening. For that seven-month period, Dr. Nguyen identified 226 serious/significant and 11 life-threatening
drug-related problems among the 394 patients enrolled in the ECP. Overall, 133 patients (34%) required a pharmacist intervention. For example, a 90-year-old woman with atrial fibrillation and chronic heart failure had been discharged on a supratherapeutic home warfarin dose. The pharmacist recommended switching the patient to the lower inpatient dose and checking her international normalized ratio as soon as possible. The intervention avoided a potential adverse outcome of bleeding in this patient. Another patient, a 79-year-old man with end-stage renal disease and Staphylococcus aureus bacteremia, was discharged without a continuation order for vancomycin. The pharmacist notified the
nurse practitioner, and vancomycin was continued. A third patient, an 89-year-old woman with type 2 diabetes and deep vein thrombosis (DVT), was discharged on rivaroxaban (Xarelto, Janssen) twice daily, although she had been receiving the medication once daily at her SNF. Glimepiride and insulin glargine also were being continued in error. The pharmacist recommended twice-daily rivaroxaban with meals for three weeks, followed by 20 mg daily thereafter; she also recommended discontinuation of glimepiride and insulin glargine. The intervention prevented possible morbidity and mortality due to hypoglycemia and progression of DVT to pulmonary embolism. Dr. Nguyen stressed the importance of building relationships with SNF team members, which she said requires special effort because the pharmacist works remotely. To encourage the timely faxing of MARs to the pharmacy to ensure timely medication reconciliations, she contacted administrators at the SNFs to elicit their support. Cedars-Sinai plans to expand the ECP to other SNFs and to provide postdischarge follow-up for home health and high-risk frail patients. “There is definitely opportunity to provide this service to more patients and possibly collaborate with other surrounding hospitals,” Dr. Nguyen said. (In addition to her responsibilities with the ECP, Dr. Nguyen also conducts post-discharge and admission medication reconciliation for the emergency department.) Edward Szandzik, RPh, the pharmacy director at Henry Ford Hospital in Detroit, said the ECP represents “where we’re heading as a profession. We’ve known for a long time that pharmacists can add value [in care transitions]. Absent a pharmacist, we see problems. We have to partner with SNFs; otherwise, we’re at risk.” He called the CedarsSinai approach “the right way to do it.” Mr. Szandzik participates on a multidisciplinary committee at Henry Ford Hospital that is exploring opportunities to work with SNFs to support care transitions. Although the hospital has not implemented a medication-focused care transitions protocol specifically for SNF patients, it does have pharmacist-led care transitions programs for several highrisk populations, including patients taking anticoagulants, as well as transplant, HIV and nephrology patients. “Some of these patients are seeing multiple physicians,” he said. “Sometimes coordination is not as smooth as it should be, and that’s where pharmacists can come in.” —Susan Birk
38 Operations & Management
Pharmacy Practice News • April 2014
Leadership in Action
Creating Highly Performing Teams
I
n the previous four articles in this column, we looked at the relationship between our thinking—that is, our actual brain function—and the effect that it has on our creativity, productivity and leadership. We looked at the importance of paying attention and focusing on the relevant, inhibiting the distractions and using our working memory of relevant information to make decisions. We also looked at the importance of cultivating a positive emotional climate in ourselves, and how that can help us to make strong, productive connections with others. In the last article, we explored the importance of concentrating on the factors that you have control over as a leader to get the necessary results from your staff. This time we focus on highperformance teams.
The Power of Vision As all good managers know, a highperformance team needs more than good relationships and good communication. The team needs a vision. This reminds me of the proverb, “Where there is no vision, the people perish …” (Proverbs 29:18, King James Version). Shared vision and shared goals are the glue that holds people together. I visualize looking down a railroad track, where the rails are the values, behaviors and relationships by which the locomotive is guided. The destination is that shared vision or the shared goal. In politics, we sometimes hear of the bridge to nowhere that supported a person’s political ambitions to garner money for their district or state, but served no real purpose. High performance, in contrast, involves working together on the right things, at the right time and in the right way toward a common goal. The role of the pharmacy leader is to cast that vision in alignment with the broader picture of what is happening in health care. Such vision and leadership is sorely needed in these tumultuous times because the old order is being turned on its head. Specifically, we are moving from fee-for-service (FFS) and sick care to bundled payments, accountable care and preventive health. This is an exciting path because it moves us away from the perverse incentives of “more is better” for both treatment and dollars, to a rational basis of care and of payment based on keeping people well and at home. The big question for pharmacy in this new mode of health care is this: Do we have the vision of our role in the new paradigm and have we executed the vision with our staffs? We are certainly making progress, but that process is still evolving. For
“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at ernestanderson1130 @gmail.com
Ernest R. Anderson Jr., MS, RPh
