April 2015

The Pharmacist’s News Source

pharmacypracticenews.com

3 4

Q&A: Eric Tichy, PharmD, on organ transplant pharmacy.

6

A.S.P.E.N. shines light on hospital malnutrition.

OPERATIONS & MGMT

12

Are you automatizing mediocre skills sets in your pharmacy?

POLICY

24 26 32

New ICD codes can derail reimbursement.

Tips for surviving a 340B audit.

Generic drug labeling triggers a fierce debate over patient safety.

TECHNOLOGY

34

Barcoding, automation boost outpatient pharmacy performance.

EDUCATIONAL REVIEW

Medication Errors: A Year in Review See insert after page 36.

Spotlight on BLEEDING MANAGEMENT

CLINICAL FDA, ISMP warning: chemotherapy may melt some CSTDs.

Volume 42 • Number 4 • April 2015

Careful planning, standardized protocols among keys to success

New Treatments, New Challenges T

here’s a lot of encouraging news if you’re a hospital pharmacist managing patients with bleeding disorders.

The FDA, for example, recently approved a new therapy for adults with acquired hemophilia A. Although a rare condition, affected patients can pose a huge treatment challenge due to the complexity of this autoimmune disorder. Thus, any new agent represents a significant advance, according to one expert we interviewed as part of our special section on bleeding management, which begins on page 14.

Other timely section topics focus on the newer anticoagulants that have reshaped this drug class. Although it’s always a plus to have expanded treatment options, one downside is the formulary juggling that may occur when deciding on a preferred agent. For one hospital’s experience in choosing its go-to glycoprotein IIb/ IIIa inhibitor for acute coronary syndrome, see page 22.

And just to keep this therapeutic area even more interesting, the FDA last month approved another new anticoagulant: a t: edoxaban (Savaysa, Daiichi Sankyo), which got the agenccy’s nod for reducing the risk for stroke and systemic embolissm in patients with non-valvular atrial fibrillation (page 20).

Also on tap is the latest standardized approaches to warfarin reversal (page 16), how to assess the evidence supporting off-label use of antithrombin concentrates (page 15) 5) and a new study showing the benefits of low-molecular-weight heparin for preventing blood clots in cancer patients (page 18).

Hurdles Remain For Biosimilars— Including Savings Arlington, Va.—Is the March FDA approval of Zarxio, Sandoz’s filgrastim biosimilar, a) the dawning of a new age of access to low-cost complex biologic agents in the United States, or b) the first step on a long road to convincing stakeholders of the drugs’ savings potential, safety and efficacy?

Experts speaking at a recent symposium on biosimilars tended toward the latter camp. They identified a number

Part 1 of a 2-Part Series

Cost-Cutting Initiatives Have A Happy Ending: Quality Care Anaheim, Calif.—Science trumps marketing! Education devours ignorance! Data defeat fear! The narratives behind a batch of studies presented at the American Society of Health-System Pharmacists 2014 Midyear Clinical Meeting are the stuff of novels, but they also have a more pragmatic resonance: Pharmacists keep finding ways to slash costs while preserving safety and efficacy.

The Pharmacy and Therapeutics (P&T) Committee at Kalispell Regional Healthcare in Kalispell, Mont., is a case in point, having likely won friends in the C-suite after implementing two cost-cutting initiatives. The first—a conversion from the granulocyte colony-stimulating factor (G-CSF) analog filgrastim (Neupogen, Amgen) to its biologic equivalent, tbo-filgrastim (Granix, Teva Pharmaceuticals/Cephalon)—yielded a 59% savings in spending (poster 4-080).

see BARRIERS, page 28

see BOOSTING SAVINGS, page 10

New Product Tev va introduces seven new enoxaparin dosa age strengths.

See page 32

Get the App

Take a bite out of G-CSF acquisition costs Based on whole esale acquissition cosst (WAC AC A C) of alll sho ort r -a act c in ng GG CS CSF F pr prod o uc od u ts as of November 11, 201 0 3.

3 WAC rep epre ese sent ntts pu p bl blis ishe is he ed ca cata t lo ta l g gue gu e or lisst prric i es and n may not represent acctual tra ansa a tion ac o al a pri r ce ces. s Ple s. leas ase e co con ntac actt yo your urr sup uppl plie ierr fo forr ac actu tual al pri rice ces. ce s

GRANIX® is an option in short-acting G-CSF therapy » A 71 7 % red ducttio ion n in n dur urat attio on off sev ever ere e ne n ut u rro ope p nia a vs placebo (1.1 days vs 3.8 da dayss, p<0 <0.0 000 001) 1)1 – Effica c cy cy was eva valu l at a ed e in a m mult mu ltin nattio iona n l, m multi t ce enter, randomized, controlled, Phase III study of chem motherapy-naïve patients tss witth hi hig g -r gh - is iskk br brea east stt can nce cer receivving do oxorubicin (60 mg/m2 IV bo olus)/docetaxel (75 mg/m2)1 » Th he sa safe fe etyy of GR GRA A IX was est AN sa ablishe ed in 3 Phase III trials,, with 680 p patients receiving g chemotherapy py for either breast 1 ca anccer er,, lu lung ng g can nce er, or no nonn-Ho odgkin lympho oma (N NHL) » No Now w of offe ferri fe ring ng a new e pre r se s ntation for self-ad dministration

Indication » GR G AN ANIX IX is a le leukocyte ocyte growth factor indicat indicated ted forr reduction in the duration of severe ne neutropenia eutropenia in p patients atients w th non wi onm mye oid malig myel gnancies receiving myelosuppresssive anticancer drugs associated with a clinically significant i ci in cide denc nce e of febrile neu utropenia.

Important Safety Information » Sple Sp eni n c ru upture: Splen nic rupture, including fatal cases, can occur following the administrattion of human granulocyte colo co lony ny-stimulating facttors (hG-CSFs). Discontinue GRAN NIX and evaluate for an enlarged spleen or sp s le enic rupture in pati pa tien e ts who report up pper abdominal or shoulder pain after receiving GRANIX. » Ac Acut ute resspiratory disttress syndrome (ARDS): ARDS ca an occur in patients receiving hG-CSFs. Evaluate pa p tients t who wh o de d ve elop fever and d lung infiltrates or respirator o y disstress after receiving GRANIX, forr ARDS. Disco c ntinue GRANIX X in pat atients with ARDS. » Al A lergic reactions: Serrious allergic reactions, including anaphylaxis, can occur in patientts receiving hG G-CSF S s. Reactions n can ca n occurr on initial exp exposure. posure Permanentlyy discontinue GRANIX GRA ANIX in patients with serious allergic reactions. reac a tions Do Do no n t administe ad er GRANIX to patients with a histo ory of serious allergic reactions to o filgrastim or pe egffilgrastim. » Us U e in pa atients with sickle cell disease: Severe and sometimes fatal sickle e cell crises can occur in patients with sick ckle e cell diseasse receiving hG-CSFs. Consider the potential risks and benefits prrior to the administration of GRAN NIX X in p tients with sickle cell disease. Discontinu pa ue GRANIX X in patients undergoin ng a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and iss characteriize z d by hyp ypote ensiion, hypoalbuminemia, edema and hemoconce entration. Episodes vary in freque ency, severity and may be life-thre eatening if treatme ent is delayed. Patients who develop symptoms of CLS should be closelyy monitored and d re ece ceive e sttanda ard r symptoma atic treatment, which may include e a need for intensive care. » Potential for tumor growth stimulatory effects on malign g ant cells: The granulocyte colony-stimulating facctor (G-CSF) re eceptor, through which GRANIX acts, has been fo f und on tumor ce ell lines. The pos o sibi b lity tha hat GR G AN NIX X act ctss as a grow wth factor for any tumor type, inclu uding myelo oid malignancies and myelodysplasia, diseases e for which GRA ANIX i not app is proved, cannot be excluded. » Most com mmon treatment-emergent adve erse e reaction: The most common n treatment-eme ergent advers r e re ea action tha h t occurred in patients treated with GRANIX at the recommended dose with an incidence off at least 1% % or gre eat a er and t o timess more frequent than in the placebo group wass bone pain. tw Plea Pl ase s see brief summary of Full Prescribin ng Inforrmation on adjacent page.

For more information, visit GRANIXhcp.com.

Refe Re fere renc nce: e 1. GRA ANI N X® (tbo-filgrastim) Injection Prescribing g Info ormation. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva a Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved.. GRX-40582 January 2015.

Clinical 3

Pharmacy Practice News • April 2015

Oncology

Chemotherapy May ‘Melt’ Some CSTDs

T

he Institute for Safe Medication Practices (ISMP) and the FDA have issued warnings that closed system drugtransfer devices (CSTDs) made out of polycarbonate plastic should not be used with chemotherapy agents containing the solvent N,N-dimethylacetamide.

The ISMP cited bendamustine (Treanda, Teva), amsacrine and busulfan as agents that when diluted with the solvent can melt or dissolve the polycarbonate

plastic found in some CSTDs. This can cause spills and potential infusion of the dissolved plastic into the patient.

“I think people are not fully aware of this,” said Matthew Grissinger, RPh, FASCP, the director of error reporting programs at the ISMP. The February 26 ISMP Medication Safety Alert! newsletter stated that drugs diluted with N,N-dimethylacetamide should not be used with the Tevadaptor

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,ië À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À iÊ[see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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 clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

(Teva), ChemoClave (ICU Medical) or PhaSeal (BD) because these CSTDs contain polycarbonate. However, PhaSeal was incorrectly identified as one of the devices that has this problem and, at press time, ISMP said it was running a correction to its announcement.

BD “has not contraindicated the use of the BD PhaSeal system components on any hazardous drugs which include [medications] that are dilut-

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

ed with ... N,N-dimethylacetamide,” said Michael Van Fleet, the company’s senior business director of pharmacy solutions. “Polycarbonate is not used in any [PhaSeal] components, as it offers poor compatibility with N, N-dimethylacetamide.”

The ISMP said its warning included bendamustine because of one report it received through its medical error reporting system, which claimed that the drug melted the plastic parts of Tevadaptor. Mr. Grissinger said any CSTD device made out of polycarbonate plastic would have this problem and advises pharmacists to check the manual of their CSTD to verify a device’s composition.

Tevadaptor product information states that the device should not be used with amsacrin, busulfan and other drugs diluted with N,N-dimethylacetamide, but it does not specify bendamustine. Product information for ChemoClave states it should not be used with drugs diluted with the solvent, but that tests show the device can be used with diluted busulfan at a 0.536 mg/mL concentration.

On March 10, the FDA issued its warning on Treanda and CSTD incompatibility, urging health care professionals to stop using Treanda injections with CSTDs, adapters and syringes containing polycarbonate or acrylonitrile-butadiene-styrene. The FDA further warned that only polypropylene-containing syringes that contain a metal needle and a polypropylene hub should be used to withdraw and transfer the drug. The agency based its warning, in part, on 40 complaints of incompatibility issues related to Treanda and CSTDs that Teva forwarded to the agency, including CSTD leakage or operational failure of the device components and signs of particulate matter in the IV bag after dilution.

Although the FDA cited N,N-dimethylacetamide as the likely culprit in the CSTD malfunctions, it did not mention any other chemotherapy agents containing the solvent in its warning. An FDA representative said the agency is aware of the ISMP alert mentioning amsacrine and busulfan as potential causes of CSTD malfunction, “but a search of FDA’s Adverse Event Reporting System did not identify additional U.S. reports of syringe or transfer device incompatibility associated with [these agents].”

The FDA added that it is not aware of any incompatibility issues associated with any other chemotherapy drugs that contain N,N-dimethylacetamide.

—Kate O’Rourke Mr. Grissinger reported no relevant financial conflicts of interest.

Mr. Van Fleet works for BD.

4 Clinical

Pharmacy Practice News • April 2015

PPN: THE CONVERSATION

A Bridge To Managing Complex Patient Care During the American Society of Health-System Pharmacists 2014 Midyear Clinical Meeting in Anaheim, Calif., David Bronstein, the editor of Pharmacy Practice News, sat down with Eric Tichy, PharmD, who is an organ transplant pharmacy specialist at Yale-New Haven Hospital, in Connecticut, to discuss how his team approaches the care of a particularly complex and challenging group of patients—those with mechanical circulatory support devices implanted as a bridge to heart transplantation.

PPN: Who is a likely candidate for mechanical circulatory support?

Dr. Tichy: Patients who get these devices typically have advanced heart failure but who cannot be managed with pharmacologic means alone. They have an acute need for a heart transplant, but because there is a limited number of organs available, we need other options, op o , much uc likee patients p e with kidney d ey disease d e e who o require dialysis. Mechanical circulatory support is the best alternative in such a scenario.

Transcutaneous Ventricular Assist Device PPN: What do these patients require in the way of medication therapy management?

Dr. Tichy: First and foremost, they need anticoagulation to prevent blood clots and other thrombotic events. The assist devices are sometimes the cause of these events: The surface of the devices can interact with a patient’s blood and cause platelet activation and other inflammatory processes that tend to promote clot development.

Excessive bleeding is also a concern in this setting, with gastrointestinal (GI) bleeds a particular challenge. Again, the mechanical devices are sometimes at fault. Specifically, the devices cannot recreate the pulsatile blood flow of the beating heart; instead, they pump out a continuous blood flow. The hypothesis is that although pulsatile flow generates some elasticity in the blood vessels that deliver blood to the GI tract, that’s nott the case with continual flow; with the latter, you actually lose elasticity, which can lead to arteriolar vascular malformations and a corresponding increase in the risk for GI bleeds.

And then there are all of the other medications patients require for advanced heart failure. These complex treatment regimens demand a high level of vigilance and involvement by a highly skilled pharmacist.

PPN: Can treatment algorithms help ensure these drug regimens are being managed effectively?

Dr. Tichy: Absolutely. At my center, we’re developing algorithms around warfarin management because we find that the more the patient is out of the thera-

peutic target range for anticoagulation, the more complications they start to develop. These tools are invaluable when we interact with our transplant surgeon colleagues; they enable us to help them do a better job of dosing warfarin or other anticoagulants. We’ve found that this type of medication management is not necessarily the surgeons’ area of expertise. Fortunately, e y, they ey appreciate our deep understanding of drug therapy an nd see the value of having a pharmacist on the care team m who is well trained in this area of practice.

PPN PN: The data you presented on the efficacy of m mechanical assist devices during the ASHP meeeting are pretty striking. One study showed thaat patients who are managed on left ventricular assist devices one year out had survival rattes approaching 90%, whereas patients managged on drug therapy alone fared much worse.

How dependent are those positive outcomes H on optimizing drug therapy?

Dr. Tichy: They are very much dependent on executing those regimens with precision, o and that’ss why it’s so important to have highly trained pharmacistts on the transplant team. And yes, with drug therapy alo one, these patients are lucky if they survive that first yeear after diagnosis of advanced heart failure.

PPN: Are the newer anticoagulants an option in patients with mechanical circulatory support?

Dr. Tichy: I’m not aware of any programs that are using them for such patients, in part because they haven’t been well studied in this setting. Also, unlike warfarin, there is no monitoring required for the newer agents, so regular follow-up would be lacking, and as a result, I’d be worried that we could miss some adverse event. There also are no great reversal agents for the newer anticoagulants, so that could be a problem as well. With warfarin, in contrast, there are several well-established reversal agents, such as administering vitamin K, some factor concentrates, etc.

PPN: Patients on mechanical assist devices also are at risk for developing infections, in part due to the “drive lines” that connect the devices to external power sources, which are prone to contamination.

How does the transplant pharmacist factor that into management protocols?

Dr. Tichy: There are different ways of managing those drive-line sites to decrease the risk for infection, such as prophylactic antibiotic therapy. If an infection does occur, sometimes you have to take the device out to optimally manage it. That is a major procedure and prone to complications. So prevention is definitely the way to go.

PPN: Some of the interventions you’ve mentioned cut across multiple specialty areas, whether it’s infection control, interventional cardiology, etc. This must require a multidisciplinary approach to be a success.

Dr. Tichy: Very much so. A lot of it involves communication and collaboration: that is, having the key care providers get together to discuss optimal management strategies. The idea is to reach consensus on who’s going to be responsible for the main components of patient care. To that end, it is important for the pharmacist who is working with the team to speak as one voice for Pharmacy, to avoid any confusion. So yes, a pharmacist may consult with an infectious disease or cardiac specialist, but when it’s time to make a recommendation to the organ transplant team, that ideally should come directly through the pharmacist who is acting as point person.

PPN: That raises the question of training and education. What do you generally require of a pharmacist who is going to take on such a key role?

Dr. Tichy: There aren’t necessarily specific programs that train someone to be an advanced heart failure and heart transplant pharmacist. But the organ transplant pharmacy programs certainly include experiential training and education in these areas, as do some of the cardiology and critical care pharmacy programs. So pharmacists from any of those backgrounds have the basics to be part of the heart transplant and advanced heart failure care team. Of course, some of this does require on-the-job training, where an observant, motivated clinician can learn the key issues and apply them appropriately. But regardless of the route, we certainly are seeing the emergence of a group of pharmacists who truly are specialists in advanced heart failure, mechanical circulatory support and heart transplant—this is a core area of expertise for them. And in centers that are fortunate to have such individuals on staff, both providers and patients are reaping the benefits.

■

Video Exclusive To learn more about transplant pharmacy, go to www.pharmacypracticenews.com to see a video with David Bronstein and Eric Tichy, PharmD (right) and join The Conversation.

Kcentra

WHEN PATIENTS NEED URGENT WARFARIN REVERSAL…

plex m o C n i hromb l t o r P r ersa -Facto v 4 e R y l n n i arfar and O W t s t r i n F e a—the -PCC) for Urg r t n e c K (4F e t a r t n Kcentra—Ready When You Need It Conce Important Safety Information Kcentra is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. Kcentra is for intravenous use only.

WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding.

Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months.

Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with disseminated intravascular coagulation. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT).

Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment.

In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.

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

The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed.

Please see brief summary of full prescribing information on reverse.

The first and only non-activated 4F-PCC for urgent warfarin reversal in adult patients with: – Acute major bleeding or – Need for an urgent surgery/invasive procedure Mean infusion time ~7x faster than plasma Room temperature storage for 36 months

Kcentra has over 15 years of clinical experience as Beriplex® outside the US. www.Kcentra.com Kcentra Hotline: 1-855-4KCENTRA (1-855-452-3687)

Urgent Warfarin Reversal Kcentra is manufactured by CSL Behring GmbH and distributed by CSL Behring LLC. Kcentra® and Beriplex® are registered trademarks of CSL Behring GmbH. ©2015 CSL Behring LLC 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901 USA www.CSLBehring-us.com www.Kcentra.com KCT15-01-0006 3/2015

6 Clinical

Pharmacy Practice News • April 2015

Critical Care Part 1 of a 2-Part Series

In-Hospital Malnutrition a Major Issue for Critically Ill Long Beach, Calif.—Nourishment is essential to a functioning human body— especially when that body is battling illness or healing a wound. Why, then, is providing proper calories, protein and other nutrients so often overlooked in the care of a critically ill patient?

A key barrier to such a seemingly obvious consideration, according to Phil Ayers, PharmD, BCNSP, FASHP,

the chief of clinical pharmacy services for Baptist Health Systems in Jackson, Miss., is the current lack of a gold standard for estimating caloric and protein needs in this population. Furthermore, health care providers lack the resources they need to ensure that the allotted nutrients reach the patient.

Several abstracts presented at the American Society for Parenteral and

KCENTRA® (Prothrombin Complex Concentrate [Human]) For Intravenous Use, Lyophilized Powder for Reconstitution Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kcentra safely and effectively. See full prescribing information for Kcentra.

WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding.

• Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events.

• Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months.

---------------------------------INDICATIONS AND USAGE-----------------------------------Kcentra, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with: • acute major bleeding or • need for an urgent surgery/invasive procedure.

-----------------------------DOSAGE AND ADMINISTRATION--------------------------------For intravenous use only • Kcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight.

• Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished.

• The safety and effectiveness of repeat dosing have not been established and it is not recommended.

• Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min.).

Pre-treatment INR

Enteral Nutrition (A.S.P.E.N.) annual conference address these voids, underscoring the role that nutrition can play in hospital outcomes, and providing at least some hints of much-needed direction. Specifically, researchers suggested that worries about overfeeding obese patients might have been overblown. Of greater concern, they said, might be a situation in which a

2–<4

4–6

>6

Dose* of Kcentra (units† of Factor IX) / kg body weight

25

35

50

Maximum dose‡ (units of Factor IX)

Not to exceed 2500

Not to exceed 3500

Not to exceed 5000

* Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20-31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡ Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

--------------------------------DOSAGE FORMS AND STRENGTHS-------------------------• Kcentra is available as a single-use vial containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S as a lyophilized concentrate.

-------------------------------------CONTRAINDICATIONS ------------------------------------Kcentra is contraindicated in patients with: • Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin.

• Disseminated intravascular coagulation.

• Known heparin-induced thrombocytopenia. Kcentra contains heparin.

--------------------------------WARNINGS AND PRECAUTIONS-----------------------------• Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment.

• Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months.

• Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

------------------------------------ADVERSE REACTIONS--------------------------------------• The most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia.

• The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis.

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-

patient’s calorie or protein count has fallen too low.

“If you don’t feed these people, especially if you don’t give them adequate protein, then wound healing is impaired, length of stay is longer, and morbidity and mortality rates are higher,” added Dr. Ayers, who was not involved in the studies.

In-hospital feeding issues have been noted as far back as the 1970s, when Charles E. Butterworth Jr., MD, called it the “skeleton in the hospital closet” ((Nutr Today 1974;9:4-8). The figures are stark. An estimated one in three Americans enter a hospital malnourished ((Int J Environ Res Public Health 2011;8:514-527). More patients, even many who arrive well nourished, tend to end up short on nutrition during their stay.

Some deficits result by design, as studies in recent years suggested that reducing caloric goals might be optimal for certain patients’ health. In reality, those counts usually are further trimmed: Only 50% to 66% of prescribed calories and protein—whether or not the amounts are actually appropriate—are delivered to a patient, noted the researchers of a study presented at A.S.P.E.N. (abstract 4). The same team highlighted this dangerous inconsistency at last year’s conference (abstract 1).

“If we didn’t complete a prescription for an antibiotic or blood pressure medicine, it would be unacceptable,” said Daniel (Dante) Yeh, MD, a trauma surgeon at Massachusetts General Hospital, in Boston, and the lead researcher of abstract 4. “But it’s pretty much routine for nutrition.”

“Years ago, we were initially overfeeding,” added Carol Rollins, MS, RD, PharmD, a coordinator for the Nutrition Support Team at the University of Arizona Medical Center, in Tucson, who also was not involved in the abstracts.

“Then I think we took a swing way over the edge with underfeeding; and now, we’re coming back to the middle— where we should be.”

6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dangerous Deficits

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

Malnutrition in incoming patients is generally out of the control of providers.

“We are stuck with the hand we’ve been dealt,” Dr. Yeh said. “We can’t really exchange cards. But there are things we can do after they arrive.”

For starters, the Joint Commission now requires that health care providers conduct a nutrition assessment when a patient enters a hospital. What providers do with that information is left up to them. The lack of guidance follows the lack of consensus on ideal calorie or

Based on March 2014R version.

Clinical 7

Pharmacy Practice News • April 2015

Critical Care protein counts among a diverse population of critically ill patients. “Nobody really knows” how much nutrition is needed, Dr. Yeh added.

To that end, Dr. Yeh and his colleagues investigated the association between feeding in the hospital and a patient’s chances of being discharged home versus transferred to a rehabilitation or skilled nursing facility (abstract 4). They specifically looked at what he called a patient’s “cumulative debt” in terms of calories and protein. “Like the national debt, that number is always changing,” Dr. Yeh said.

In the analysis of 213 patients admitted to the surgical intensive care unit, they found that those whose cumulative caloric debt surpassed 6,000 kcal— based on their prescribed nutrition goals—were three times less likely to be discharged home than patients with deficits that did not reach that threshold (6% vs. 19%; P=0.02). A similar difference appeared when they compared patients with protein deficits above and below 300 g (7% vs. 19%; P=0.02).

The relationship remained consistent after adjusting for body mass index and APACHE II scores.

“Nutrition is required for every single process in the body—from fighting infection to proper functioning of the lungs and heart. You need those building blocks,” Dr. Yeh said.

“The effects of malnutrition are magnified in the critically ill,” he added.

“This presents a potential opportunity for improvement.”

Complicating efforts to stave off malnutrition are the frequent interruptions to enteral nutrition faced by hospitalized patients. Last year at A.S.P.E.N., Dr. Yeh and his team estimated that nearly three-fourths of interruptions in surgical patients were unavoidable (abstract 1). He noted that it is imperative to “make up for lost time” by increasing nutrition before and after extubation, operations and other periods in which feeding is not possible. Of course, this still leaves open the question of how many calories and how much protein is enough. The answer, whatever it may be, is far from one-size-fits-all.

“The patient population that has us all somewhat stumped right now is the obese,” Dr. Rollins said.

Casting Doubt on Hypocaloric Goals Another pilot study presented at A.S.P.E.N. (abstract 10) sought to clarify the confusion regarding obesity and caloric intake. Researchers randomized 83 surgical ICU patients to receive either their standard calculated daily caloric requirement (eucaloric) or half of that goal (hypocaloric). Protein targets were kept the same. They focused on the obese patients in the

eucaloric and hypocaloric groups—11 and 19, respectively. What the researchers found surprised them.

A total of 17 infections occurred among obese patients on the eucaloric diet compared with 58 infections among those receiving reduced calories. The mean number of infections per patient (1.5 vs. 3.1; P=0.29) and the percentage of patients who acquired an infection (45.5% vs. 79%; P=0.07), however, did not reach statistical significance.

Furthermore, the two feeding protocols didn’t appear to influence weight

gain differently. Added weight from fluid overload has been linked with worse outcomes in critically ill patients.

The results “cast some doubt as to the appropriateness of broadly applying hypocaloric feeding to all critical care surgical patients,” said Eric Charles, MD, a surgeon with the University of Virginia Health System, in Charlottesvillle, and the lead researcher of the abstract.

Based on the findings, Dr. Charles said his team will “continue to target full eucaloric goals.” He added that they see MALNUTRITION, page 8

For the Management of Postsurgical Pain

EXPAREL® (bupivacaine liposome injectable suspension)

Patient-Focused Pain Control With A Single Dose Long-Lasting Pain Control With Less Need for Opioids1,2 • Indicated for administration into the surgical site to produce postsurgical analgesia • Reduce pain and opioid requirements1,2 without the need for catheters or pumps

hemorrhoidectomy procedures.

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

Important Safety Information: EXPAREL is contraindicated in obstetrical paracervical block anesthesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL. Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL as with other local anesthetic products. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. In clinical trials, the most common adverse reactions (incidence ≥10%) following EXPAREL administration were nausea, constipation, and vomiting.

References: 1. Gorfine SR et al. Dis Colon Rectum. 2011;54(12):1552-1559. 2. Golf M et al. Adv Ther. r 2011;28(9):776-788.

Please see brief summary of Prescribing Information on opposite page.

For more information, visit www.EXPAREL.com ©2014 Pacira Pharmaceuticals, Inc., Parsippany, NJ 07054

PP-EX-US-0502

11/14

(bupivacaine liposome injection)

8 Clinical

Pharmacy Practice News • April 2015

Critical Care

MALNUTRITION continued from page 7

have also discussed using volume-based feeding protocols to hit nutrition targets.

Such strategies allow for the adjustment of the enteral feeding rate based on interruptions. Take, for example, an initial calorie-per-hour rate calculated by dividing a patient’s daily requirement by 20 hours to account for an estimated four hours of interruptions. Then if that patient’s feeding ends up interrupted for six hours of the day, the health care

team can simply increase the hourly rate to make up the difference.

Still, Dr. Charles emphasized that the bigger question remains unanswered.

“We’re never really sure what the optimal caloric goal is or the optimal way to determine it,” he said. “Should it be based on body weight, a standard formula or something else?”

Prioritizing Protein Also missing from providers’ toolkits, according to Dr. Ayers, has been a commercial formula appropriate for

critically ill obese patients—one that contains adequate protein relative to a lower number of calories. Dr. Rollins agreed that researchers and health care practitioners “need to put more emphasis on protein.”

A unique enteral formula designed to fill this void was highlighted in another pilot study presented at A.S.P.E.N. (abstract 12). The Nestlé Health Care Nutrition recipe—which contains 37% protein (100% whey hydrolysate), 31% carbohydrates, and medium-chain triglycerides, fish oil and prebiotic fiber—

is currently available under the trade name “Peptamen Bariatric.”

In a study of 16 critically ill obese patients who received enteral nutrition for at least three days, researchers found the high-protein, low-carbohydrate formula to be safe and well tolerated. Specifically, among the study patients, it appeared to facilitate glucose control (average, 142.8 mg/dL) and nitrogen balance (seven patients had positive balance) without exceeding hypocaloric feeding goals.

“We love it. It’s the highest proteinto-calorie formula that I know of, and is perfect for the at-risk obese patient,” said Andrew Bernard, MD, a surgeon at the University of Kentucky, in Lexington, who participated in the study, which was supported by Nestlé Health Care Nutrition.

“This addresses what’s long been a challenge in nutrition,” Dr. Ayers added. “Although the study is small, it opens up opportunities for other researchers to create larger placebocontrolled trials looking at formulas with higher amounts of protein and lower calories.”

Of course, as abstract 10 noted, whether or not obese patients should receive curtailed calorie counts remains unclear.

“We have seen contradictory studies and statements,” Dr. Ayers said, noting that although the various studies presented at A.S.P.E.N. may be too small and preliminary to change practice today, they help toward clarification and “create ideas and insight for further studies.”

—Lynne Peeples Drs. Yeh, Rollins and Charles reported no relevant financial conflicts of interest.

Dr. Ayers reported serving as a consultant for Baxter, B. Braun and Fresenius Kabi.

Dr. Bernard reported that he is currently an investigator in a Nestlé-sponsored study.

Next issue: Part 2 will focus on tools for achieving adequate nutrient intake in critically ill children.

An Alliance For Better Nutrition The Alliance to Advance Patient Nutrition has issued a progress report on alleviating hospital-based malnutrition. For more details on the report, visit http://www. malnutrition.com/progressreport.

Our coverage of the report can be accessed at pharmacypracticenews. com/Alliance or by scanning the adjacent 2D barcode.

EXP-AP-0020-201301

Clinical 9

Pharmacy Practice News • April 2015

Cardiology Risk for bleeding, cardiac events increased

NSAIDs and Antithrombotics a Bad Combination

T

aking a nonsteroidal anti-inflammatory drug (NSAID) with antithrombotic therapy after a myocardial infarction (MI) almost doubles the risk for bleeding compared with not using NSAIDs—even after short-term treatment, according to a study published in the Journal of the American Medical Association (2015;313:805-814).

The cardiovascular event risk also was increased. The risks were evident regardless of antithrombotic treatment, types of NSAIDs or duration of use.

All patients with an MI are typically prescribed dual antithrombotic therapy (aspirin and clopidogrel) for up to 12 months and then switched to a single agent. Although bleeding risks associated with antithrombotic agents are increased when patients take NSAIDs, certain agents, such as ibuprofen, may also impede the antithrombotic effects of aspirin and may increase the risk for cardiovascular events, the researchers found.

These risks are of considerable public health concern given the widespread use of NSAIDs, they added.

Anne-Marie Schjerning Olsen, MD, PhD, of Copenhagen University Hospital Gentofte in Hellerup, Denmark, and her colleagues examined the bleeding risk and cardiovascular events in patients with a prior MI taking antithrombotic drugs and a prescription NSAID. The researchers looked at nationwide administrative registries in Denmark between 2002 and 2011 to determine who was being treated with aspirin, clopidogrel or other oral anticoagulant and their combinations, as well as ongoing concomitant NSAID. Patients aged 30 years or older with first-time MI and who were alive 30 days after hospital discharge were included in the study. The researchers reviewed information for 61,971 patients, whose average age was 68 years old. Of these,

34% filled at least one NSAID prescription. During a median follow-up of 3.5 years, 18,105 (29.2%) of the patients died, 5,288 (8.5%) suffered bleeding events and 18,568 (30%) experienced cardiovascular events.

The researchers said that there was no safe therapeutic window for concomitant NSAID use because even treatment for less than three days was

associated with an increased risk.

“The cumulative evidence available is an important reminder that while NSAIDs can be helpful and at times necessary medications for satisfactory quality of life, use of these medications among patients with a history of MI is likely to be associated with clinically meaningful bleeding and ischemic risks,” Charles L. Campbell, MD, wrote

in an accompanying editorial ((JAMA 2015;313:801-802).

Dr. Campbell said the effects might be even greater in the United States, where NSAIDs are widely available over the counter.

—PPN Staff

For more news on bleeding management, see pages 15-22

10 Operations & Management

Pharmacy Practice News • April 2015

Finance 20,000

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Mark Donaldson, RPh, PharmD, the director of pharmacy services at Kalispell, admitted that transitioning from a branded drug to its generic is not a novel cost-cutting strategy, but this switch was different: It was the first time his institution substituted a branded biologic with its bioequivalent.

“Our physicians have always clearly understood what it means to interchange a brand name with a generic, but with this shift we needed to provide education regarding the differences between a biologic and a biosimilar from a regulatory, efficacy and safety standpoint,” Dr. Donaldson said, noting that tbo-filgrastim received regulatory approval before the FDA introduced its biosimilar approval pathway and is therefore not technically labeled a “biosimilar.” He stressed, however, that tbofilgrastim is in fact a biologic equivalent ((J Thorac Oncol 2009;4[6]:736-740).

In 2014, after the hospital implemented an automatic therapeutic interchange of the two agents, spending on G-CSFs at the 155-bed, acute care hospital dropped 59% compared with the previous five-month period, Dr. Donaldson reported (Figure).

He said biosimilars have not arrived with the same “deep 60% to 70% discount we’re used to seeing with generic drugs,” but the reduction in price with tbo-filgrastim is “still very good.”

In fact, “we received an additional price reduction from the manufacturer beyond what we were initially paying when we entered into this automatic therapeutic interchange,” Dr. Donaldson said.

Most importantly, the hospital has not seen any changes in the efficacy and safety of the new G-CSF. “It’s been a win–win all around,” he said.

For their second cost-cutting initiative, Kalispell’s P&T Committee chopped 58% off its inhaler-related spending over a one-year period by eliminating use of single-inpatient metered-dose inhalers (MDIs) and nebulizers and creating a therapeutic interchange protocol for these medications (poster 4-079).

Ed Kent, BSP, RPh, helped design and implement the initiative and is the executive director of the Mountain States Pharmacy Network as well as senior consultant at VHA Performance Services, the consulting arm of VHA Inc., a national network of not-for-profit health care organizations headquartered in Irving, Texas. He said using singleinpatient MDIs generates “an incredible amount of waste,” because 42% of patients with asthma stay in the hospital for less than one day (2010 National Hospital Discharge Survey; http://www.cdc. gov/nchs/nhds.htm). “Meanwhile, most inhalers contain between seven and 50

Current Trend

Figure. Cost reductions from a therapeutic interchange program favoring tbo-filgrastim.

days of drug product,” he said.