example, one major treatment change we all have to learn how to deal with is the growing importance of pharmacogenomics in our patients’ care. There are a host of genetic polymorphisms we now have to test for to give patients the individualized care plan they need to ensure optimal outcomes. Think of the specificity in cancer care. As more is done with genetic markers, we will be able to tailor chemotherapy and no longer just blanket the patient with a standard therapy for everyone or move from first-line drugs to second, to third. We may move directly to third-line therapeutics that are dictated by genetic markers. This will be more cost-effective, patient-specific and compassionate. Moreover, delivery locations will no longer be hospital-centric; more care will be delivered in the home, where patients and providers will use apps, remote telemonitoring and other digital modalities to track patient health. In that unfolding scenario, patients will be the center, not physicians. Imagine, for example, physiologic data being captured on the patient’s smartphone through wireless technology, being uploaded into the cloud for storage and being run through algorithms on that same smartphone, which will monitor the patient’s health and warn of impending problems. Sotera Wireless has developed the Visi Mobile System, which includes a device that is slightly larger than a wristwatch (http://www.visimobile.com) m and can monitor a patient’s vital signs the same as would be done in the ICU. Technology is moving at breakneck speed. How does this influence our vision? Costs must be taken out of the health care system, quality must be improved and patient ownership of their care must increase; technology can help bridge these changes. In this period of change, the pharmacy profession has to take steps to ensure that it is part of the health care team. Indeed, many physicians already are acquiescing to care provided by teams including pharmacists. In this new para-
digm, it is not cost-effective, or warranted, for physicians to see all patients. As Clay Christensen and his coauthors wrote in “The Innovator’s Prescription: A Disruptive Solution for Health Care” (McGraw-Hill;2009), “The challenge that we face—making health care affordable and conveniently accessible to most people—is not unique to health care. The transformational force that has brought affordability and accessibility to other industries is disruptive innovation.” They said, “Most disruptions have three enablers: a simplifying technology, a business model innovation and a disruptive value network.” I believe that we are on the cusp of seeing disruptive innovation in the health care system. It is being driven by reimbursement changes and technology. Effective leaders will be aware of new innovations to see how these may change the paradigm as we move down the railroad tracks toward that vision of affordable and accessible health care.
Mobilizing Your Team Disruptive innovation creates tension. There are many decisions necessary to achieve the vision. This requires a motivated team to accomplish the end game. What are some of the operative values that make successful teams? Henry Cloud articulates some of these values in “Boundaries for Leaders” (HarperCollins;2013): Behavior is in our power to control. We are responsible for our actions. If we change our behavior from being overwhelmed to being empowered, we enable extraordinary outcomes. By changing behavior, we can change outcomes. Values provide structure and language to create boundaries. These boundaries identify behaviors we encourage and behaviors we prohibit. The freedom to be totally honest drives the behavior of a common language. This language of openness at all levels ensures no hidden agendas or holding back. It encourages being
understood and seeking to understand. Take action on the vital. There is a difference between what is urgent and what is vital. This must be strategically measured against the values of both short- and long-term goals continually pressing toward defining and executing what is vital. Have national and global awareness. Understanding the health care incentives at a national level and looking globally to the experience in other countries will refine the values and direction for your pharmacy. This requires going beyond pharmacy to stay current in the health care literature, attending conferences and seminars, and speaking to colleagues in and out of pharmacy. Know your customer intimately. Our customers in pharmacy are broadly defined; however, we must start with the patient if we are going to affect change. We need to be good listeners and interact with patients in their world, not just in our own. For example, I heard of an elderly patient whose caseworker provided for a ride home after an inpatient stay; however, when the patient was dropped off, the steps were covered in snow, the heat had been turned off due to lack of payment and there was no food in the house. Be connected. Partnering with our colleagues to achieve results requires knowing who should be involved on a project or team, when to connect with them and how to build trusting relationships to achieve the goals. Deliver on commitments. Doing what you say you will do is basic, but often missing in the face of competing priorities. Delivering on agreed-on milestones is essential. Build our talents. We work to develop others and ourselves. We value the talents and contributions of all team members. We work together with unity and commitment even when we disagree. We give feedback and develop each other.
Defining Values Will Drive Results Our defined values must be an integral part of our daily operation. As we prioritize our movements and decision points toward our vision at the end of the railroad tracks, our values allow us to set the priorities to actualize the vision. This is the results-based decision-making process that is essential to our pharmacy business of patient care. ■
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Medication Errors: A Year in Review Partt 1 off a 2 2-Part P tS Series i
Horsham, Pennsylvania
T
he prevention of medication errors is an essential component of pharmaceutical care and
must be a core mission of every pharmacy. For medication error prevention efforts to be effective, they must become a priority.
The first step in setting up an error-reduction program is to establish a multidisciplinary team to improve medication use. The team must be given reasonable time and resources to assess medication safety and implement system-wide changes that make it difficult or impossible for practitioners to make mistakes that reach the patient. This multidisciplinary team should accept ownership of the medication-use process and enthusiastically embrace the opportunity
to improve medication safety. The goals of the team should include the following: • Promote a culture of safety to lower medication errors; • Increase detection and reporting of medication errors and potentially hazardous drug-use situations; • Explore and understand the root causes of medication errors; • Educate practitioners about the system-based Text continues on page 5
KEY TO TABLES
1
Computerized prescriber order entry (CPOE)—A fully integrated CPOE system includes the capability to build medication safety alerts (eg, look-alike names) and clinical decision rules. Additionally, the CPOE system should directly interface with the laboratory system and pharmacy, list drug– drug and drug–disease interactions, and offer clinical order-screening capability.
2
Bar-code–enabled point-of-care (BPOC) systems—These systems are designed to prevent medication errors at the point of medication administration. BPOC systems verify and record all medications administered to the patient through the use of a barcode scanner that matches the medication to the patient by scanning a bar code on the medication and a bar code on the patient’s wristband.
3
“Smart” infusion pumps—These infusion systems allow users to enter various drug infusion protocols into a drug library with predefined dose limits. If a dose is programmed outside of established limits or clinical parameters, the pump halts or sounds an alarm, informing the clinician that the dose is outside the recommended range. Some pumps can integrate patient monitoring and other patient parameters, such as age or clinical condition.
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
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Automated dispensing cabinets (ADCs)—These are robust, point-of-use dispensing systems. ADCs should be integrated with the health care facility’s information system and directly interface with the pharmacy system. Additionally, ADCs must be able to use barcoding technology for the restocking process to prevent medication errors.
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“Robust” pharmacy order entry system— This order entry system is fully interfaced with a CPOE system. The pharmacy system must be able to produce medication safety alerts as well as directly interface with a health care facility’s information systems, such as the laboratory system. Additionally, this system must be used to generate a computerized medication administration record (MAR) to be used by the nursing staff while they administer medications.
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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title
Problem/Discussion Point
Recommendation
Technology
Acetaminophen suspension labeling
• The word “Children’s” is on the labels of unitdose containers of 325 and 650 mg cups of acetaminophen oral suspension from Precision Dose, implying that the total dose in the cup is suitable for children. • Depending on the child’s age and weight, 325 or 650 mg might be an overdose.
• For children, pharmacies should dispense patientspecific doses of acetaminophen suspension in oral syringes. • The unit-dose cups should only be dispensed if the child’s dose is exactly the total dose in the cups (325 or 650 mg).
1,2
Confusion between ado-trastuzumab emtansine (KADCYLA, Genentech) and trastuzumab (HERCEPTIN, Genentech)
• The ISMP and the American Society of HealthSystem Pharmacists (ASHP) sent a warning through the National Alert Network (NAN) about possible name confusion between the newly approved ado-trastuzumab emtansine (Kadcyla) and trastuzumab (Herceptin). Ado-trastuzumab emtansine may not be fully communicated or may be misread when prescribed, leading to confusion with trastuzumab.
• Alert practitioners to the risk for incomplete presentation or miscommunication of the generic name of Kadcyla. • Promote the use of both brand and generic names when communicating orders on order sets or computerized prescriber order entry systems. • For more information, view the recent NAN Alert: www.ismp.org/Newsletters/acutecare/ hazardalerts.asp
1,5
Confusion between “factor” and “PCC”
• Historically, several bleeding reversal products have been referred to as “prothrombin complex concentrate,” or “PCC.” • Since there is a newly approved product, KCENTRA (CSL Behring), with the actual generic name prothrombin complex concentrate, the use of “prothrombin complex concentrate” or “PCC” may result in confusion regarding which drug is intended.
• Determine which of these reversal products will be on the formulary, and educate staff about the appropriate use of each agent and the risk for confusion when using the terms “prothrombin complex concentrate” or “PCC.” • Always clarify orders requesting “prothrombin complex concentrate” or “PCC” to determine the specific brand name. An alert in electronic systems may help remind staff to do this.
1,2,5
ED starter doses are not child-resistant
• EDs and physician practices often send patients home with drug samples or starter doses in unit-dose packages that may not be child-resistant. • If medications are dispensed in plastic bags or envelopes, they may be accessed easily by children. • Other safety issues with dispensing samples and starter doses include little to no labeling with directions for use and failure to monitor lot numbers and expiration dates.
• Organizations that dispense drug samples or starter doses should evaluate their practices and modify their procedures as needed to ensure the safety of patients and their children. • With the increased number of 24-hour community pharmacies, samples and other starter doses may not be necessary.
Heparin label changes
• As of May 2013, the labeling of heparin vials must express the total amount of units in the container as well as include the units per mL in parentheses, rather than just listing the units per mL. • Older labels only list the per mL amount, leading to overdoses in which the amount per mL was thought to be the amount in the entire vial. • If heparin vials with both the old and new labels are available, the risk for mistaking the per mL amount as the total vial amount is high.
• To minimize the risk for confusion, hospitals should consider transitioning fully to the newly labeled heparin, even if this means discarding older vials. • Alternatively, at a minimum, pharmacists should apply auxiliary labels to the older-style vial to highlight the total number of units in the container. • As space permits, pharmacy and nursing databases should express drug amounts the same way they are expressed on the vial label (ie, 10,000 units/10 mL [1,000 units/mL]).
Influenza vaccine—always shake well!
• An immunization-certified pharmacist said he was not aware that all injectable influenza vaccine products must be shaken before use. He said that he had not been doing this, although the implications of this omission are not clear. • The vaccine cartons are labeled “shake well,” but the vial and syringe labels of influenza vaccine that the ISMP has examined do not have this label.