Prior data have documented that a common canister protocol can reduce waste by 72% to 96% per inhaler, Mr. Kent said (2010 NHDS).

As per the newly implemented common canister protocol, Kalispell patients who are prescribed inhalers now receive their own antistatic, one-way valve holding chamber. “This not only facilitates reuse by creating a physical barrier between the reused inhaler and the patient’s mouth, but perhaps equally, if not more, importantly, it improves the deposition of drug and therefore its efficacy,” Mr. Kent said ((Hosp Pharm 2012;47[9]:700-711).

Before the holding chamber is connected to the inhaler, a respiratory technician wipes both devices using an alcohol or bleach swab, he explained. “The patient doesn’t even come in contact with the inhaler,” emphasized Mr. Kent, adding that staff hand hygiene is an important part of the protocol. After the inhaler is administered, it is removed from the holding chamber and swabbed again.

Along with the common canister protocol, the pharmacy also implemented a therapeutic interchange for several inhalers also with the goal of reducing costs. The two initiatives reduced total spending on inhalers by approximately 58% over a 12-month period after the changes were rolled out in September 2013, Mr. Kent said.

“That doesn’t include savings from reduced inventory carrying costs,” he noted. “We’ve saved over $8,000 in inventory by cutting the number of products ordered in half, and we have much better turnover for the products we do use.”

Although he did not present data on infection rates associated with the common canister protocol, Mr. Kent said the

hospital’s infection prevention specialists have not seen any related increases in hospital-acquired infections.

Mr. Kent urged clinicians apprehensive of pathogen exposure through a common canister protocol to consider that conventional inhalers are “carried in pockets and placed in patients’ drawers and on counters that aren’t necessarily routinely cleaned and sterilized, and that process has never been studied for infection potential.”

In contrast, he said, there are at least 10 studies supporting the safety of a common canister protocol, which employs aseptic techniques, universal precautions and physical separation and barriers for infection prevention (Hosp ( Pharm 2012;47[9]:700-711).

Fluid Resuscitation Switch Pays Off in Safety and Cost According to an analysis of 3,000 patients with systemic inflammatory response syndrome (SIRS) conducted

by Baxter Healthcare, switching from a fluid resuscitation regimen consisting primarily of 0.9% saline to one composed largely of calcium-free balanced crystalloids can dramatically reduce complications and, for a 300-bed hospital, doing so can cut up to $1,360,000 in related spending (poster 6-137).

Lead researcher Suzanne Laplante, the director of health economics, Global Medical Products at Baxter, which is headquartered in Deerfield, Ill., and her colleagues turned to a large Cerner administrative database and compared the frequency of complications in 3,000 patients who met SIRS criteria and received one of two fluid resuscitation regimens: one in which roughly 75% of fluid is 0.9% saline, 21% is Ringer’s lactate and 2% is 0.45% saline; and another in which approxi-

mately 55% of the fluid is calcium-free balanced crystalloids, 25.5% is 0.9% saline, 17% is Ringer’s lactate and 1.7% is 0.45% saline.

Their analysis showed significantly fewer instances of sepsis, pneumonia, cardiac dysrhythmia, cardiac stress and heart failure, as well as other complications, among patients with SIRS who received the balanced crystalloid regimen. These patients also had shorter hospital stays, required less medication and less fluids over a 72-hour period, had fewer diagnostic procedures and their treatment demanded less staff resources.

Ms. Laplante’s team linked these findings with published cost data and generated cost-savings projections for 100-, 300- and 600-bed hospitals. For example, if a 300-bed hospital switched from a saline-predominant regimen to a balanced crystalloid-based regimen in 75% of an estimated 504 annual SIRS cases, the hospital would save an estimated $1,360,000 annually, with the bulk of savings attributable to shorter inpatient stays, reduced staff resource requirements and fewer diagnostic tests, Ms. Laplante reported.

Although calcium-free balanced crystalloid products are more costly than saline-predominant solutions (average wholesale prices from Thomson Reuters’ Red Book: $6.41 per unit for Baxter’s Plasma-Lyte 148 Replacement IV Infusion vs. $2.04 for 0.9% saline), Ms. Laplante said pharmacies would still see significant cost reductions due to a decreased need for additional medical treatment in these patients.

“A pharmacy in the same 300-bed hospital scenario would save an estimated $389,262 annually thanks to reduced medication costs,” Ms. Laplante said.

In light of her group’s current findings as well as a recent study that showed few-

Operations & Management 11

Pharmacy Practice News • April 2015

Finance er complications when balanced crystalloid-based regimens are used in surgical patients ((Br J Surg 2015;102[1]:24-36), Ms. Laplante issued a clear recommendation. “Clinicians, pharmacists and hospital budget holders should consider increasing their use of calcium-free balanced crystalloids for IV fluid therapy as a way of improving patient outcomes and managing costs.”

Keeping a Lid on Quadrivalent Flu Vaccine Use The logic seems clear enough: With two B-type strains of influenza, quadrivalent influenza vaccines confer greater protection against the illness than trivalent formulations, which include only one B-type strain.

However, despite the added protection, national organizations such as the Centers for Disease Control and Prevention have not recommended one formulation over the other, leaving institutions and providers with little guidance on when to use which vaccine, and for whom (http://www.cdc.gov/flu/protect/vaccine/quadrivalent.htm).

At the largest not-for-profit health system in the country, choosing to reserve the quadrivalent vaccine only for pediatric patients has yielded an estimated $1.3 million in influenza drug savings without compromising infection prevention (poster 4-107).

Roy Guharoy, PharmD, MBA, the chief pharmacy officer and vice president at Ascension Health, which is headquartered in St. Louis, framed Ascension’s impetus to develop a clear policy for use of the quadrivalent vaccine in these terms: “In our care delivery model, marketing often trumps science, so we wanted to make sure clinicians were basing their decisions on the clinical evidence.”

According to Dr. Guharoy, the most robust data on the efficacy and safety of quadrivalent vaccines derive from a study of more than 5,000 children in several tropical countries ((N Engl J Med 2013;369[26]:2481-2491).

One group received GlaxoSmithKline’s quadrivalent vaccine (FluLaval Quadrivalent) and a control group received the company’s hepatitis C vaccine (Havrix).

The results showed the quadrivalent vaccine was 55% effective, which is not significantly higher than published rates of efficacy with the trivalent vaccine (Vaccine 2012;31[1]:49-57). The findings also indicated the quadrivalent vaccine is 74% effective in preventing moderate to severe infections in the study population.

“Because the pediatric population historically are more likely than adults to be affected by type B influenza, and because illness can be more severe in younger patients, we left it up to clinicians to use their judgment when deciding whether to use the quadriva-

lent vaccine in pediatric patients,” Dr. Guharoy said.

For adults and health care workers, they recommended only the trivalent vaccine be used, he noted.

The Ascension team circulated their recommendations among hospital physician groups and pharmacists and encouraged adherence to the policy by provid-

ing their hospital clinicians with a toolkit that included summaries of the relevant literature and addressed frequently asked questions, Dr. Guharoy explained.

“We also tracked orders on a weekly basis during the 2014-2015 flu vaccination season to reinforce our policy with prescribers who were not adhering to the new recommendations,” he said.

According to Dr. Guharoy, the campaign was a success and quadrivalent vaccines were ordered only 20% of the time. Keeping a lid on use of the quadrivalent vaccine led to a $1,293,307

savings, compared with a scenario in which only the quadrivalent formulation would have been used, he said.

“Moreover, year-to-date prevalence of the virus showed a very low B-type strain, so there’s been no impact on infection rates,” Dr. Guharoy noted.

—David Wild Ms. Laplante is director of Health Economics, Global Medical Products at Baxter. Mr. Kent and Drs. Donaldson and Guharoy reported no relevant financial conflicts of interest.

AN OUTPATIENT OPPORTUNITY IN TREATING ABSSSI When moving beyond daily IV infusions to a once-a-week infusion for two weeks 1000 mg followed one week later by 500 mg

For more information, visit www.dalvance.com INDICATION DALVANCE® (dalbavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus).

IMPORTANT SAFETY INFORMATION Contraindications DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin.

Warnings and Precautions HYPERSENSITIVITY REACTIONS Serious hypersensitivity (anaphylactic) and skin reactions have been reported with glycopeptide antibacterial agents, including DALVANCE. Exercise caution in patients with known hypersensitivity to glycopeptides due to the possibility of cross-sensitivity. If an allergic reaction occurs, treatment with DALVANCE should be discontinued.

INFUSION-RELATED REACTIONS Rapid intravenous infusion of DALVANCE can cause reactions, including flushing of the upper body, urticaria, pruritus, and rash.

HEPATIC EFFECTS ALT elevations with DALVANCE treatment were reported in clinical trials.

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including DALVANCE, with severity ranging from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.

DEVELOPMENT OF DRUG-RESISTANT BACTERIA Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%).

Use in Specific Populations • There have been no adequate and well-controlled studies with DALVANCE in pregnant or nursing women. DALVANCE should only be used if the potential benefit justifies the potential risk in these populations.

• In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen for DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis.

• Caution should be exercised when prescribing DALVANCE to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients.

Please see the DALVANCE Brief Summary of full Prescribing Information on the adjacent page. © Actavis 2015. All rights reserved.

ActavisTM and its design are trademarks of Actavis, Inc. or its affiliates.

Dalvance® and its design are trademarks of Durata Therapeutics Holding C.V., an Actavis affiliate.

DAV24642 2/15

12 Operations & Management

Pharmacy Practice News • April 2015

Leadership in Action Practice makes perfect

Coaching to Greatness “Insanity [is] doing the same thing over and over again and expecting different results.”

—Albert Einstein Sound familiar? We all repeat behaviors that yield poor outcomes. Whether it’s publicly blaming a nurse or pharmacist for a medication error and wondering why the subsequent error reporting

rates tumble, or letting poorly trained staffers conduct medication reconciliation and then bemoaning a steady rise in 30-day hospital readmission rates, there is no lack of flawed thinking and deci-

sion making in pharmacy that almost guarantees failure.

In fact, we have become very skilled at automatizing mediocre skills sets in our profession. The question is why is this so common?

Daniel Goleman’s “Focus, The Hidden Driver of Excellence” (HarperCollins 2013) offers some clues. Our older,

DALVANCE® (dalbavancin) for injection, for intravenous use Brief Summary of Full Prescribing Information INDICATIONS AND USAGE: DALVANCE (dalbavancin) for injection is indicated for the treatment of adult patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureuss (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiaee and Streptococcus anginosuss group (including S. anginosus, S. intermedius, S. constellatus). s Usage–To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALVANCE and other antibacterial agents, DALVANCE should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS: DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin. No data are available on cross-reactivity between dalbavancin and other glycopeptides, including vancomycin.

WARNINGS AND PRECAUTIONS: Hypersensitivity Reactions–Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction occurs, treatment with DALVANCE should be discontinued. Before using DALVANCE, inquire carefully about previous hypersensitivity reactions to glycopeptides, and due to the possibility of cross-sensitivity, exercise caution in patients with a history of glycopeptide allergy [see Patient Counseling Information in the Full Prescribing Information]. Infusion-Related Reactions–DALVANCE is administered via intravenous infusion, using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of DALVANCE can cause reactions that resemble “Red-Man Syndrome,” including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions. Hepatic Effects–In Phase 2 and 3 clinical trials, more DALVANCE- than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than 3 times the upper limit of normal (ULN). Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in the DALVANCE and comparator arms [see Adverse Reactions]. Clostridium difficile-Associated e Diarrhea –Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including DALVANCE, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile. C. difficilee produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficilee should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Development of Drug-Resistant Bacteria–Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Adverse Reactions in Clinical Trials–Adverse reactions were evaluated for 1778 patients treated with DALVANCE and 1224 patients treated with comparator antibacterial drugs in seven Phase 2 and Phase 3 clinical trials. A causal relationship between study drug and adverse reactions was not always established. The median age of patients treated with DALVANCE was 47 years, ranging between 16 and 93 years old. Patients treated with DALVANCE were predominantly male (60%) and Caucasian (78%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation–Serious adverse reactions occurred in 109/1778 (6.1%) of patients treated with DALVANCE and in 80/1224 (6.5%) of patients treated with comparator. DALVANCE was discontinued due to an adverse reaction in 53/1778 (3%) patients and the comparator was discontinued due to an adverse reaction in 35/1224 (2.8%) patients. Most Common Adverse Reactions–The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%). The median duration of adverse reactions was 4.0 days in both treatment groups. Table 1 lists selected adverse reactions occurring in more than 2% of patients treated with DALVANCE in clinical trials.

Table 1. Selected Adverse Reactions in Phase 2/3 Trials (Number [%] of Patients) Dalbavancin Comparator* (N = 1778) (N = 1224) Nausea 98 (5.5) 78 (6.4) Vomiting 50 (2.8) 37 (3) Diarrhea 79 (4.4) 72 (5.9) Headache 83 (4.7) 59 (4.8) Rash 48 (2.7) 30 (2.4) Pruritus 38 (2.1) 41 (3.3) *Comparators included linezolid, cefazolin, cephalexin, and vancomycin.

The following selected adverse reactions were reported in DALVANCE-treated patients at a rate of less than 2% in these clinical trials: Blood and lymphatic system disorders: anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis; Gastrointestinal disorders: gastrointestinal hemorrhage, melena, hematochezia, abdominal pain; General disorders and administration site conditions: infusion-related reactions; Hepatobiliary disorders: hepatotoxicity; Immune system disorders: anaphylactoid reaction; Infections and infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection; Investigations: hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased; Metabolism and nutrition disorders: hypoglycemia; Nervous system disorders: dizziness; Respiratory, thoracic and mediastinal disorders: bronchospasm; Skin and subcutaneous tissue disorders: urticaria; Vascular disorders: flushing, phlebitis, wound hemorrhage, spontaneous hematoma. Alanine Aminotransferase (ALT) Elevations–Among patients with normal baseline ALT levels, more DALVANCE- than comparator-treated patients had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN), 12 (0.8%) vs. 2 (0.2%), respectively, including three subjects with post-baseline ALT values greater than 10 times ULN. Eight of 12 patients treated with DALVANCE and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis and a history of alcohol abuse. In addition, one DALVANCE-treated subject in a Phase 1 trial had post-baseline ALT elevations greater than 20 times ULN. ALT elevations were reversible in all subjects. No comparator-treated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN. DRUG INTERACTIONS: Drug-Laboratory Test Interactions –Drug-laboratory test

interactions have not been reported. Drug-Drug Interactions –No clinical drug-drug interaction studies have been conducted with DALVANCE. There is minimal potential for drug-drug interactions between DALVANCE and cytochrome P450 (CYP450) substrates, inhibitors, or inducers [see Clinical Pharmacology in the Full Prescribing Information].

USE IN SPECIFIC POPULATIONS: Pregnancy Category C –There have been no adequate

and well-controlled studies with dalbavancin in pregnant women. DALVANCE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No evidence of embryo or fetal toxicity was found in the rat or rabbit at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis, respectively). Delayed fetal maturation was observed in the rat at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). In a rat prenatal and postnatal development study, increased embryo lethality and increased offspring deaths during the first week post-partum were observed at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). Nursing Mothers–Dalbavancin is excreted in the milk of lactating rats. It is not known whether dalbavancin or its metabolite is excreted in human milk; therefore, caution should be exercised when DALVANCE is administered to a nursing woman. Pediatric Use–Safety and efficacy in pediatric patients have not been established. Geriatric Use–Of the 1778 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 313 patients (17.7%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, no dosage adjustment is necessary based on age alone. DALVANCE is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group. Renal Impairment–In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen for DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis [see Dosage and Administration and Clinical Pharmacology in the Full Prescribing Information]. Hepatic Impairment–No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients [see Clinical Pharmacology in the Full Prescribing Information].

OVERDOSAGE: Specific information is not available on the treatment of overdose with

DALVANCE, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered single doses of up to 1500 mg, and cumulative doses of up to 4500 mg over a period of up to 8 weeks, with no signs of toxicity nor laboratory results of clinical concern. Treatment of overdose with DALVANCE should consist of observation and general supportive measures. Although no information is available specifically regarding the use of hemodialysis to treat overdose, in a Phase 1 study in patients with renal impairment less than 6% of the recommended dalbavancin dose was removed [see Clinical Pharmacology in the Full Prescribing Information].

Manufactured for: Revised: May 2014 Durata Therapeutics U.S. Limited, Chicago, IL 60606 ® Dalvance is a registered trademark of Durata Therapeutics Holding C.V., an Actavis affiliate.

Please also see full Prescribing Information at www.dalvance.com.

DAV26625 02/2015

“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

lower brain is more impulsive and likely to be influenced by emotions such as fear and anger. When this part of our brain kicks in, we are much more prone to impulsive thinking that is hard to resist. Goleman refers to this as “bottomup” thinking. The good news is that we can, with effort, rewire our brain circuitry and make more considered, less emotional decisions that can, in time, be executed effortlessly. Goleman calls this “top-down” thinking or wiring. Selfawareness, reflection, deliberation and planning—all of those high-level executive functions occur when we tap into top-down thought processes.

The fact that we can actually accomplish such a change in thinking—albeit with considerable effort—underscores the fact that our brains have “neuroplasticity,” which is another important tenet of Goleman’s writings. As we focus on improving our skills and patterns of thinking, particularly those related to dealing with the “people issues,” he notes, we become more adept at problem-solving and inspiring our employees toward greatness. Making your people successful makes you successful. Although each issue may seem unique, your ability to apply the right principles to the specifics becomes easier and automatic.

Goleman calls this growth process “crystallized intelligence,” in which “our cognitive capacity … continues to increase as the years go on.” The effort, he points out, involves “recognizing what matters, [discerning] the signal within the noise. Some call it wisdom.”

This is where a coach comes in. Pharmacy leaders who want to strengthen their cognitive skills and “top-down” thinking should seek out a coach to help counteract impulsive, automatic, bottomup learned skills. On a recent consulting site visit, I encountered a new pharmacy director who was far too autocratic in the way he requested actions from his staff. As a result, the staff was afraid to ask clarifying questions and executed the request incorrectly. This director needs a good coach, but he also needs to have a willingness to listen and a desire to learn.

That brings us to the next key to growing as a pharmacy leader: mindfulness.

Mindfulness and Self-Control Do you fly off the handle, say things you regret later, intimidate your employees to the extent they give you their eight hours but not a commitment of their

Pharmacy Practice News • April 2015

Operations & Management 13

Leadership in Action minds and hearts? Are you aware when your limbic amygdala region begins to “hijack” your brain and you begin to lose control? The first step is to recognize that loss of control; the second is to get yourself back from the brink and instead tap into the cognitive area of your brain, the prefrontal cortex.

Perhaps you’ve told your children when they get out of control to take a deep breath and relax, or to go to their room and come back when they calm down and are ready to talk about the issue. This is a good mindfulness approach that you can apply to on-thejob situations. Once you recognize that you are about to lose control, take several breaths using what is called “belly breathing”—that is, deep diaphragmatic breathing in which your belly rises but your shoulders do not. This physiologically relaxes you, decreases your stress and shifts your cognitive focus to make rational decisions. If you want a smartphone app to practice, try “Breathe2Relax.”

Warning Signs I can feel a loss of control coming on when I am provoked and sense that I am about to shift to a dictatorial, commanding tirade. My lip quivers a little and my facial expression changes. If I don’t stop myself at this dangerous point, I regret it later. Understanding what is taking place in your mind allows you to stop and take countermeasures. It may be something as simple as “we need to talk about this later.”

You may also sense that a co-worker or subordinate is about to fly off the handle directed at you. I would make the same suggestion of talking about this at a later time.

There also is group mindfulness, which is necessary for focusing on the task at hand. When your group or committee is sidetracked by private conversations between members or a constant barrage of emails coming in on smartphones and any number of other distractions that may be going on outside the group’s agenda, it’s time to call a time-out.

There may be people on your team who believe that fielding all of those emails and other demands on their time is a beneficial skillset—they’re great multitaskers. I would argue that such an approach is nott effective—it results in a lack of focus on the task at hand. Thus, it may be time to take such individuals aside after a meeting and talk to them about the need to sharpen their focus on the group’s agenda—not their own.

In fact, I am a “recovered” multitasker as a result of reading Goleman’s writings on the topic.

I would also encourage you to take a critical look at all of the meetings you are attending. Can you delegate the task

to your subordinates rather than be in meetings every hour of every day, with no time to focus on getting your own work completed? As leaders, we need to take time to pause and reflect to be the vvisionary for our group or department.

Mindfulness can help with that process—provided it includes our own well being, that of others and then the larger, b broader direction of your hospital or b health system.

■ For more information, visit Daniel Goleman’s website at http://goo.gl/p1kBT4.

14 Spotlight on Bleeding Management nt

Pharmacy Practice News • April 2015

More Choice for Physicians Treating AHA

T

he recent FDA approval of antihemophilic factor (Recombinant), porcine sequence (Obizur, Baxter) to treat acquired hemophilia A (AHA) provides clinicians more opportunity to help patients with this rare bleeding disorder, said Annette von Drygalski, MD, PharmD, the director of the Hemophilia and Thrombosis Treatment Center, University of California (UC) Health Sciences in San Diego.

AHA is caused by the spontaneous development of antibodies, called inhibitors, directed against the body’s own factor VIII (FVIII) in individuals with previously normal hemostasis, Dr. von Drygalski said. Unlike inherited hemophilia, AHA is an autoimmune disease that can affect men and women, most often postpartum women and the elderly with malignancies.

Because there is no family history of

hemophilia and the condition is very rare (about one in 1 million individuals), AHA is not often included in a physician’s differential diagnosis. Frequently, the condition is identified because of excessive bleeding postpartum or during surgery. The bleeding can be profound, according to Dr. von Drygalski, and in some cases, fatal.

Obizur is the first treatment approved for AHA that allows clinicians to man-

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age the treatment’s efficacy and safety by measuring FVIII activity levels in additional to clinical assessments, according to the FDA. Obizur contains a recombinant analog of porcine FVIII, which is used because it is similar enough to human FVIII to be effective in blood clotting, but is less susceptible to inactivation by circulating human FVIII antibodies.

Before Obizur’s approval, AHA was treated with activated prothrombin complex concentrate (FEIBA) or recombinant factor VIIa, due to the agents’ ability to reduce bleeding without the need for FVIII, said Dr. von Drygalski, who treats about one or two AHA patients a year. FVIII is not typically used in AHA because it is often inefficient in the presence of antibodies directed against FVIII. These drugs, known as bypassing agents because they bypass the FVIII inhibitor to allow thrombin generation and clot formation, have some “drawbacks,” she said, most notably a higher risk for thromboembolic events. Additionally, “not everyone responds to bypassing agents,” she stressed.

The safety and efficacy of Obizur was evaluated in a global, prospective, controlled, multicenter Phase II/III openlabel clinical trial (N=29 patients). All of the patients treated with Obizur showed a positive response, meaning an effective or partially effective response with bleeding stopped or reduced and clinical improvement at 24 hours after the initial infusion.

In all, 86% (24 of 28) had successful treatment of the initial bleeding episode.

The investigator determined the overall treatment success based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.

The most common adverse reaction observed in more than 5% of 29 patients was the development of inhibitors to porcine FVIII. “However, it is my understanding that even if patients [developed] cross-reactive antibodies that also neutralized Obizur, it may still be efficacious in stopping a significant amount of bleeding in patients,” Dr. von Drygalski said, if target FVIII activity levels are reached.

However, the Baxter studies did not rechallenge those who developed inhibitors, so this is not confirmed by data.

Other than monitoring, no special steps must be taken to switch factors. “If the patient is not responding to one, you can [switch to another agent],” she said.

“This is a really rare form of hemophilia,” she added, so it is good to have “more opportunities to really help patients with bleeding, especially those who have not responded to conventional bypassing.”

—Marie Rosenthal

NAROPIN-US.com

Dr. von Drygalski has received research grants from Baxter.

0793-NAR- 05-1/ 15

Spotlight Sp p on Bleeding Management 15

Pharmacy Practice News • April 2015

Data Lacking on Off-Label Use of Antithrombin Concentrates

C

linicians are calling for more guidance on the use of antithrombin (AT) concentrates for off-label indications, which at one hospital accounted for 70% of the use of the agents.

A dearth of data documenting how best to use these anticoagulants for offlabel indications has translated to significant variation in target AT levels, differing dosing protocols and potentially unnecessary spending on what is a costly therapy, they say. “[Because of the lack of published data], prescribing the appropriate AT dosage for off-label indications can be a complex task for physicians and pharmacists,” said Cristina Salas, PharmD, a clinical practice pharmacist at Jackson Memorial Hospital in Miami, and who coauthored a small case series on her hospital’s experience using AT concentrates ((P&T 2013;38:764-767, 779).

Dr. Salas and a colleague reviewed data from 10 patients treated with Thrombate III (Grifols/Talecris), the human plasma–derived AT concentrate, between January 2009 and April 2013.

Her hospital’s P&T committee had chosen that agent for their formulary over its competitor, the recombinant formulation ATryn (Ovation).

According to Dr. Salas, although both Thrombate III and ATryn are only approved for use in patients with hereditary AT deficiency, 70% (7/10) of the patients treated with the AT concentrate at Jackson Memorial Hospital during the study period had an acquired, rather than hereditary, form of AT deficiency.

The patients were treated with the agent for prevention of veno-occlusive disease after bone marrow transplantation or as anticoagulation during the perioperative cardiac surgery period.

Dr. Salas reviewed the relevant literature as part of her study and found that although data on off-label use of AT concentrates were generally lacking, several publications supported the use of Thrombate III for unapproved indications, such as the prevention of venoocclusive disease ((Blood Coagul Fibrinolysis 2008;19:203-207). In contrast, she found no publications related to ATryn use for this unapproved indication.

“If ATryn were to be included on the formulary as our institution’s AT formulation of choice, a dosage recommendation for nonapproved indications would be difficult to devise,” she said.

Since Dr. Salas’s publication more than two years ago, she said there have been no significant additions to the literature on off-label use of AT concentrates.

The paucity of literature has left Marc Reichert, PharmD, who is the team lead for heart, vascular and transplant surgery in the Department of Pharmacy at Wake

Forest Baptist Health, in Winston-Salem, N.C., and his colleagues in his area of specialty with differing opinions regarding the optimal use of AT concentrates for off-label indications.

Dr. Reichert, who was not involved in Dr. Salas’s research, noted that target levels for the FDA-approved indication of managing patients with hereditary AT deficiency range from 80% to 120% of normal, but clinicians are uncertain what

levels to aim for in patients undergoing certain procedures, such as extracorporeal membrane oxygenation. “Some clinicians use a target of 60%, some go for 80% and others use 100% of normal AT levels as their target,” Dr. Reichert said.

“It’s not clear what the best approach is.”

Clinicians also vary on when they choose to replace AT in these patients, he pointed out. “Some centers monitor AT levels and replace with AT III

if levels are low, regardless of whether adequate anticoagulation has been achieved, while some only monitor and replace AT if anticoagulation is inadequate. These agents are expensive, and we need to determine how to use them most cost effectively.”

—David Wild Drs. Salas and Reichert reported no relevant financial conflicts of interest.

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16 Spotlight on Bleeding Management nt

Pharmacy Practice News • April 2015

Consistency Is Key in Warfarin Reversal Anaheim, Calif.—Hospitals should develop a standard approach for reversing anticoagulation but it should be adaptable based on patient needs, according to a presentation at the American Society of Health-System Pharmacists (ASHP) 2014 Midyear Clinical Meeting.

The first step in managing patients with a bleed is to assess the situation, according to William Dager, PharmD, a pharmacist specialist at the University of California, Davis Medical Center, in Sacramento, and a clinical professor of pharmacy at the Touro University School of Pharmacy, in Vallejo, Calif.

clotting factors are procoagulants and can cause thrombotic events.

Next, treatment options need to be explored. The anticoagulant can be held or losses can be replaced through blood transfusions. Because there is citrate in blood products that lower calcium, which is used in the clotting cascade, supplemental calcium may be necessary. If the site of the bleed is within reach, a stitch can sometimes be one of the best therapies. Topical thrombins also may be effective local adjuncts.

Pharmacologically, he said, the intensity of the anticoagulation, whether the goal is to get the patient back in a

nothing for warfarin reversal if vitamin K is also being used. Prothrombin complex concentrates (PCCs), including PCC3s, PCC4s and activated PCCs, are typically dosed at 25 to 50 units/kg. Recombinant activated factor VII (FVII) at a low dose (1-2 mg) can be quite effective as well, and Dr. Dager said he has used it successfully in several hundred patients.

Low doses of IV vitamin K appear to be just as effective as higher doses in reversing warfarin, according to a study of more than 400 patients ((Ann Pharmacother 2012;46[12]:1617-1626) co-authored by Dr. Dager. “We got to our INR target goals with 2 mg or less,” with a shorter

Rebound Vit K IV Vit K PO

FFP

INR rFVIIa PCC PCC or rFVIIa + Vit K

6

12

24

Time (hours)

Figure. Reversing warfarin.

FFP, fresh frozen plasma; INR, international normalized ratio; IV, intravenous; PCC, prothrombin complex concentrate; PO, oral; rFVIIa, recombinant factor VIIa; Vit K, vitamin K

Where is the bleed coming from? Even a small amount of blood can be devastating in areas like the eye or the spine.

How urgent is the problem? Is there time, or is the patient exsanguinating?

It’s also important that the level of anticoagulation is assessed. Is the patient in the target range or supratherapeutic, and how much reversal is needed?

The hospital setup must be considered—how fast can the emergency department turn an international normalized ratio (INR) around? Can the lab drop everything and do an assay rapidly? Additionally, is the patient taking antiplatelet agents? Long-term consideration may be necessary to determine when to restart anticoagulation because certain patients are at such a high risk for thrombosis. Patients with intracranial hemorrhage (ICH) are more challenging, Dr. Dager said, but some guidelines suggest starting prophylaxis after a bleed. This should be carefully weighed with existing treatments, he cautioned. Concentrated

normal target level of anticoagulation or complete reversal, must be considered. Heparin can be neutralized with protamine, vitamin K can be given for warfarin or concentrated clotting factors to independently recreate hemostasis. Above all, he said, the impact of any comorbid conditions, such as renal failure, must be considered.

Vitamin K a Place To Start There are several options for reversing warfarin, starting with vitamin K, Dr. Dager said. The oral or IV forms of vitamin K work faster than subcutaneous injection and show the same degree of INR reversal after 24 hours, he noted (Dougherty J. Chapter 7: Anticoagulation Reversal. In: Dager WE et al. Anticoagulation Therapy: A Point-of-Care Guide. 1st ed. Bethesda, MD: American Society of Health-System Pharmacists 2011;123-154). Other choices include fresh frozen plasma (FFP), although that needs time to thaw and may cause transfusion reactions. Additionally, giving FFP a day before a procedure does

duration of reversal allowing a quicker INR response when reinitiating warfarin, and shorter periods of bridge therapy compared with higher doses, he noted.

Two other studies have reported similar results ((Br J Haematoll 2011;154:626-634; Transfusion 2013;53:491-498).

There may be rebound anticoagulation effects after giving FFP, FVII or PCCs. To really keep the INR down, vitamin K for patients on warfarin should be combined with the other treatments, he said.

ICH Data Not Conclusive It is unclear what the most effective long-term strategy is in managing patients with ICH, Dr. Dager said. STICH (Surgical Trial in Intracerebral Haemorrhage) ((Lancet 2005;365[9457]:387-397) found no benefit for neurosurgery in most cases, but patients who were anticoagulated appeared to have some benefit. It is hard to tell if PCCs make a difference for ICH, according to PCC trials. Overall, Dr. Dager advised, pharmacists should assess within their own institution if they can

get the patient to surgery, and what INR will be needed so the surgeon will operate. In some cases, concentrated clotting factors can be used to get to a certain INR so a patient can undergo surgery.

When it comes to reversing newer anticoagulant agents, patients taking dabigatran (Pradaxa, Boehringer Ingelheim) can be dialyzed; however, patients taking rivaroxaban (Xarelto, Janssen) or apixaban (Eliquis, Bristol-Myers Squibb) cannot, because both drugs are highly protein bound, Dr. Dager said ((Am J Health Syst Pharm 2013;70[21]19141929). Factor VIII inhibitor bypassing activity (FEIBA; Baxter) may minimize risk for bleeding during placement of a dialysis catheter, and the dialysis process may take as much as 12 to 16 hours depending on how much drug is in the system to remove the dabigatran, he said. A thrombin time should be done after dialysis to ensure the drug is cleared, Dr. Dager advised.

Reversal antidotes in development include idarucizumab for dabigatran, an antibody with a long-duration effect; and for the anti–factor Xa agents, andexanet, which may have some rebound after a bolus and potentially require subsequent continuous infusions; and aripazine, which lasts about 24 hours. PCCs can be used to independently create hemostasis, but the recommended dose has not yet been determined. There are some case reports demonstrating that activated PCCs can help stop bleeding rapidly but only a few patients have been treated in this manner. Results for treatment with FVII are less encouraging, he said, with only some studies showing an effect.

When using concentrated clotting factors, the setting must be considered, Dr. Dager said, whether it’s a bleeding patient in the emergency department or someone requiring an emergent procedure. Delays in getting the drug to the patient can occur, so one must keep in mind what is available and feasible.

Drugs such as FEIBA, which is packaged in one vial, can be administered to patients faster than PCC4s, which may require admixturing multiple vials, Dr. Dager pointed out. If there is time, a lower dose should be initiated and then titrated up, he noted. However, if you give too much of FEIBA, PCCs or recombinant factor VIIa (FVIIa), the bleed may completely dry up and it will be difficult to detect and treat the source, especially when dealing with gastrointestinal bleeds, he noted. Also keep in mind that the more FEIBA and PCCs you give, the higher the risk for thrombosis, he said.

Overall, Dr. Dager noted, if there’s time to reverse dabigatran or rivaroxaban/ see WARFARIN, page 18

18 Spotlight on Bleeding Management nt

Pharmacy Practice News • April 2015

Tinzaparin a Good CATCH in Cancer Patients

R

esults from the international, Phase III CATCH trial have demonstrated that cancer patients who receive the low-molecular-weight heparin (LMWH) tinzaparin (Innohep, LEO Pharma) have a lower rate of recurrent venous thromboembolism (VTE) than patients who receive warfarin.

During the six-month trial period, 6.9% of patients receiving tinzaparin experienced recurrent VTE compared

with 10% of patients receiving warfarin (hazard ratio [HR], 0.65; P=0.07).

“This study reinforces clinical guidelines supporting the use of low-molecular-weight heparins instead of warfarin to prevent recurrent blood clots,” said lead investigator Agnes Lee, MD, the director of the Thrombosis Program, Vancouver General Hospital, University of British Columbia, in Canada.

She presented the study at the annual

meeting of the American Society of Hematology (abstract LBA2).

Current guidelines from the American Society of Clinical Oncology and the American College of Chest Physicians recommend five to 10 days of anticoagulation with LMWH, followed by a minimum of six months of therapy with LMWH to prevent recurrent VTE in cancer patients.

Mary Cushman, MD, a professor of

Differentiation.