• Injectable influenza vaccines are suspensions with the exception of FLUBLOK (Protein Sciences), which is a solution. • All injectable influenza vaccines including Flublok must be shaken before use, whether they are packaged in a single- or multiple-dose vial, or in a prefilled syringe. • This is a reminder for health professionals and office-based staff who administer influenza vaccine.
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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title
Problem/Discussion Point
Recommendation
Technology
Large-volume products increase risk for error
• A 50-mL vial of lidocaine was retrieved from an ADC matrix drawer instead of a 50-mL vial of 50% dextrose.
• Limit availability of vials of lidocaine to 10 or 20 mL to differentiate it from other drugs in 50-mL containers, such as sodium bicarbonate, 50% dextrose, and mannitol. • This strategy also reduces the risk for harm in the event of a mix-up with another vial if the whole vial is administered. • Reducing container volume also limits the risk for solution contamination, given that large vials are associated more often with multiple re-entries.
2,4
Look-alike vials of HYDROmorphone and morphine
• Westward’s 1-mL vials of HYDROmorphone 2 mg/mL and morphine 5 mg/mL look very similar, especially once the caps are removed, and this may increase the risk for mix-ups between these 2 drugs.
• Do not dispense these vials together to the same patient care area. • If possible, dispense only unit-dose syringes of these medications. • If vials must be dispensed, purchase one of the products from a different manufacturer to help differentiate the vials.
2,4
Mix-up between leucovorin and LEVOleucovorin
• 2 errors occurred at a hospital involving mix-ups between leucovorin and LEVOleucovorin (FUSILEV, Spectrum), due to name similarity. • There is significant potential for dosing errors if leucovorin and LEVOleucovorin are interchanged. • The dose of LEVOleucovorin is one-half the dose of racemic leucovorin injection (leucovorin).
• Separate these drugs wherever they are stored. • If using ADCs, consider using tall man lettering for the ADC software listings. • Pop-up messages also should be considered because they may be useful to educate, alert, and remind staff of a possible mix-up.
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Mix-ups between nalbuphine and naloxone
• 3 patients received nalbuphine instead of naloxone: One event involved the accidental selection of nalbuphine, which appeared immediately before naloxone on an ADC screen; another involved an ADC stocking error; and the third involved selection of the wrong product from an anesthesia tray during anesthesia reversal. • In the first 2 events, nurses administering the drug thought the patient’s condition warranted bypassing a bedside bar-code scanning system.
• Using tall man lettering on ADC screens and pharmacy labels and adding the words “rescue agent” next to naloxone entries, if space permits, may help prevent mix-ups. • Locked lidded drawers for nalbuphine and naloxone also could prevent inadvertent selection of the wrong drug.
2,4
Name confusion between pazopanib and ponatinib
• Two new oral chemotherapy agents—pazopanib used to treat renal cell cancer, thyroid cancer, and soft tissue sarcoma, and ponatinib used to treat chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia—have names that may cause confusion. • Fortunately, tablet strengths and dosages differ between the drugs, which should help prevent and detect errors.
• Computer systems that list oral chemotherapeutic agents linked to available dosage strengths will help to minimize the potential for error, as will listing appropriate dosing information for labeled indications. • The use of tall man lettering with the unique letter characters differentiated (PONATinib and PAZOPanib) also can be helpful.
1,5
RABAVERT (rabies vaccine) requires a diluent
• A pharmacy found a box of RabAvert (Novartis) containing the diluent vial but not the vaccine powder, which could have resulted in an ineffective vaccination if only the diluent was administered. • Both the diluent and vaccine vials are small vials with similar green labels and caps. If the diluent vial is partially turned, the words “sterile diluent for” can be hidden, leaving only the word “RabAvert” visible. • A fatal outcome is almost certain in people infected with rabies virus who do not receive post-exposure vaccination.
• Hospitals may want to consider purchasing IMOVAX (Sanofi Pasteur), a rabies vaccine produced by a different company, which is provided in a sealed tray that holds a prefilled diluent syringe for reconstitution of the vaccine.
2
Tuberculin PPD
• A pharmacy inadvertently dispensed an entire 1-mL (5 units/0.1 mL) vial of tuberculin (10 doses) as a single dose. • The vial’s label on the front states only 5 units/0.1 mL and must be turned to display the notation of 10 doses in the vial.
• All PPD doses should be dispensed from the pharmacy in unit-dose, intradermal syringes containing the proper dose.
ADC, automated dispensing cabinet; ED, emergency department; ISMP, Institute for Safe Medication Practices; PPD, purified protein derivative
Table 2. Title
Problem/Discussion Point
Recommendation
Apothecary strengths confused
• There is a risk for errors when apothecary strengths such as “gr” (grains) are used for certain drugs such as ferrous sulfate and PHENobarbital. • Grains could be confused with “g” (grams).
• Consider purchasing products from manufacturers that do not use apothecary strengths on labels to minimize the risk for confusion. • If this is not possible, ensure that labels generated from the pharmacy for these products do not contain apothecary strengths.
DOXOrubicin liposome injection
• A safety concern might exist in the product description field for some listings of a generic liposomal DOXOrubicin product, which was approved by the FDA in February 2013. • Listings of this product may not be reflected correctly in various drug information databases or computer systems. • Mistaking the drug for a conventional product could cause death.
• Check to see if the drug is listed correctly as “DOXOrubicin HCl liposome injection” in your computer systems. • The ISMP suggests using “HCl” instead of “hydrochloride” to place “liposome” closer to “DOXOrubicin,” which will make it easier to read. • The word “pegylated” or “peg-” (which sometimes precedes liposomal), seen in some listings, is unnecessary in formulary systems. • To make the word “liposome” stand out, some hospitals include asterisks around it (*liposome*).
1,5
Methadone mistaken for metoprolol
• A nurse obtaining a drug history of a new patient inadvertently selected methadone 100 mg BID from the computer screen instead of metoprolol 100 mg BID. • The physician reviewed the medication list and continued all the medications. • The pharmacist questioned the high methadone dose, but the physician instructed to give the medication as written. • After receiving 2 doses, the patient experienced cardiorespiratory arrest.
• Require prescribers to specify the indication if methadone is prescribed. • If the patient is being treated for opioid addiction, confirm the dose with a methadone clinic. • Have the patient/caregiver confirm (even sign) the medication reconciliation list to verify accuracy. • Reinforce an expectation that all questionable orders are fully resolved before dispensing and administering the medication.
1,5
“NoAC” is an unsafe abbreviation
• Recently the abbreviation “NoAC” was mistakenly interpreted to mean “no anticoagulation.” • The prescriber intended the abbreviation to stand for “New (or novel) oral anticoagulant.”
• The ISMP will be adding “NoAC” to the “do not use” list of potentially dangerous abbreviations, and strongly suggests cautioning providers not to use it clinically.
Null sign misread
• A null sign (Ø) has been misread as various numbers: the number 8 for a lockout interval; the number 4 for a basal rate for PCA; the number 6, especially if the circle is not closed above the hash mark; and the number 9, especially if the tail of the hash mark through the circle is long.
• The null sign appears on the ISMP List of ErrorProne Abbreviations, Symbols, and Dose Designations, and should not be used on medical orders. • Also, a setting of zero for a lockout interval, which may not be an available choice with some PCA infusion pumps, is dangerous, even if the number of boluses is limited within a certain timeframe.
Protecting vulnerable patients
• Medication errors that occur in a LTC facility often originate in the hospital. • Studies show large inconsistencies between medications on discharge summaries and transfer forms, leading to error rates of 21% or higher during transitions between hospitals and LTC facilities, particularly with warfarin, insulin, opioids, and cardiovascular medications. • For example, unnecessarily including the strength of insulin (100 units per mL) without the actual dose on a transfer form led a LTC nurse to misunderstand a new resident’s dose as 100 units, which led to his death.
• Establish a list of drugs that often are not continued after hospitalization, and refer to the list during discharge medication reconciliation to determine if clarifications are needed. • Require prescribers to cosign (verify) transcribed discharge summaries, and reconcile the transfer/ referral form with the discharge summary to enhance comparison and consistency. • Have pharmacists review the prescribed medications for patients being transferred to LTC facilities, and provide reasons for differences between the discharge medications and the medications administered in the hospital. • Standardize the documents that accompany transfer forms.
Search function leads to wrong medication choice
• A prescriber who typed “aceta” to enter an electronic order for acetaminophen chose acetaZOLAMIDE from the search results. Fortunately, differences in the dose and frequency led to discovery of the error. • Other drug name pairs that have resulted in this kind of error are: hydroxychloroquine/ hydroxyurea; MUCOMYST (acetylcysteine)/ MUCINEX (guaifenesin); valACYclovir/ valGANciclovir; and penicillAMINE/penicillin.
• Use tall man lettering to differentiate drugs with look-alike names. • Require more than just a few letters when searching for drugs in electronic databases. (Some systems require a certain number of letters before a list will appear.) • Require entry of the intended purpose of drugs with similar names or alert the pharmacist to match the patient’s condition to the drug’s indication.
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Table 2. Safety Issues Associated With Order Communication Title
Problem/Discussion Point
Recommendation
Technology
Tiotropium (SPIRIVA, Boehringer Ingelheim) dose confusion
• The recommended dose of tiotropium is 2 inhalations of the powder contents of 1 capsule. • Many order entry systems will default to a dose of 1 inhalation, and if this is changed to 2 inhalations, it may result in the patient receiving the contents of 2 capsules. • If the dose is entered as 1 capsule, the patient might receive the product orally.
• Make sure the dosing for tiotropium is expressed clearly in your order entry system to avoid administering the wrong dose or by the wrong route. • Express the dose in a way that lessens the risk for confusion (eg, 1 capsule = 2 inhalations). • Provide patient education, and ensure the patient understands how to properly use the medication (and the inhalation device).