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medicine and pathology at the University of Vermont, in Burlington, who was not involved with the study, said that while the primary end point of the trial did not reach statistical significance, the study was clinically significant. “In this trial, the chance that this outcome is false is about a 7% chance, rather than a 5% chance,” Dr. Cushman said. “To me as a clinician, the effect size was clinically relevant, and it was in the direction you would expect, in favor of low-molecularweight heparin preventing recurrence without any difference in bleeding.”

CATCH randomized patients with a variety of cancers to receive tinzaparin (n=449) or warfarin (n=451).

Roughly 10% of patients had a hematologic malignancy. The most common malignancies were gynecologic (23%), colorectal (13%), lung (12%) and breast (9%). Approximately 55% of patients had metastatic disease.

In addition to the recurrent VTE results, the study also found that dur-

WARFARIN continued from page 16

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apixaban, patients should be monitored and labs checked. In more urgent situations, PCCs or low-dose FVII (aPCC), or dialysis for dabigatran should be considered. In a life-threatening emergency situation, aPCC 25 units/kg or PCC3 or PCC4 25 to 50 units/kg should be considered, and hemodialysis for dabigatran arranged, according to recently published guidelines ((Am J Health Syst Pharm 2013;70[21]:1914-1929).

“Always think about the long-term consequences of what you do,” Dr. Dager said. “Don’t walk away and say, ‘I did my job. They stopped bleeding,’ and forget about [venous thromboembolism] prophylaxis, when to reinitiate anticoagulation and risks for subsequent clots.”

Michael Gulseth, PharmD, chair of the ASHP session on anticoagulation, told Pharmacy Practice News that when reversing target-specific anticoagulants (dabigatran, rivaroxaban, apixaban), “step back from the edge” to assess the situation calmly and make treatment decisions. Is the bleeding life-threatening or in a critical space? If patients are not in a life-threatening situation, “generally if you keep them perfused, the drugs will clear fairly quickly on their own.”

More aggressive bleeds, he added, can be managed with concentrated products, although they do carry a thrombotic risk.

—Karen Blum

PreventIV Measures Packaging and Labeling SM

All trademarks herein are the property of Sagent Pharmaceuticals, Inc. PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc. ©2015 Sagent Pharmaceuticals, Inc. 2006

None of the sources reported any relevant financial conflicts of interest.

Spotlight Sp p on Bleeding Management 19

Pharmacy Practice News • April 2015

ing the six-month trial, the rate of symptomatic nonfatal deep vein thrombosis was higher in the warfarin arm (5.3% vs. 2.7%; HR, 0.48; P=0.04). Only two patients experienced incidental VTE, and both were taking warfarin.

Fatal pulmonary embolism occurred in 3.8% of patients in each arm. There was no difference in the incidence of major bleeding events or mortality between the two arms. Fewer patients had clinically relevant nonmajor bleeding with tinzaparin than warfarin (11% vs. 16%; P=0.03).

established ffor ti tinzaparin i iin patients ti t with renal impairment.”

The CATCH study, Dr. Kim said, confirms previous trials that have shown the superiority of LMWH over a vitamin K antagonist as anticoagulation therapy in cancer patients, but she does not see the trial results as a gamechanger. “I don’t believe there will be a major change in current practice, unless [tinzaparin] demonstrates superiority over enoxaparin in a head-tohead trial for the treatment of VTE in cancer patients or it offers significant

costt savings i tto th the h hospita hospitals it compared with treatment with other available LMWH products,” Dr. Kim said.

“A head-to-head comparison of the various LMWHs is not going to happen,” Dr. Lee said. “It is important that clinicians are aware of the important benefits of LMWH over warfarin, with LMWH having better efficacy and a lower risk of clinically relevant bleeding.”

According to Dr. Cushman, in choosing a treatment for a patient, clinicians need to consider what is going to be best, not only in terms of health out-

comes and quality of life, but affordability. “Low-molecular-weight heparin is much more expensive than warfarin,” Dr. Cushman noted. “The challenge is whether the person has health insurance and coverage for the cost of lowmolecular-weight heparin.”

—Kate O’Rourke Dr. Lee reported relevant relationships with LEO Pharma. Dr. Cushman reported relationships with Daiichi Sankyo, dia Dexus and Merck. Dr. Kim had no relevant disclosures.

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No Guidance in Guidelines?

Sara Kim, BS, PharmD, BCOP, an oncology clinical pharmacy specialist at Mount Sinai Hospital, in New York City, pointed out that clinical guidelines recommend LMWH to prevent recurrent VTE and the guidelines do not specify one LMWH product over another. Dalteparin is the only LMWH with regulatory approval for use as extended therapy in cancer-associated thrombosis. Tinzaparin has discontinued marketing in the United States.

“The choice of LMWH products is based on the institution’s formulary status and/or patient’s insurance reimbursement,” Dr. Kim noted. Enoxaparin [Lovenox, Sanofi] is “probably the most preferred LMWH product in many institutions,” because of its lower cost, he added. “Furthermore, enoxaparin provides dosing guidance for patients with renal impairment (creatinine clearance <30 mL/min), whereas no specific dose reduction information is

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20 Spotlight on Bleeding Management nt

Pharmacy Practice News • April 2015

New Anticoagulant Approved by FDA for DVT and PE

E

doxaban (Savaysa), Daiichi Sankyo’s anticoagulant approved by the FDA on Jan. 8, is now commercially available in the United States. The medication is approved for reducing the risk for stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), and for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following five to 10 days of initial therapy with a parenteral anticoagulant.

You can see the difference. ff

Edoxaban is an oral, once-daily drug that specifically inhibits factor Xa (FXa), a key enzyme in the anticoagulation process. For the reduction in the risk for stroke and systemic embolism in NVAF, the recommended dose is 60 mg per day, or 30 mg per day in people with a creatinine clearance of 15 to 50 mL/min. For the treatment of DVT and PE following initial use of five to 10 days with a parenteral anticoagulant, the recommended dose is 60 mg per day, or 30 mg per day in people with a creatinine clearance of 15 to 50 mL/min, those who weigh less than or equal to 60 kg, or those who are taking certain concomitant P-glycoprotein inhibitor medications.

An ‘Exciting’ Addition “We’re really excited about the profile of this drug,” said Howard Rutman, MD, the vice president of medical affairs for Daiichi Sankyo Inc., in an interview with Pharmacy Practice News. “It offers convenient, once-daily dosing without the need for routine blood monitoring, and can be taken with or without a meal.”

One of two large clinical trials evaluating the drug’s safety, the ENGAGEAF TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation), found that 60 mg daily of edoxaban demonstrated a 32% decrease in the risk for stroke or systemic embolism within the treated population, with significantly less major bleeding compared with warfarin, he said ((N Engl J Med d 2013;369[22]:20932104). In the treatment of NVAF in patients with low body weight or in patients who use certain P-glycoprotein inhibitors, he said, “There is no dose adjustment requirement, so it’s a very convenient choice for patients, and for physicians to prescribe.”

The ENGAGE-AF TIMI 48 study compared two doses of edoxaban (60 mg or 30 mg dose-reduced, or 30 mg or 15 mg dose-reduced) with

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Spotlight Sp p on Bleeding Management 21

Pharmacy Practice News • April 2015

warfarin for their effects on rates of stroke and systemic embolism over a median 2.8 years. The study, conducted in 21,105 patients with NVAF at moderate to high risk for thromboembolic events, at 1,393 centers in 46 countries, found that the annualized stroke and systemic embolism rate was 1.18% for high-dose edoxaban compared with 1.5% for warfarin (hazard ratio [HR], 0.79; 97.5% confidence interval [CI], 0.63-0.99; P<0.001). The annualized rate of major bleeding was 3.43% for warfarin versus 2.75% for high-dose edoxaban (HR, 0.80; 95% CI, 0.71-0.91; P<0.001). Differences in cardiovascular mortality rates also were significant, at 2.74% for high-dose edoxaban and 3.17% for warfarin (HR, 0.86; 95% CI, 0.77-0.97; P=0.01).

ferent options ns ffor patients patients, ti t said id Edith Nutescu, PharmD, MS, an associate professor of pharmacy practice and pharmacy systems outcomes and policy at the University of Illinois at Chicago.

The ability to give edoxaban once a day for AF and VTE is convenient, she said, and having two doses offers options to customize the dose for patients at high risk for bleeding.

Patient characteristics such as age, degree of renal impairment, weight and potential drug interactions will drive the choice of anticoagulant medica-

ti tions, tions she h said. said id Th The d drugs are not interchangeable, she noted, and clinicians need to pay attention to the clinical and patient-specific nuances.

A More Tempered View Michael Gulseth, PharmD, the program director for anticoagulation services at Sanford USD Medical Center in Sioux Falls, S.D., has a more tempered view of the drug, based on his reading of the literature. “In the treatment of DVT/ PE, you have to use a lead-in parenteral product, which is a major disadvantage

compared with rivaroxaban/apixaban,” he told Pharmacy Practice News. “The creatinine clearance limitations in atrial fibrillation also would be a problem for about a quarter of patients considered for therapy. I’m struggling in seeing a clear patient I would use this for in comparison to other drugs.”

—Karen Blum Dr. Rutman is an employee of Daichii Sankyo. None of the other sources disclosed any relevant financial conflicts of interest.

Equivalency in NEJM M Trial In the second study, the Hokusai-VTE trial (N ( Engl J Med 2013;369:1406-1415), patients with acute venous thromboembolism who initially received heparin were randomly assigned to receive edoxaban 60 or 30 mg daily, or warfarin, for three to 12 months. The results, in 8,292 patients (4,921 with DVT and 3,319 with PE) from 439 clinical sites in 37 countries, showed that 3.2% of patients taking edoxaban had a symptomatic recurrent venous thromboembolism event compared with 3.5% of those taking warfarin (HR, 0.89; 95% CI, 0.70-1.13; P<0.001).

The most common side effects of edoxaban include bleeding and anemia.

Edoxaban comes with boxed warnings that it should not be used in patients with a creatinine clearance greater than 95 mL/min because of increased risk for ischemic stroke. The warnings also note that premature discontinuation of the medication increases the risk for ischemic events, and that epidural or spinal hematomas could occur in patients receiving neuraxial anesthesia or undergoing spinal puncture. The drug also is contraindicated in patients with active pathologic bleeding.

Edoxaban is priced at $9.24 per pill, about 12% less than other similar products, Dr. Rutman said. A savings plus program for the drug allows eligible patients to pay $4 per month with a savings card; a patient assistance program will provide free product to eligible uninsured patients. The company also has a reimbursement hotline to serve patients and prescribers who need help understanding a patient’s available coverage.

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22 Spotlight on Bleeding Management nt

Pharmacy Practice News • April 2015

Tirofiban Switch Yields Savings—and Debate T

he jury is still out on the leading glycoprotein IIb/IIIa inhibitor (GPI).

Medical studies, guideline changes and drug pricing have convinced some hospitals to select tirofiban over others in the class. Although these centers report saving hundreds of thousands of dollars, some pharmacists continue to express concern that outcomes from the drug have not been measured sufficiently.

Pharmacists at Intermountain Medical Center in Murray, Utah, five years ago performed an analysis comparing the total cost of tirofiban (Aggrastat, Medicure) with eptifibatide (Integrilin, Millennium) for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCI) such as angioplasty or stent placement. Their results, presented at the American College of Clinical Pharmacy’s annual meeting in 2009, estimated that by switching from eptifibatide to tirofiban, the medical center could save about $400,000 annually with no detriment to the approximately 3,000 patients with ACS treated there each year.

After making the switch in early 2013, the medical center saved $250,000 that year and $350,000 in subsequent years, said Katy Mathews Cox, PharmD, who led the transition at Intermountain but is now a cardiac transplant pharmacist at Baylor University Medical Center, in Dallas.

Patient outcomes are still being collected, Dr. Cox said, but the cost savings were reported at the American College of Cardiology’s (ACC) annual scientific session in March.

Other medical centers have made similar choices. In 2012, clinicians at Emory University, in Atlanta created an ACS algorithm using a highdose bolus of tirofiban as the preferred GPI; the algorithm was rolled out to all four of Emory’s hospitals by 2014.

The change resulted after Medicure representatives approached the hospital in early 2012 with newer data for tirofiban, Emory interventional cardiologist Michael McDaniel, MD, told Pharmacy Practice News. Around the same time, the hospital was trying to standardize practices for conditions like ACS, and Dr. McDaniel was part of a multidisciplinary working group looking at this area.

“Although the ACC/American Heart Association [AHA] guidelines are helpful, they allow for different options for different situations,” Dr. McDaniel said. Emory’s cardiology leaders asked

the group to pinpoint a single best therapy to maximize value in each scenario, with the term “value” encompassing safety, efficacy and cost of therapy, he said. They compared data for the two GPIs on their formulary, eptifibatide and abciximab (ReoPro, Janssen), with that for tirofiban.

2009;53[18]:1668-1673; Circ Cardiovasc Interv 2009;2[3]:230-236), he said, and the 2011 PCI guidelines “give a similar recommendation for all three GPIs in STEMI.” Registry data also show similar efficacy among the drugs, he said.

The only area where tirofiban was not similar was cost, Dr. McDaniel said;

STEMI Cardiac Catheterization Lab Protocol

ACT, activated clotting time; GPI, glycoprotein IIb/IIIa inhibitor; PCI, percutaneous coronary intervention; PO, oral; STEMI, ST segment elevation myocardial infarction

The protoc ol they developed (Crit Pathw Cardiol 2013;12[3]: 141-149) rec ommends the use of high-dose tirofiban but no other GPI agents for conditions like STEMI, with the rationale driven largely by cost considerations, Dr. McDaniel said. Although early studies using lower doses of tirofiban suggested it was inferior to other GPIs regarding platelet inhibition and outcomes ((Am J Cardiol 2002;89[12]:647-650; N Engl J Med d 2001;344[25]:1888-1894), “more contemporary studies using higher loading doses and infusions have demonstrated that tirofiban is equally efficacious as other GPIs,” he noted ((Am Heart J 2007;154:344 e1-344.e5; Am J Cardiol 2006;97[4]:489-493; JAMA 2008;299[15]:1788-1799). Meta-analyses in STEMI patients suggested that tirofiban resulted in similar outcomes like ST resolution and Thrombolysis in Myocardial Infarction (TIMI) 3 flow compared with abciximab ((Am J Cardiol 2010;106[2]:167-174; J Am Coll Cardiol

it was quite lower than the others. By switching, Emory halved the money spent on GPIs, said Collin Lee, PharmD, the assistant director of pharmacy at Emory. In 2011, the institution spent about $500,000 on GPIs; in 2014, the total was about $225,000.

There was some holdout from physicians at Emory’s community hospitals who were used to using eptifibatide and didn’t want to switch, “but they eventually did because of cost savings and the need for market share,” Dr. Lee said. A lot of that resulted from people “just being comfortable with what they know,” Dr. McDaniel said.

High-Dose Bolus In October 2013, the FDA approved a supplemental new drug application for a high-dose bolus regimen of tirofiban (25 mcg/kg over three minutes, followed by 0.15 mcg/kg/min for up to 18 hours) for the reduction of thrombotic cardiovascular events in patients with non-ST elevated ACS, spurring additional buzz on pharmacy listservs. The high-dose bolus is recommended in the ACC/AHA guideline for unstable angina/non-ST elevation myocardial infarction (Circu-

lation 2012;14[7];126:875-910) and the ACC/AHA/Society for Cardiac Angiography and Interventions guideline for PCI (Circulation 2011;124[23]:e574-e651), and has been evaluated in at least 30 studies in more than 8,000 patients, according to a Medicure press release.

But not everyone has jumped on the bandwagon. Paul Dobesh, PharmD, an associate professor of pharmacy practice at the University of Nebraska Medical Center’s College of Pharmacy in Omaha, said that pharmacists should use caution when making these kinds of substitutions. “It’s not like there has been this big study that says now tirofiban at this dose is just as good, or noninferior, to these other agents,” said Dr. Dobesh, whose medical center does not use tirofiban.

As for the studies that have been done on tirofiban, Dr. Dobesh noted that they have used “surrogate end points” such as time to ST segment resolution or improvement in TIMI flow. “Although these are typically solid end points, they have failed us in the past, and so it’s really a leap of faith,” he said. “To take that leap just to save some money, we’re not adequately considering the patient.”

Clinicians who want to use tirofiban in ACS patients should demand more rigorous outcomes studies, Dr. Dobesh added.

Medicure is enrolling patients in the SAVI-PCI (Shortened Aggrastat vs Integrilin in Percutaneous Coronary Intervention) clinical trial, which will assess a high-dose bolus of tirofiban plus a shortened infusion duration compared with label-dosing eptifibatide in patients undergoing PCI to look at composite rate of death, PCI-related myocardial infarction, urgent target vessel revascularization or in-hospital major bleeding within 48 hours following PCI or hospital discharge, according to clinicaltrials.gov.

Dr. Cox said that many of the changes affecting use of tirofiban “have been driven by new studies becoming available, and guideline updates,” she said, with such information helping to validate expert opinion about the GPI. “Not to mention tirofiban now has FDA approval for high-dose bolus [therapy],” she said. “The reality is that the true highrisk ACS population (STEMI, high-risk NSTEMI) has been studied more with high-dose bolus tirofiban versus doublebolus eptifibatide. I have new appreciation for knowing the literature, because it has affected how much money we saved and how we manage these patients.”

—Karen Blum Dr. McDaniel is a consultant for Medicure.

Dr. Cox has received speaking fees as a clinical consultant for Medicure.

Dr. Dobesh reported no relevant financial conflicts of interest.

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24 Policy

Pharmacy Practice News • April 2015

Reimbursement Matters

ICD-10 Codes and Pharmacy: Seize the Initiative

C

omplexity is the operational word for reimbursement, and this includes the rules and nuances that tie drugs and biologics to the disease states in which they’re being used.