1,5
Topotecan overdoses
• The FDA and the ISMP have received reports of medication errors involving 10-fold topotecan overdoses. • Several of these errors occurred because the decimal point in the dose was overlooked when the order was read (eg, .7 mg dose misread as 7 mg; 2.5 mg dose misread as 25 mg) or because a trailing zero was used after a whole number dose (4.0 mg mistaken as 40 mg).
• Always include a leading zero (eg, topotecan 0.7 mg) and avoid using trailing zeros (eg, topotecan 2.0 mg) when expressing doses. • Include the intended dose in mg/m2, in addition to the total calculated dose, to allow other health care providers to verify that the calculated dose is correct. • Consider the use of standardized order sets to avoid topotecan dosage confusion.
1,3,5
ISMP, S , Institute for Safe Medication Practices; LTC, long long-term term care; PCA, patient patient-controlled controlled analgesia
Tables continue on next page
Text continued from page 1
causes of errors and their prevention; • Recommend methods to facilitate the implementation of organization-wide, system-based changes to prevent medication errors; • Respond to potentially hazardous situations before errors occur; and • Learn from errors occurring in other organizations through the ISMP Medication Safety Alert! and other published accounts of medication errors, and proactively take measures to prevent similar errors. Effective results depend on understanding the entire medication-use process through varied perspectives and disciplines. ISMP is a nonprofit organization that works closely with health care practitioners and institutions, regulatory agencies, professional organizations, and the pharmaceutical industry to provide education about medication errors and their prevention. ISMP independently reviews medication errors that practitioners and patients have submitted voluntarily to the ISMP Medication Error Reporting Program. ISMP is an accessible resource for any pharmacist or organization interested in implementing the actions recommended herein. Among the many products and services that ISMP offers is the ISMP Medication Safety Alert!! Acute Care Edition, a biweekly newsletter that provides timely information related to error prevention. It identifies errors that have been reported by other
organizations and offers recommendations to prevent those errors from occurring in the pharmacy. The information in the tables of this review summarizes many of the significant error-prevention strategies that were recommended in the ISMP Medication Safety Alert! Acute Care Edition during 2013. The errors presented in the tables are actual or potential errors reported to ISMP. Each table consists of 4 columns. The first column lists the medications, devices, or other problematic issues involved. The second column describes the specific error or problem involved. The third column contains ISMP’s recommendations to proactively address and prevent errors from occurring. The fourth column lists technology that may help prevent these errors. Technology can be a powerful tool in the fight against medication errors but only when it is used appropriately within a well-designed medication-use system. The key summarizes the technology addressed in the tables, along with specific criteria that ISMP feels should be included.
Suggested Reading Cohen MR, ed. Medication Errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007. Institute for Safe Medication Practices. ISMP Medication Safety Alert! Acute Care Edition newsletters 2013. www.ismp.org/newsletters/ default.asp. Accessed March 20, 2014. Institute for Safe Medication Practices website: www.ismp.org.
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Table 3. Problems Involving Drug Information, Patient Information and Staff Education Title
Problem/Discussion Point
Recommendation
Chemotherapy overfill confusion
• More than 1,100 patients may have received lower doses of cyclophosphamide and gemcitabine than prescribed because the hospital and compounding pharmacy that provided the chemotherapy did not have a common understanding of the amount of overfill in the containers. • Although the total amount of drug in the bag was correct, the failure to understand the final concentration and the need to infuse the total amount of fluid in the bag resulted in some patients receiving a lower dose than intended when the full volume was not infused. • Several methods can be used to prepare sterile products, each with specific means for managing the overfill volume, which can lead to confusion.
• Establish a standard process to identify the overfill volume on the pharmacy label for compounded IV chemotherapy/biotherapy solutions. • Ensure that nurses who administer these products can locate the final volume on the label, and can recognize that the correct dose requires the full volume to be infused (unless otherwise stated). • Choose the most appropriate method of preparing each medication infusion according to whether or not the volume/concentration is critical. • Obtain a list of overfill amounts of commonly used products from vendors for reference as needed. • For continuous infusions titrated to effect, ensure consistency in the preparation process to avoid variations in concentration and inconsistencies in the dose delivered. • For a single-dose drug infusion, the most critical aspect of the process is ensuring that the entire dose in the container is administered. The label should include a reminder: Infuse entire contents for full dose.
Dosage form confusion with dinoprostone
• PROSTIN E2 (dinoprostone; Pfizer) 20-mg vaginal suppository indicated for the evacuation of uterine contents in the management of missed abortion or fetal death was cut in half and used in place of CERVIDIL (dinoprostone; Forest) 10-mg vaginal insert intended to promote cervical ripening in a pregnant women near the time of delivery. • Cervidil inserts gradually release the medication, whereas Prostin E2 suppositories melt in place and lead to tetanic contractions that restrict placental blood flow. • In this case, the error resulted in prolonged fetal deceleration, necessitating an emergency cesarean delivery.
• Prostin E2 should not be available on nursing units and should only be dispensed from the pharmacy after the indicated use has been verified. • Staff who might encounter pregnant women should be warned that, although the generic name for both products is the same, Prostin E2 should only be used for intrauterine fetal death and termination of pregnancy, not for cervical ripening.
Fatal PCA event linked to inadequate monitoring
• An opioid-naive surgical patient was started on morphine PCA with a 3-mg demand dose, 10-minute lockout, and a basal rate of 1 mg/h. • That night, the patient was found in respiratory distress and died. • Gaps in patient monitoring, including a failure to employ pulse oximetry, despite the presence of the equipment in the patient’s room, were the predominant factors, as was the failure to recognize progressive signs of impending respiratory depression.
• Basic physical assessment, vital signs, and other parameters are vitally important when monitoring patients receiving PCA. • The patient’s level of pain, quality of respirations, and sedation must be continually assessed. • Sedation generally precedes significant respiratory depression; thus, early recognition of excessive sedation and intervention is essential. • Respiratory assessments should include evaluation of the rate, depth, quality of respiratory effort, pattern of respirations, and breath sounds. • Technology to continuously monitor ventilation in patients known to be at risk for respiratory depression is recommended and should be considered for all patients receiving PCA.
FentaNYL patch fatalities
• A 15-month-old child who had been sleeping with his mother gained access to her fentaNYL patch, ingested it, and was found unresponsive when his mother awoke. • Similar events before this one have been just as tragic. Why has there been so little action taken by those in positions to educate patients about proper use and storage of fentaNYL patches? • Until every health care professional and health system accepts personal responsibility for promoting safe use of this powerful opioid, we are exposing one of the most troubling examples of bystander apathy in health care: a belief that we don’t need to intervene because others will.
• No patient should be allowed to leave a doctor’s office, hospital, clinic, or pharmacy without faceto-face instructions on the use of the fentaNYL patch and related safety concerns, as well as verification of consumer understanding. • All health professionals must individually instruct patients and caregivers on the use of the patch and not rely on others to do it. The ISMP has developed a free patient education checklist and consumer leaflet that can be used during consumer education and then given to the patient for reference.
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Table 3. Problems Involving Drug Information, Patient Information and Staff Education Title
Problem/Discussion Point
Recommendation
Technology
Fleet ENEMA SALINE, not plain saline
• Fleet Enema Saline contains the active ingredients sodium phosphate monohydrate 19 g and dibasic sodium phosphate 7 g. • Because the label states “saline,” the phosphate content may be overlooked. Phosphate toxicity is possible from even a single enema, although elderly patients with renal insufficiency, those using more than one enema per 24 h, and patients who do not expel the enema as directed are at highest risk.
• Avoid Fleet enemas in elderly patients with renal insufficiency and patients with diseases that decrease intestinal motility. • When they are used for other patients, the enemas should be expelled as directed after use, and a second dose should not be administered for at least 24 h. • Patients should be warned to carefully follow label directions and avoid using more than one enema in 24 h.
In utero medication administration
• Certain procedures performed in utero may require administration of drugs directly to the fetus. • Because the fetus may not have a medical record, drugs intended for the baby are sometimes ordered on the mother’s chart. • In preparation for an intrauterine transfusion to a fetus, a neuromuscular blocking agent was ordered for the fetus to keep the baby still. • The medication, which had been ordered on the mother’s chart, was administered IV to the mother, leading to respiratory arrest. • The mother died and the infant sustained central nervous system injury.
• Establish a process for prescribing fetal medications (eg, temporary record, generic record for Baby Doe using the mother’s identifier) if a separate medical record for the fetus is not possible. • Avoid prescribing fetal drugs on the mother’s record. • Develop order sets for fetal medications. • Pharmacy drug preparation and labeling should make it clear that the drug is intended for the fetus. • Require a “time-out” process to verify all information before fetal drug administration.
1,5
Oral niMODipine liquid administered intravenously
• A patient died after receiving oral liquid niMODipine via a central IV line instead of an NG tube. • The pharmacy, unaware that the drug was being given via an NG tube, dispensed capsules, the contents of which were drawn into a syringe with a needle and diluted. The drug was accidentally administered IV, resulting in severe hypotension and cardiac arrest. • Unless pharmacy prepares the liquid and dispenses it in an oral syringe, nurses must extract the product from the gel capsule with a syringe and needle. • On at least 25 occasions, the liquid extracted from a capsule was accidentally injected IV, resulting in 5 deaths and 5 near-death events.
• Pharmacy should prepare all doses of enteral or oral liquid niMODipine. • A study provides evidence that the liquid extracted from capsules, stored in amber oral syringes, and placed in light-protected bags, is stable at room temperature for 31 days. • A mechanism should be established to alert pharmacy to NG, orogastric, or percutaneous gastric tubes. • If pharmacy does not extemporaneously prepare a liquid formulation of niMODipine from capsules and dispense the drug in oral syringes, the hospital should use a new commercial product for adults, NYMALIZE (niMODipine) oral solution, available from Arbor Pharmaceuticals (www.ismp.org/ sc?id=191). This product is indicated for improvement of neurologic outcomes in adult patients with subarachnoid hemorrhage.