The various codes we use in our billing endeavors are the key for making those connections accurately—for “getting it right,” as I’ve stated in prior columns.

For example, we all should know by now the importance of using the correct

Healthcare Common Procedure Coding System (HCPCS) codes and billing units, as defined by the Centers for Medicare & Medicaid Services (CMS), and being cognizant of local and national coverage determination (LCD, NCD) requirements or prior authorizations for an everincreasing number of medications. These rules are designed to ensure that the drug chosen is appropriate for the condition for which the patient is being treated.

They often rely on published national guidelines or on well-documented pathways of treatment. In essence, they link the drug chosen with a diagnosis and the procedures performed.

However, your efforts can’t stop there: Proper reimbursement also hinges on the correct use of the standardized diagnostic International Classification of Diseases (ICD) codes. The challenge here is that those ICD codes are about to undergo

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some fundamental changes. Are you ready for the tranBonnie Kirschenbaum, sition? Handling MS, FASHP this properly can have a profound effect on your drug budget, so this is definitely not the time for a head-in-the-sand approach.

Created years ago to categorize death during war time and the responsibility of the World Health Organization, ICD standardizes codes for medical conditions and procedures. Athough most countries already use the 10th code revision (ICD-10), the United States is still adopting this version and is the last major industrialized nation to do so.

ICD-9 codes now are more than 35 years old. As a result, they are inconsistent with current medical practice. So much so that several ICD-9 codes often have to be cobbled together or modified to accurately represent the actual complexity of the patient. The ICD-10 code set has thousands more codes to choose from to drill down to that level of specificity. And therein lies one of the problems with the transition: It’s not just a simple one-toone crosswalk, but a process of relearning an entirely new way of thinking about how disease states are coded.

ICD-10 Transitions Several years ago, work began on changing the coding system used to describe diagnoses and procedures, building increased complexity and specificity into the code sets. This is continuing with ICD-11. However, the country can’t just bypass ICD-10 and go straight to ICD-11 because the future revision is built on the substantial redesign basics of the 10th one. The April cover story in Health Data Management, “The Big Wish for ICD-10,” provides some interesting background and perspectives on this process (http://goo.gl/4HVsnX).

Just as we emphasize telling the drug component of the patient’s story accurately and completely so that correct HCPCS codes can be assigned and billing units calculated, clinicians (including physicians) need to articulate their patients’ stories in a sufficient way to allow coders to perform their own roles effectively. Today, coders rely on approximately 14,000 descriptive codes under the current ICD-9 system. ICD10, when implemented Oct. 1, 2015, will expand that to more than 72,000 codes. Has your facility been training physicians and other clinicians to communicate essential facts in their documentation for this much more nuanced and specific coding system? Does your computerized prescriber order entry (CPOE) system support this?

The additional year to prepare for the

Policy 25

Pharmacy Practice News • April 2015

Reimbursement Matters Prior Approval vs. NCDs and LCDs

CPOE, computerized prescriber order entry system; LCDs, Local Coverage Determinations; NCDs, National Coverage Determinations; PDM, pharmacy drug master

Prior Approval (Payor)

NCDs and LCDs

Applies to:

Third-party carriers (possibly Medicaid)

Medicare (possibly Medicaid)

Need patient’s payor status?

Yes

Yes

Drug tagged in CPOE/PDM?

Yes

Yes

Link to actual rule needed?

Yes

Yes

Rule requirements:

Ask permission first before drug administration

Understand and follow requirements; document completely and thoroughly; code correctly as required.

Payment:

Only if permission is given first

Determined after the fact and may be denied if all rules not followed

transition is more than half over. Although this may seem an almost insurmountable burden, treat it as an opportunity to improve your practice site’s performance.

Think of this as a clinically driven revenue cycle process that applies to both inpatients and outpatients, covered by all payors (not just Medicare and Medicaid).

Achieving a revenue-neutral conversion requires staff training and testing of new systems in the next few months. CMS has multiple resources dedicated to this effort. Circulating the ICD-10 Fact Sheet to educate your staff would be a good start (http://goo.gl/vAe3pm). ICD-10 also has its own website within CMS; check it frequently for updates and resources (http://goo.gl/Ek3YJX).

CMS April Updates Don’t spend all of your time focused on ICD; for general reimbursement, using ASP files from CMS is essential to ensuring that pharmacy computer system and CDM files are in sync with CMS files. These quarterly updated files can be found at http://goo.gl/hKd1WL. Details on second-quarter 2015 payment trends, plus which drugs have moved to lower AMP-based payment limits, are in the web version of this article at pharmacypracticenews.com/ RMApril2015.

■

WE TAKE PAIN PERSONALLY REASON #10 *

ON-Q IS DESIGNED TO HIT THE MARK.†

7 Habits of Strong ICD Planning 1. Prepare a list of all drugs with LCD and NCD or prior authorization requirements, because correct linkage to the new ICD-10 codes will determine their payment. Pick one or two to use as an example of impact. Although a patient navigator or other individuals may be responsible for actually seeking and fulfilling these requirements, it’s your budget that’s negatively affected if it all falls apart and payment is denied or delayed.

2. Review all medication orders in your CPOE system that are connected to a particular disease state or defined pathway, because correct linkage to the new ICD-10 codes is essential. Choose a few drug order sets to use as examples of impact and review all clinical trials in which you may be involved, because documentation of patient eligibility will be changed with the new codes.

3. Meet with the ICD-10 transition team. Is the team optimistic about being ready by Oct. 1? Is your facility currently on track to meet the deadline?

4. Don’t neglect education. What are the plans for staff training to ensure IT readiness?

5. Stay focused. Although the team is dealing with many transition priorities and complexities, focusing on the effect of the transition on drug reimbursement also is an essential component.

6. Keep an open mind. You may leave reassured or with a lengthy “to do” list.

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1. Data on file. 2. Golf M, Daniels SE, Onel E. A Phase III, randomized, placebo controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. Sep 2011;28(9):776-788. 3. Gorfine SR, Onel E, Patou G, et al. Bupivacaine extendedyelease liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: A multicenter, randomized, doubleblind, placebo-controlled trial. Dis Colon Rectum. Dec. 2011;54(12):1552-1559. 4. Sherwinter DA, et al. Continuous infusion of interperitoneal bupivacaine after laparoscopic Surgery: A randomized controlled trial. Obes Surg. 2008: 18 (12): 1581-6.

ON-Q* Pain Relief System. *Registered Trademark or Trademark of Halyard Health, Inc. or its affiliates. © 2015 HYH. All rights reserved.

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26 Policy

Pharmacy Practice News • April 2015

Compliance

340B Audits 101: To Survive, Foresight Is Key Anaheim, Calif.—The best thing that a hospital can do to survive a Health Resources and Services Administration (HRSA) audit of its 340B drug discount program is to be prepared, presenters said during two talks on surviving audits at the American Society of Health-System Pharmacists 2014 Midyear Clinical Meeting.

The strategies include involving hospital leadership; conducting regular self-audits to look for potential problems; and maintaining accurate, up-todate records.

“At this point, anyone who is in the 340B program can expect to be audited at some point, so you really need to be auditready,” said Steven Silverstein, PharmD, the pharmacy health system director for Comprehensive Pharmacy Services, which provides pharmacy services at Mercy Hospital and Medical Center, in Chicago. It is critical, Dr. Silverstein said, “to understand the requirements and understand your program inside and out.”

HRSA is doubling the number of audits in fiscal year 2015, from 99 in 2014 to 200 this year, said Thomas Pettin, a public health analyst with HRSA’s Office of Pharmacy Affairs. Some covered entities will be randomly selected for audits based on the volume of purchases and complexity of their programs, and others will be targeted for audits if allegations are made that something is awry.

Audits will be grouped into several focus areas, Mr. Pettin said, including

ensuring covered entities are eligible for participation in the program; confirming entities are not causing manufacturers to pay 340B discounts and Medicaid rebates on the same drug transactions; and making sure 340B medications are dispensed to eligible patients.

Of all entities eligible for 340B programs, hospitals “are the most complex and have the greatest opportunity for compliance problems and scrutiny,” said Christopher A. Hatwig, MS, RPh, FASHP, the president of Apexus, the prime vendor for 340B participants.

Hospitals make 85% of all purchases in the program, he said, and many depend on the program for survival.

‘[Hospitals] are the most complex [340B-eligible entities] and have the greatest opportunity for compliance problems and scrutiny.’

—Christopher A. Hatwig, MS, RPh, FASHP The 340B program is so complicated that it cannot be considered just a pharmacy program, Mr. Hatwig told Pharmacy Practice News. After enrolling, it is important to pull together an oversight committee including the hospital’s C-suite and representatives from the information technology, legal, finance, government reporting and other departments as necessary to maintain compli-

A Tale of Two Audits

H

ance. The committee also could include representatives from contract pharmacies or wholesalers.

Mr. Hatwig and others recommended the following tips for entities to prepare for audits: Conduct regular self-audits. Once your oversight committee is established, conduct periodic self-audits to assess compliance, advised Mr. Hatwig and Steven L. Gratch, PharmBSc, RPh, the director of compliance and regulatory services for Comprehensive Pharmacy Services, a consultancy based in Fort Worth, Texas.

A good compliance plan reviews all key elements of the 340B program, including

ospitals that have undergone 340B audits by the Health Resources and Services Administration (HRSA) offer several lessons that can be valuable to other 340B-eligible entities.

Several months after Chicago’s Mercy Hospital was audited in July 2012, hospital leaders received preliminary results citing minor issues, including a need to update its 340B database because it still listed a clinic that had been closed. HRSA also questioned the validity of some of the hospital’s contracted prescribers, according to Steven Silverstein, PharmD, the pharmacy health system director for Comprehensive Pharmacy Services, which provides pharmacy services at Mercy Hospital and Medical Center.

The next phase of the process began in February 2013, when the hospital was given 30 days to respond with a corrected action plan. The hospital submitted documentation showing that the prescribers in question were acting as agents of the institution, which HRSA accepted. Final audit results were received in May; Mercy submitted its corrective action plan in June; and the agency considered the audit completed in mid-July, nearly a year after the audit. (The agency no longer issues preliminary results, Dr. Silverstein said.)

As a result of Mercy Hospital’s audit experience, “we monitor things [like the HRSA OPA 340B database] more closely than we did before,” he said. The hospital now performs a review at least quarterly, more often when information needs to be updated, and documents those reviews, he said.

Denver Health and Hospital Authority had a clean audit in February 2012, which Jason Atlas, RPh, MBA, the director of the outpatient pharmacy, said he attributes to several factors: He and three colleagues had attended the 340B University; the hospital had a 340B oversight committee including executives, pharmacy and finance personnel; and they could quickly access documents including the Medicare cost report, a list of the hospital’s 340B clinics, and electronic prescription and health care provider data files. Even now, the hospital includes people knowledgeable about the 340B program in all discussions about growth.

—K.B.

purchasing, billing and contract pharmacies, Mr. Gratch said. Check the status of your facility against the latest Medicare cost report. Review hospital pharmacy departments and make sure all are registered as “ship to” addresses in the hospital database. If you’re using orphan drugs, have a process in place to track the indication of each drug and why it was used. Make sure any pharmacy operating outside the four walls of the parent hospital is registered as a child site.

“Hospitals that have been doing their own audits seem to fare the best with HRSA, and have the least amount of problems,” Mr. Gratch said. Self-auditing is very important, he stressed: “It will keep the program where you want it, and you’re not going to have to worry about auditors walking through the door.”

Identify key resources within the pharmacy department to focus on 340B. “You’re going to be in trouble if you don’t put some resources on 340B because it’s complex enough that somebody needs to be focused on it,” Mr. Hatwig said. That could be a senior technician or other staffer, but pharmacy department leaders need to be involved, he said: “They can’t just delegate this. They need to be on top of things, and they certainly should be managing relationships with other departments and higher-ups.”

Know where your data are. HRSA auditors not only confirm a hospital’s eligibility status, but also evaluate the 340B drug procurement, inventory and dispensing processes; evaluate contract pharmacy operations; and test the hospital’s prevention of 340B drug duplicate discounts. It’s not unusual to have

to pull a Medicare cost report, prescription files and up-to-date lists of providers. When the audit notice is received, “you get a big data request and there’s not a lot of time,” Dr. Silverstein said. “It’s important to know how to access your documents so you can pull them together quickly.”

Take advantage of free resources.

HRSA has ample information about the 340B program, including a one-page document on the audit process, available at www.hrsa.gov/opa. Apexus runs 340B University, a day-long seminar held in different cities throughout the year. In addition, the organization features a number of resources on its website ((www.340bpvp. com), m including nearly 300 frequently asked questions, and maintains a confidential, toll-free call center called Apexus Answers (1-888-340-BPVP). Questions also can be emailed to the organization at ApexusAnswers@340bpvp.com. The company will soon launch several online training modules and create a higher end program targeted to provide individual, role-specialized 340B training to pharmacy staff and 340B consultants.

With all of the resources available, it is “inexcusable” for hospitals not to have 340B policies and procedures in place by now, Mr. Hatwig stressed: “If you don’t have them, you can guarantee that’s going to be a finding, or at least something mentioned in the audit.”

Be selective in choosing contract pharmacies, based on where their patient population resides, Mr. Hatwig said, adding that you need to retain control of the program. Work with software vendors to ensure regular updates to provider and patient lists, so you don’t inadvertently fill a prescription for a patient who is 340B-ineligible.

Network with others recently audited to learn what’s going on and what the expectations are. This can be done at professional meetings or at 340B University, which features speakers who have been through the audit process.

Jason Atlas, RPh, MBA, the director of outpatient pharmacy at the Denver Health and Hospital Authority, which has been audited by the HRSA (sidebar), said that readiness is key. “Preparing for an audit doesn’t begin upon notification of the audit,” he said. “It begins upon the day of registration in the program.”

—Karen Blum None of the sources reported any relevant financial conflicts of interest.

Q & A 27

Pharmacy Practice News • April 2015

Medi-Dose

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MILT 4

Q: Is there a network version of MILT 4?

Q: MILT 3.0 has been the industry-leading solution for labeling and barcoding unit-dose medications for years. Why did you decide to create a new version of this program?

A: MILT 4 is sold as an unlimited individual-site license. You can install the program on as many computers as you need. It’s easy to share your database with all the computers in just a standard folder on the network—no server installation is required.

A: MILT 3.0 has been extremely well received by pharmacists in facilities of all kinds and sizes.

We would have continued to add features and enhancements indefinitely. But with 64-bit Windows becoming popular, the existing code had to be rewritten to support it. Rather than just reconfiguring MILT 3.0 for 64-bit, we chose to use the knowledge we gained working with so many pharmacists and rewrote the program to even better suit their specific needs.

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A: MILT 4 allows you to include up to seven pieces of information in a 1-D or 2-D barcode, and to include identifiers that distinguish each

piece of information. For example, you can create a barcode incorporating an NDC number, expiration date and lot number. If your barcode medication administration (BCMA) or point-ofcare (BPOC) systems can accommodate it, MILT 4 can generate it.

Q: What types of labels does MILT 4 support?

A: We have a complete line of thermal and laser labels designed specifically for pharmacy and nursing use. From moisture-resistant, tamper-evident labels for sealing solids in our blisters, to butterfly and flag shapes for syringes, to

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A: The faster printing, cleaner fonts and easier interface will be the most obvious improvements for existing users. One of the most asked-for features is the ability to have different date calculations associated with specific medications. MILT 4 will automatically calculate the appropriate beyond-use date each time someone opens that medication. Another requested feature is the ability to be prompted for specific data, like a lot number, each time a medication is selected. Both of these features allow pharmacists to guide their staff toward completing the packaging task correctly, but still allow for intervention when special occasions arise.

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A: That’s right. The pharmacist can configure everything from the type of information to be collected, to the rules for how barcodes are created, to easily limiting or expanding the access that staff members have to features within the program, ensuring that those choices are enforced. Labels for each medication type can be customized, and packaging logs and reports can retrieve desired information about the work that has been done.

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28 Policy

Pharmacy Practice News • April 2015

Drug Development

BARRIERS continued from page 1

of barriers impeding U.S. biosimilar adoption, including a still-developing patchwork of state laws limiting pharmacists’ ability to substitute biosimilars for reference or brand-name products; the lack of FDA guidance on naming conventions and clinical testing requirements; skepticism among physicians and patients that biosimilars can be substituted safely; and uncertainty about how private and public payors will reimburse for biosimilars when they become available.

Another roadblock may be the Biologics Price Competition and Innovation Act (BPCI Act), which was passed in 2010 and established a regulatory approval pathway for the medications. Although the act paved the way for Zarxio to be approved, the law’s provisions could keep pioneer and generic manufacturers

Madsen said during the “Biosimilars and Follow-On Biologics 2015 Americas” symposium presented by Paradigm Global Events in February.

Billions of Dollars in Savings In the European Union, the European Medicines Agency has approved 16 biosimilars since 2005 through a less onerous regulatory pathway than the FDA’s.

There, biosimilars are generally priced about 25% less than their reference products. A recent analysis by the RAND Corporation (http://www.rand.org/pubs/ perspectives/PE127.html) estimated that biosimilars would result in savings in the United States of more than $44 billion over 10 years (see Pharmacy Practice News December 2014, p. 33). This represents only about 4% of the total sales of biologics during the period. But the study cautioned that much will depend on final FDA regulations, degrees of competition

‘Interchangeability is a very high hurdle to meet at this time. It will be very difficult for any applicant to accomplish.’

—Kevin M. Nelson

entangled in litigation for years, further delaying biosimilar entrants.

“The debate over biosimilars is similar to the early debates over generics years ago,” said Steinar Madsen, MD, the medical director of the Norwegian Medicines Agency. “While patients and physicians have become less skeptical about biosimilars, many still don’t get it. It’s hard for them to understand the evidence behind their approval,” Dr.

‘A unique biosimilar name could make a [drug] label misleading because it suggests a clinically meaningful difference when there is none.’

and the acceptance of biosimilars. “And it remains unclear how savings will be shared between payers, patients, providers, and taxpayers,” the study concluded.

A new report from Matrix Global Advisors found that regulatory and other barriers will lead drug manufacturers to develop biosimilars for only the biggest-selling biologics, those having average annual sales of more than $898 million, while biosimilars

—Bruce A. Leicher for drugs with smaller sales may never reach consumers (http://www.matrixglobaladvisors.com/storage/MGA_biosimilars_2015_web.pdf.) “The decision of a biosimilars manufacturer to enter the U.S. market is more tenuous than commonly perceived,” said the report’s author, Alex Brill, in a statement accompanying the report. “Without careful policy consideration of the costs associated with biosimilar development, a robust biosimilars market may not be realized.”

A follow-on biologic is “highly similar” to an FDA-approved biological reference product that has lost patent protection, with no clinically meaningful differences in terms of safety and effectiveness. The BPCI Act outlines two categories of follow-on biologics: a “biosimilar” product having the same mechanism of action, route of administration, dosage form and strength as the reference product for the same indications; and an “interchangeable” product having the same clinical result as the reference product and having no greater safety or efficacy risks than the reference product itself when switching to or alternating with the reference medication.

For all intents and purposes, an interchangeable product is identical to the reference. “Interchangeability is a very high hurdle to meet at this time,” said

FDA Approves Zarxio, First U.S. Biosimilar

T

he FDA’s recent approval of Zarxio (filgra astim), the first biosimilar to get the agency’s nod in the United States, illustrates the type of data needed to establissh a biosimilar’s bona fides for market entry.

Under current FDA rules, evidence must show that a biosimilar is highly similar to an already ap pproved biological formulation, known as a reference e product. Data also must document that the biosimilar has no clinically meaningful differences in terms of safety and effectiveness from the reference product; only minor differences in clinically inactive components are allowed.

Sandoz provided data from the head-to-head PIONEER study demonstrating that Zarxio was highly similar to Neupogen (Amgen). In the PIONEER study, Zarxio and the reference product both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy (1.17 and 1.20 days for Zarxio and the reference product, respectively). The mean time to absolute neutrophil count recovery in cycle 1 was also similar (1.8±0.97 days in Zarxio arm vs. 1.7±0.81 days in reference product arm). No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The FDA said that its approval of Zarxio was based on the above data, along with a review of evidence that

included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other evidence demonstrating that Zarxio is biolo ogically similar to Neupogen.

Zarxio has been approved as a biosimilar, not as an interchangeable product, the FDA warned.

Under the e Biologics Price Competition and Innovation Act of 2009, a biological product that has been approved as “interchangea able” may be substituted for the reference product withoutt the intervention of the health care provider who h prescribed ib d the reference product, as a chemical generic drug can be for a branded formulation.

Zarxio stimulates the growth of neutrophils, which are important in the body’s fight against infection. The biosimilar is approved for the same indications as Neupogen, including the treatment of severe chronic neutropenia and in patients undergoing autologous peripheral blood progenitor cell collection and therapy.

Zarxio will be marketed in the United States with a BD UltraSafe Passive Needle Guard that provides one-handed passive activation. Sandoz, a subsidiary of Novartis, does not disclose its launch timing or marketing plans, a company spokesperson said.

—Marie Rosenthal

Kevin M. Nelson, a partner at the Duane Morris law firm, which is headquartered in Singapore. “It will be very difficult for any applicant to accomplish,” he told the symposium.

State Substitution Laws Because generic chemical drugs are therapeutically equivalent to their brand-name counterparts, most states have passed laws allowing pharmacists to substitute generics without physician approval. In contrast, under the BPCI Act, only an interchangeable biotech product—and not a biosimilar—is considered therapeutically equivalent to the reference product. As a result, every state will need to pass new legislation outlining the circumstances under which pharmacists may substitute biosimilars. A half-dozen states have already enacted laws variously limiting pharmacists from substituting biosimilars without physician notification and/ or approval, and bills are pending in several other states.

Generic and branded drug industry organizations have been battling the issue, but last year agreed on compromise model language (http://goo.gl/ zKNQZo) that would allow substitution without prior notice or approval if the pharmacist enters the substituted product information into the patient’s electronic medical record, interoperable pharmacy record, or faxes or telephones the information to the prescriber.

“The electronic record is the best way to go,” agreed Bruce A. Leicher, a senior vice president and general counsel, Momenta Pharmaceuticals, a Cambridge, Mass.-based company that develops biosimilars and generic versions of complex drugs. But Mr. Nelson urged manufacturers to remain cautious because states may pass more restrictive laws, “which will be a disincentive to biosimilars development.”

Another obstacle is the absence of FDA guidance on naming. Brand-name drug companies want the nonproprietary names of reference products (such as filgrastim or erythropoietin) to be different from those used by biosimilars to avoid confusion and facilitate tracking in case of adverse events.

Biosimilar companies argue that this will only confuse patients and physicians more. They note that European and other countries require pioneer see BARRIERS, page 30

Read Pharmacy Practice News Anywhere, Anytime!

30 Policy

Pharmacy Practice News â&#x20AC;˘ April 2015

Drug Development

BARRIERS

â&#x20AC;&#x2DC;The [biosimilars] statute, as currently drafted, will result in significant litigation.

Itâ&#x20AC;&#x2122;s going to slow entry into the U.S. market.â&#x20AC;&#x2122;

continued from page 28

and biosimilars to use the same International Nonproprietary Name (INN). â&#x20AC;&#x153;Unique naming suggests that biosimilars are not biosimilar. A unique biosimilar name could make a label misleading because it suggests a clinically meaningful difference when there is none,â&#x20AC;? Mr. Leicher said.

Indeed, nearly three-fourths of pharmacists in a recent survey said they would feel confident or very confi-

â&#x20AC;&#x201D;Liz Fuller

dent substituting an interchangeable biosimilar for the reference biologic if the two products shared the same nonproprietary name ((J Manag Care Spec Pharm 2015;21[3]:188-195). FDA

has yet to issue draft guidance on the matter, and has designated â&#x20AC;&#x153;filgrastimsndzâ&#x20AC;? as the â&#x20AC;&#x153;placeholder nonproprietary nameâ&#x20AC;? for Sandozâ&#x20AC;&#x2122;s just-approved filgrastim. The agency plans to issue

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draft guidance on the naming issue â&#x20AC;&#x153;in the near future.â&#x20AC;?

FDA also expects to issue draft guidance sometime this year on the clinical studies needed for the interchangeable designation. These will likely include switching studies, but because they are costly (more than $50,000 per patient), experts expect companies will not pursue the designation. Richard DiCicco, the symposium chairman and cofounder of Harvest Moon Pharmaceuticals USA Inc., a Falls Church, Va.-based company that focuses on the manufacture of complex generic drug products and biologicals, noted that biosimilar manufacturers are frequently able to boost production yields and make other improvements to pioneer biologicals.

Many believe these â&#x20AC;&#x153;biobetterâ&#x20AC;? or â&#x20AC;&#x153;biosuperiorâ&#x20AC;? products will be preferable because biosimilars can be marketed only after patents expire on the reference product, which in the case of the BPCI Act is 12 years. â&#x20AC;&#x153;From the biosimilar developerâ&#x20AC;&#x2122;s standpoint, they may consider just doing a standalone development or developing a biobetter. After all, these products will already have been on the U.S. market for 12 years,â&#x20AC;? said Liz Fuller, an IP consultant with Bird & Bird LLP.

Closer Is Better But the closer a biosimilar is to its reference product from an analytical perspective, the more streamlined FDAâ&#x20AC;&#x2122;s clinical requirements will be when compared with a biosimilar that is less equivalentâ&#x20AC;&#x201D;but with differences that may be acceptable, said Hillel P. Cohen, PhD, the executive director of scientific affairs at Sandoz. â&#x20AC;&#x153;Paradoxically, the average health care professional and the public will interpret the lesser amount of clinical data as representing a lower level of supporting evidence for biosimilarity,â&#x20AC;?

Dr. Cohen told the symposium. â&#x20AC;&#x153;Therefore, we will need a lot of education on the concept of the â&#x20AC;&#x2DC;totality of evidenceâ&#x20AC;&#x2122; that FDA uses in its determination.â&#x20AC;?

Even after a biosimilar company successfully navigates FDAâ&#x20AC;&#x2122;s clinical requirements, there is no guarantee the product will be marketed promptly. For example, FDA has approved Zarxio, but Amgen has filed a federal lawsuit against Sandoz, claiming the company violated the BPCI Act by failing to provide it with a copy of its application and detailed manufacturing information. The litigation must be resolved before Zarxio can enter the marketplace, a process that can take years. â&#x20AC;&#x153;The statute, as currently drafted, will result in significant litigation,â&#x20AC;? Ms. Fuller said. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s going to slow entry into the U.S. market.â&#x20AC;? â&#x20AC;&#x201D;Ted Agres None of the sources reported any relevant ďŹ nancial conďŹ&#x201A;icts of interest.

Policy 31

Pharmacy Practice News • April 2015

FDA Watch Avycaz Gets Nod For Complicated UTI, Abdominal Infections

T

he FDA approved ceftazidimeavibactam (Avycaz, Actavis) for adults with complicated intraabdominal infections (cIAIs) and complicated urinary tract infections (cUTIs), including pyelonephritis.

The antibiotic should be reserved for use in patients who have limited or no alternative treatment options, according to the FDA. Avycaz is a fixed-combination drug containing ceftazidime, a previously approved cephalosporin, and avibactam, a new β-lactamase inhibitor. The addition of avibactam to ceftazidime protects it from breakdown by extended-spectrum β-lactamases (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and AmpC-producing pathogens. The drug is indicated for the treatment of cUTIs including pyelonephritis caused by the following susceptible microorganisms: E. coli, K. pneumoniae, Citrobacter koseri, C. freundii, E. aerogenes, E. cloacae, Proteus spp. and P. aeruginosa.

Ceftazidime-avibactam demonstrated in vitro activity against Enterobacteriaceae in the presence of some β-lactamases and ESBLs of the following groups: TEM, SHV, CTX-M, KPCs, AmpC, and certain oxacillinases, as well as P. aeruginosa in the presence of some AmpC β-lactamases, and certain strains lacking outer membrane porin. Ceftazidime-avibactam is not active against bacteria that produce metallo–β-lactamases and may not have activity against gram-negative bacteria that overexpress efflux pumps or have porin mutations.

The most common adverse reactions were vomiting, nausea, constipation and anxiety.

FDA Approves Opdivo For Metastatic Squamous NSCLC

T

he FDA granted a new indication for nivolumab (Opdivo, BristolMyers Squibb) to treat patients with metastatic squamous non-small cell lung cancer (NSCLC) whose disease progresses during or after platinumbased chemotherapy.

The new indication was based in part on a Phase III, open-label, randomized, multinational clinical trial that compared nivolumab (3 mg/kg IV over 60 minutes every two weeks) in 135 patients with the standard of care— docetaxel (75 mg/m2 every three weeks in 137 patients. All of the patients had metastatic squamous NSCLC who had progressed during or after platinum doublet–based chemotherapy. The trial did not exclude patients based on

PD-L1 status. The primary end point was overall survival (OS).

The median OS was 9.2 months in the nivolumab arm (95% confidence interval [CI], 7.3-13.3) and six months in the docetaxel arm (95% CI, 5.1-7.3). The hazard ratio (HR) was 0.59 (95% CI, 0.440.79; P=0.00025). This HR ratio translates to a 41% reduction in the risk for death with nivolumab compared with docetaxel.

Common adverse events included fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea and constipation.

New Inhibitor for MM

T

he FDA approved panobinostat (Farydak, Novartis), the first histone deacetylase (HDAC) inhibitor indicated for the treatment of individuals with refractory multiple myeloma (MM).

Farydak is indicated for patients who have received at least two prior standard therapies, including bortezomib (Velcade, Millennium Pharmaceuticals) and an immunomodulatory drug (IMiD). Panobinostat is to be used with bortezomib and dexamethasone, the FDA said.

The approval was based on the Phase III, randomized, double-blind, placebo-controlled multicenter PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial. The trial results demonstrated that the median progressionfree survival increased in the panobinostat patients (10.6 months; n=94) compared with patients on bortezomib-dexamethasone (5.8 months; n=99; hazard ratio, 0.052; 95% confidence interval, 0.36-0.76).

—PPN Staff

IMPORTANT CORRECTION OF DRUG INFORMATION ABOUT EXPAREL® (BUPIVACAINE LIPOSOME INJECTABLE SUSPENSION) Pacira Pharmaceuticals, Inc., received a warning letter from the US Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP) on September 22, 2014 concerning an advertisement for EXPAREL, which you may have seen published in several professional journals. This publication provides important corrective information about the false and misleading claim.

The FDA stated that the advertisement was false or misleading because it overstates the efficacy of EXPAREL. The FDA objected to the claims that EXPAREL provides pain control that lasts for up to 72 hours because the claims suggest that EXPAREL has been shown to provide pain control beyond 24 hours.

According to the Prescribing Information, “The primary outcome measure was the AUC [area under the curve] of the NRS [numeric rating scale] pain score (cumulative pain scores) collected over the first 72 hour period.…In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity.”

Excerpts from the applicable sections of the FDAapproved package insert for EXPAREL follow. The FDA has reviewed and approved this communication.

Indication for EXPAREL EXPAREL is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated for administration into the surgical site to produce postsurgical analgesia.

EXPAREL has not been studied for use in patients younger than 18 years of age.

Clinical Studies Hemorrhoidectomy The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72 hour period. There was a significant treatment effect for EXPAREL compared to placebo. ©2015 Pacira Pharmaceuticals, Inc. Parsippany, NJ 07054 PP-EX-US-0623

2/15

In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity; however, there was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated.

Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia. EXPAREL has not been studied for use in patients younger than 18 years of age.

Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL. Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL as with other local anesthetic products. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. In clinical trials, the most common adverse reactions (incidence ≥10%) following EXPAREL administration were nausea, constipation, and vomiting.

Reporting Adverse Events Heath care providers and patients are encouraged to report adverse events in patients taking EXPAREL to Pacira at 1-855-793-9727. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see accompanying brief summary of Prescribing Information.

32 Policy

Pharmacy Practice News • April 2015

Medication Safety

Proposed Generic Drug Labeling Change Sparks Debate

A

proposed FDA rule that would allow generic drug manufacturers to quickly update product safety labeling without getting the agency’s approval has sparked a backlash from the generic drug industry and various medical groups. Numerous stakeholders have lobbied hard against the rule, arguing it would cause confusion among health care providers, decrease patient safety and add unwarranted costs.

Brand-name manufacturers have had the authority to update product safety labeling without first getting FDA approval since the 1980s. Often, safety concerns come to light after a drug has entered the market, and this authority was seen as a way to get safety information to consumers quickly. Generic drug companies have not been given the same latitude, experts note.

The rule currently being debated,

which was published in the Federal Registerr in November 2013, was sparked in part by a petition from Public Citizen, a nonprofit, consumer rights advocacy group. The group argued that after generics enter the market, brand-name market share drops precipitously and manufacturers are much less vigilant about labeling updates. Additionally, brand-name manufacturers often stop making a product for which there is a generic version

and, at that point, are not monitoring the product or considering labeling updates.

The FDA saw the benefits of providing generic manufacturers with an option to change their safety labeling quickly, without FDA approval, and proposed the 2013 rule to do just this.

Since then, the FDA has received “numerous comments” from a diverse group, according to Sandy Walsh, an FDA spokesperson. This includes a letter requesting changes to the proposed rule signed by 24 health care stakeholders, including the American Society of Health-System Pharmacists, the American Pharmacists Association, the American Association of Colleges of Pharmacy and the Academy of Managed Care Pharmacy.

In a 54-page comment submitted to the FDA, Raymond Urbanski, MD, PhD, chief medical officer of Mylan Inc., pointed out a number of problems with the rule.

He noted, for example, that “in addition to increased regulatory costs associated with the CBE-O [changes being effected] supplement process, the proposed rule’s potential reallocation of private liability may impose additional litigation-related costs on generic drug manufacturers, which also would cause generic drugs to be more expensive.” A study sponsored by the Generic Pharmaceutical Association (GPhA) and conducted by the

New Product

Seven New Enoxaparin Dosages Now Available

T

eva Pharmaceutical Industries Ltd. announced the launch of the generic equivalent of Lovenox (enoxaparin sodium injection) in seven dosage strengths in the United States. Enoxaparin Sodium Injection, USP is used for prophylaxis of deep vein thrombosis (DVT) in patients undergoing abdominal surgery, hip or knee replacement surgery, or in medical patients with severely restricted mobility during acute illness; and also for the treatment of acute DVT. Lovenox had annual sales of approximately $1.8 billion in the United States, according to IMS data as of November 2014.

Under a licensing agreement, Teva has partnered with Chemi SPA to leverage its internal research-based technology in the development and manufacture of Enoxaparin Sodium Injection, USP. For more information, visit www.tevapharm.com

EXP-AP-0020-201301

Policy 33

Pharmacy Practice News • April 2015

Medication Safety economic policy consulting firm Matrix Global Advisors, estimates the proposed rule would increase generic drug spending by 5.4%, costing the government and private payors $4 billion annually.

Trade Groups Not Happy The GPhA and Pharmaceutical Research and Manufacturers of America (PhRMA) have taken a firm stance against the proposed rule.