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Syringe pull-back method unreliable
• A pharmacy technician mixed the volumes required (0.27 mL magnesium, 5.13 mL diluent) and combined 0.27 mL of a diluent with 5.13 mL of magnesium sulfate. • The syringe pull-back method was used for checking the admixture, so the error was unnoticed because it was not clear which syringe was associated with which vial. • The syringe pull-back method for checking admixtures is unreliable.
• The ISMP’s compounding safety guidelines (www.ismp.org/sc?id=251) strongly discourage the syringe pull-back method for verifying the contents of parenteral admixtures. • This method should never be used to verify contents in chemotherapy, complex solutions, pediatric/neonatal solutions, or CSPs with other high-alert medications. • The contents of these solutions should be verified immediately before adding them to the diluent, and syringes should be labeled if the verification process is not completed shortly after drawing the solution into the syringe.
Update resources during drug shortages
• During a code, a nurse administered the wrong volume of naloxone based on an information card on the crash cart that assumed a 0.4 mg/mL (2 mL) strength vial was being used. • Due to a drug shortage, naloxone 1 mg/mL (2 mL) was stocked in the crash cart, but the information card had not been updated to reflect this change.
• Remember to update all informational resources (eg, admixture recipes, dosing guidelines) or available technology (eg, electronic prescribing, bar-coding systems, smart pump libraries) when forced to use an alternative strength or drug due to a shortage.
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CSPs, compounded sterile products; NG, nasogastric
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Volume 41 • Number 3 • March 2014
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in this issue UP FRONT
3
Student’s Corner: the ‘Five Ps’ of pharmacy assessment.
CLINICAL
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Practice Pearl: a collaborative plan for enhancing the quality and safety of insulin therapy. Hep C rates slashed in liver transplant patients; results “practice-changing.” Hospitals at the tipping point for more widespread CSTD adoption.
WEB EXCLUSIVE
Part 1 of a 2-Part Series
ASP Building Tips: Going Slow Yields Big Success Orlando, Fla.—“Learn to crawl before you walk and run,” was the first piece of advice Ed Eiland, PharmD, MBA, BCPS (AQ-ID), FASHP, dispensed to a room full of attendees at the 2013 American Society of HealthSystem Pharmacists Midyear Clinical Meeting eager to implement or strengthen their own antimicrobial stewardship program (ASP). Based on the $1.34 million in savings Dr. Eiland achieved with his own revamped ASP, not to mention a 25% drop in 30-day hospital readmissions and a nearly 50% drop in Clostridium difficile infections (CDIs), the go-slow strategy can yield major dividends.
Phase 1 (2005-2007) His team’s first step in building the ASP was to assemble an antimicrobial management team (AMT), including pharmacists, infectious
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Radiofrequency Identification (RFID) reduces errors, speeds process of refilling drug trays. See Technology section, pharmacypracticenews.com
EDUCATIONAL REVIEW
Cardiovascular Medications With Food and Grapefruit Juice See page 22.
see ASP BUILDING TIPS, page 8
Nearly $1 M in cost avoidance
Pharm Technicians Praised for Spot-on Med Reconciliation
New sterile compounding legislation:
Does Bill Have the Muscle To Stop Another NECC? B
y the end of 2013, a sigh of relief could uld be heard in some patient safety circles afterr newly passed legislation gave state and federall officials broadened oversight powers to regulate ulate sterile compounders. With the new inspecpection muscle bestowed on those officials, als, the chances of another New England Comompounding Center (NECC)-type outbreak eak killing or injuring hundreds of patients nts seemed significantly diminished. The latest details on the results off those inspections, however, suggest that safety gaps still remain. Of the 20 sterile compounding facilities that have registered with the FDA under the bill’s new “outsourcing facility” category, less than half had been inspected by the FDA as of late Febru-ary. That may not be surprising, given n the early days of the legislation’s rollout. ut. The more striking finding is that only two wo of the inspected facilities have been given a clean bill of health. Sites failed inspection pection for
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see COMP POUNDING, page 26
A Push for Practice Change Yields Big Payoff at U Kansas
Emergency department (ED) pharmacy technicians (PTs) at several hospitals received praise at the 2013 American Society of Health-System Pharmacists Midyear Clinical Meeting for conducting medication reconciliations with up to 96% accuracy. The studies found that PTs were able to detect a substantial number of errors included
Chicago—Millions of dollars in new revenue. A 30 percentage-point gain in patient satisfaction score. A fourfold increase in the capture rate for pharmacist-completed admission histories and discharges. Any of those achievements would be impressive on its own. But scoring all three in less than a year’s time is a testament to the power of taking an entrepreneurial approach to practice change, according to Rick Couldry, MS, FASHP, the director of pharmacy at the University of Kansas Hospital in Kansas City, Kan. At the American Society of Health-System Pharmacists’ (ASHP) annual leadership conference, Mr. Couldry described some of the key components of his strategy for revamping pharmacy operations. One effective strategy, he noted, is to tell compelling patient stories that communicate viscerally why a proposed practice model change is needed, and be prepared to answer the question of “So what?” by delivering measurable evidence of a program’s
see ED TECHNICIANS, page 10
see BIG PAYOFF, page 30
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New Product Codonics, RIVA team up for safer labeling. See Technology section, pharmacypracticenews.com