“Allowing companies to change their labels unilaterally, and without FDA approval first, creates a scenario in which multiple different labels for the same drug become available to the health care professionals and patients,” said David Gaugh, RPh, the senior vice president for science and regulatory affairs at GPhA. “This could cause confusion among experts as well as patients.”

Mr. Gaugh added that generic companies do not have the clinical trial data or other proprietary information that the brand-name companies rely on to update their labels.

GPhA and PhRMA point out that current law (the Hatch-Waxman Act) requires generic and brand-name drugs to have the same label; the two organizations have proposed an alternative solution. They argue that after a gener-

ic manufacturer enters the market with a particular medication, neither the generic nor the brand-name manufacturer should be able to update the safety warnings without first obtaining FDA approval. They propose the FDA should establish an expedited process for reviewing new safety information from a brand-name or a generic drug manufacturer. Once the FDA determines that a label change is required, it will notify all of the drug manufacturers within 15 days that a change needs to be made. The labeling change will be done quickly through e-labeling. “All labeling [would be] available via the Internet,” Mr. Gaugh explained. “The company would need to update all Internet listservs with the new information within 30 days.”

Generic drug companies seem to be standing in solidarity against the FDA’s proposed rule as written. “We support GPhA’s position,” said Ann FaheyWidman, a spokesperson for Hospira,

a manufacturer of generic injectable products and other formulations.

Michael Carome, MD, the director of Public Citizen’s Health Research Group, said the solution proposed by GPhA would result in fewer updates, make companies less liable and slow down the communication of safety information because the FDA would have to preapprove every warning update.

Mr. Gaugh disagreed. “Our proposal actually would speed up the process,” he said. “Under the current regulation and under the [FDA] proposed rule, all labeling is done via paper labels. Updating paper labels and getting the updated labels through the supply chain channels will require months to years before reaching the health care professional and patients. E-labeling updating will be instantaneous.”

According to Ms. Walsh, the FDA sat down with members of GPhA and PhRMA to hear their alternative solution and has extended the comment

period for the proposed rule until April 27. At presstime, the FDA had scheduled a public meeting for March 27 to discuss the industry proposal and to hear from numerous stakeholders who have submitted comments about the proposed rule.

“The FDA will determine next steps based on our analysis of the comments on the proposed rule and additional information submitted as part of the public meeting on the proposed rule,” Ms. Walsh said. The projected publication date for the rule is Sept. 30, 2015.

—Kate O’Rourke Dr. Carome, Ms. Walsh, Ms. Fahey-Widman, and Mr. Gaugh have no relevant disclosures, except for their positions in their organizations.

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34 Technology

Pharmacy Practice News • April 2015

Automation

A Case of High-Tech Outpatient Savvy T

he downtown area where LSU Health Baton Rouge MidCity Pharmacy operates is “ground zero” for ailments and indigence, pharmacy manager Adria Kerr, RPh, told Pharmacy Practice News.

MidCity Pharmacy has a loyal base and helps siphon patient flow from the emergency department of its parent hospital, the 850-bed Our Lady of the Lake Regional Medical Center (OLOL), some six miles away. Its biggest users need primary and urgent care, earlyintervention HIV treatments, dermatologic procedures and diabetes care.

“Baton Rouge has one of the highest per-capita rates in the country for HIV—and our diets here lead to diabetes,” Ms. Kerr explained.

10 days, Ms. Kerr said. Also, frequent and lengthy financial discussions with patients took place at the single dropoff/pick-up window, adding long lines to the patient experience.

the end of each day now,” Ms. Kerr said.

Data from the KL60 robotic dispenser show that before it went live in April 2014, 195.3 prescriptions had been left unfilled at the end of a typical day; the

‘These technologies together give us a 100% barcode safety net, plus fingerprint ID checks to attach specific users to every step of the process.’

—Adria Kerr, RPh Fast forward to today—nearly one year since the pharmacy implemented robotic dispensing technology from Lake Forest, Ill.-based Kirby Lester— and the improvements in workflow are clear. Ms. Kerr’s team—which also

average for a 30-day period in 2015 to date is 1.8, and these are medications on order to complete the fills.

“The staff felt our goal of zero leftovers was too tough and the stack of scripts was overwhelming. But about

used to run 3% to 5%,” Ms. Kerr said. In addition to the KL60, MidCity also uses two Kirby Lester KL20 drug counters and verifiers to fill the rest of demand.

“These technologies give us a 100% barcode safety net, plus fingerprint ID checks to attach specific users to every step of the process,” she said. The pharmacy does not carry narcotics or compound drugs, and has no front end with over-the-counter products to manage.

On-hand inventory dollars were slashed from $400,000 to $134,000.

Before the workflow improvement initiative, “we held inventory in a storage room, but didn’t actively maintain it,” explained Ms. Kerr, who earned a Green Belt in Lean Six Sigma processes. “We gained control of this once we entered inventory into our QS/1 pharmacy management software system, identified overstock and set par levels based on usage. Now with robotics, our better workflow and standard operating procedures, we also order drugs on a just-in-time basis.”

That storage room is now a break room for staff, Ms. Kerr noted, and the pharmacy carved out private patient consulting space for care and financial sessions.

Return on Investment

A staffer at MidCity Pharmacy in Baton Rouge, La., uses an automated dispensing machine to fill a prescription. The technology has helped the outpatient facility boost its daily prescription volume by 15% and achieve many other operational improvements.

Pair these complex care needs with patient poverty to fully appreciate the pace and intensity at this 340B site. In addition to filling scripts and counseling patients about regimens, the pharmacy team helps uninsured patients secure medication funding each day, and select which of their drug regimens they could pay cash for and which ones must wait.

These tasks were so time-consuming that pharmacists were unable to fill each day’s prescriptions by closing time. Of 400 prescriptions per day, she estimated that nearly 200 were left unfilled, which led to fill turnaround times of up to

fills prescriptions for a sister clinic and 340B-eligible employees of the hospital—has significantly improved productivity, is faster and more accurate with better workflow, has reduced average waiting time to eight minutes per prescription, has resulted in more satisfied patients, and also has slashed the amount of capital tied up in pharmaceutical inventory.

Specifically, daily prescription volume at MidCity increased 15% from 400 to 460. “We didn’t track labor productivity before, but it shows up in our volume gains and the zero leftovers at

one month after getting the automation, when everyone was used to it, we hit that goal. We said ‘we can’t believe we did it,’ and had a pizza party,” she said.

MidCity uses the compact KL60 to fill its top 56 movers, representing a consistent 53.8% of its volume month after month; some larger pills require double cassettes, thus 56 instead of 60.

An average daily staff, which is the same size as before, fills the higher daily volumes. Three pharmacists and nine technicians include two techs who deal solely with patient financial matters. “We run practically zero overtime now. We

The Kirby Lester technology has “paid for itself already in hard dollars,” Ms. Kerr said. She is especially glad to pass most savings along to help patients cover their medication expenses. For instance: • The prior fill fee of $8 per prescription dropped to $4 per 30-day supply.

• The pharmacy designated a subformulary of essential medications such as Tamiflu, which if still beyond a patient’s ability to pay, is made available to them for $10 cash.

• Insulin vials, which it used to sell for $80 to $90 apiece, are now $3 to $4.

“Our patients average 10 prescriptions at a time,” Ms. Kerr said, adding that access and affordability go hand in hand with regimen compliance and health outcomes. That is why her team goes to the lengths it does to maximize medication availability for the “working poor” served by the pharmacy, she noted.

MidCity was the first of four outpatient pharmacies within the broader Franciscan Missionaries of Our Lady Health System, the parent of OLOL, to equip with robotics; another used a different vendor (their plans were underway first); the other two lack the volume to warrant the investment in technology.

—Al Heller None of the sources reported any relevant financial conflicts of interest.

McMahon Group Acknowledges Exemplary Staff ff takes a moment to review the past year and celebrate the achievements of its various departments and the company overall.

McMahon Group’s print and digital properties enjoyed significant successes during 2014, often ft advancing d i in i both b th readership d hi andd reevenues.

2014

The following employees were singled ouut as exemplary at this year’s annual celebration.

We thank them, and we thank our readerrs for their continued enthusiasm for our medical journalism, which has made many of our publications the best read in their specialty.

SUPPORT/ART/PRODUCTION/IT/FINANCE

SUPPORT/ART/PRODUCTION/IT/FINANCE

This award is for a commingled groupp of several vital departments within the company, without any onee of which the company would not thrive, and as such there are two recipients of this award.

MARTIN BARBIERI is the production manager for several of the company’s newsmagazines—a coomplicated task, which he accomplishes seamlessly month after month.

KWA ANGHEE CHUNG is senior lead developer in the IT Department, havinng input in all things digital, including our various websites, internnal content management systems, and apps, to name a few.

EDITOR OF THE YEAR

SALES ACHIEVEMENT AWARD tor among the publication,

copy and projects editorial staffs.

KEVIN HORTY Y won for his editorial dirrection of General Surgery News, the best-read publication in general surgery. His contributions have included an important effort to enhance our Web-based video offerings.

MATTTHEW SPOTO is senior account manager for Gastrroenterology & Endoscopy News, the best-read publication in gastroenterology. This award celebrates creative thinking to enhance sales and customer service.

SALESPERSON OF THE YEAR

THE MCMAHON GROUP PARTNERS’ AWARD

RICHARD TUORTO, the senior groupp publication director for Anesthesiology News and Pain Mediicine News, both of which are the best-read publications in their fiields, earned this award for the ninth year in a row for generatinng the most revenue in the calendar year.

ROSA ANNE MCMAHON is a partner and co-founder of the comppany and the wife of CEO Ray McMahon. For many years she was personally involved in financial oversight, but nowadays she continues to do what she has done expertly from the very beginning: supporting the CEO and family members working at the company!

THE MCMAHON GROUP PERSON OF THE YEAR RICHARD TUORTO, this year’s Salesperson of the Year, was voted Person of the Year by McMahon Group employees for his longstanding excellence in both sales and publication management.

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Medication Errors: A Year in Review

Horsham, Pennsylvania

P

reventing medication errors is an essential component of caring for patients and must

be a core mission of every pharmacy.

For medication error prevention efforts to be effective, they must become a priority.

An error-reduction program begins by establishing a multidisciplinary team to improve medication use.

To be effective, 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 endanger patients. 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 causes of errors and their prevention; • Recommend methods to facilitate the implementation of organization-wide, system-based changes to Text continues on page 4

KEY TO TABLES

1

Computerized prescriberorder 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

Barcode–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 barcode on the medication and a barcode on the patient’s wristband.

P H A R M AC Y P R AC T I C E N E WS .CO M

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.

4

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.

5

“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.

P H A R M AC Y P R AC T I C E N E WS • A P R I L 2 0 1 5

1

Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendation

Technology

Trainer EPIPEN (EPINEPHrine) used during code

• A nurse opened a carton of EpiPens and administered what she thought was EPINEPHrine to a patient experiencing a severe infusion reaction to CARBOplatin.

• The pen was actually a trainer device that did not contain EPINEPHrine. The trainer device is labeled as a trainer, but packaging both devices in the same carton makes it easy for this error to happen.

• The patient arrested and failed to regain consciousness.

• Reserve use of trainer devices to the classroom only.

• Establish a process to account for each device to be sure it does not accidently reach patient care units.

• Remove the trainer devices from the carton and either discard them or store them in non-patient care areas by themselves.

• Alert pharmacy staff that drug companies are copackaging “active” device products with “inactive” trainers for numerous products.

2,4

Mix-up between topical and injectable EPINEPHrine

• A nurse administered topical EPINEPHrine nasal solution to a patient by IM injection. The topical product was stocked in an ADC instead of a 30-mL vial of parenteral EPINEPHrine.

• The topical and injectable solutions are identical and packaged in the same size amber glass vial, although the labels and caps are different.

• Avoid routine storage of 30-mL vials of EPINEPHrine, whether injectable or topical.

• If the topical vials must be available, consider affixing a large “topical use only” auxiliary label to the vials to reinforce proper use.

2,4

Survey links PN component shortages to adverse outcomes

• An ISMP survey revealed that up to 25% of respondents had experienced serious errors associated with shortages of PN components.

Examples included: • Mix-ups between electrolyte salts; • Confusion between pediatric and adult alternative products; • Concentration differences with alternative products; • Forgetting to make changes to protocols, templates, compounders, or order entry systems; • Extravasations when administering calcium chloride peripherally; and • Bone fractures in infants who did not receive adequate phosphorus.

• When possible, use FDA imported drugs for PN components in short supply.

• When using alternative products, conduct a brief failure mode and effects analysis to identify potential sources of error and take action to reduce the risk for errors before using the product.

• Take steps to differentiate between electrolyte salts and adult/pediatric products.

• Draw attention to difference between concentrations, and ensure necessary changes are made in all associated protocols, templates, compounders, or order entry systems.

• Ideally, the FDA should provide better access to reasonably priced imported products that are more similar to the drugs in short supply.

Imported PN products from Fresenius Kabi look alike

• Due to shortages of PN components, the FDA imported several foreign products, including vials of GLYCOPHOS (an organic phosphate), PEDITRACE (pediatric trace elements), and ADDAMEL N (adult trace elements).

• These vials look alike, with a closure system similar to inhalation medications and the product name in an orange band.

• A pharmacy prepared an IV admixture using Peditrace instead of Glycophos

• If you use these products in the pharmacy, alert everyone handling these products to be aware of the similar packaging.

• Take steps to avoid a mix-up, including storing the products separately and affixing auxiliary labels as needed to differentiate the products.

Limit magnesium sulfate premix to 20-g bags

• A patient received magnesium sulfate instead of 0.45% sodium chloride injection with 20 mEq of potassium chloride.

• Pharmacy had recently added 40-g magnesium sulfate bags to an ADC in an area that previously held bags of 0.45% sodium chloride injection with 20 mEq of potassium chloride.

• The nurse had difficulty reading the red-font labels through an overwrap.

• The patient experienced seizures and a cardiac arrest.

• If needed, magnesium sulfate premixed solutions should be stocked in units using the 20 g/500 mL bags, not the 40 g/1,000 mL- bags. The smaller volume helps limit the amount of magnesium a patient might receive if a rapid infusion occurs accidentally.

• In the ED, hospitals may be able to stock only bags intended for bolus doses (eg, 2 g/50 mL, 4 g/100 mL).

• Some organizations use the 4-g minibags for maintenance infusions.

TASIGNA (nilotinib) label instructions may conflict with prescriber instructions

• Confusion may lead to dosing errors with Tasigna because printed instructions on the manufacturer’s packaging reflect ONLY the recommended starting dose.

• One patient took two 200-mg capsules twice daily, as written on the packaging, rather than once daily (400 mg), as written on the prescription label.

• The patient developed QT prolongation.

• The ISMP informed the FDA and Novartis about the incident and asked for removal of the dosing instructions from the blister packages.

• Before patient discharge or dispensing a prescription, reinforce the correct dosing instructions and tell the patient if it differs from what is suggested on the blister pack.

• Give the patient correct written instructions

2

P H A R M AC Y P R AC T I C E N E WS .CO M

2

Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendation

Technology

BRINTELLIX (vortioxetine) and BRILINTA (ticagrelor) drug name confusion

• When electronically prescribing Brintellix 10 mg daily for a patient with major depressive disorder, a physician incorrectly selected Brilinta, an antiplatelet agent.

• The patient picked up the filled prescription but, after reading an attached drug information leaflet, realized that a mistake had been made.

• Build alerts to remind prescribers to use generic names (in addition to brand names) • List the indication when prescribing these drugs.

1,5

Confusion between NAROPIN (ropivacaine) and OFIRMEV (acetaminophen injection)

• Glass vials of Naropin, intended for epidural use, have been repeatedly confused with glass vials of Ofirmev, intended for IV use.

• Either product can be administered without further dilution. Although the labels are dissimilar, the drugs may be the only 2 available in similar glass vials in some patient care areas.

• The risk for error is highest if they are stored near each other, such as in the same ADC drawer.

• Store the products in different drawers or, when possible, limit ADC storage to only one of the drugs.

• Use barcode scanning for stocking and removal of the products from ADCs. • Consider adding auxiliary labels (“For nerve block and epidural use only”) to the Naropin containers before dispensing the product from the pharmacy.

2

Baxter DOBUTamine overwrap label change contributes to error

• With the new labeling on Baxter’s DOBUTamine IV bags, the concentration appears on the overwrap but there is no longer reverse print used for the 250 mg/250 mL bag to differentiate it from the 500 mg/250 mL bag.

• A mix-up occurred when 500 mg/250 mL bags were accidentally used in place of the lower concentration to restock an ADC.

• Standardize to a single concentration when possible and use barcode scanning when restocking or removing the product from ADCs. • In hospitals where more than one concentration must remain, consider storing only one concentration in the ADC, and dispense the less common strength from the pharmacy.

• Add bold auxiliary labels to draw attention to the concentration differences.

2

Nitroglycerin injection labeling issues during shortages

• Baxter labels nitroglycerin with the mg per total volume (100 mg/250 mL) listed first, and the mcg/mL concentration (400 mcg/mL) below in parentheses, whereas Hospira does the opposite and labels nitroglycerin with the mcg/mL (100 mcg/mL) listed first, and the total mg/volume below it in parentheses.

• In a recent report, a nurse set an infusion pump for 200 mg/250 mL after misreading 200 mcg/ mL on a container label.

• During shortages, draw attention to the nitroglycerin label information that matches the way staff are used to it appearing on nitroglycerin labels, and reprogram infusion pump libraries as necessary.

• Meanwhile, the FDA is examining the differences in the labels, and the ISMP is conducting a survey regarding nurses’ preferences.

2

Misleading KCENTRA (prothrombin complex concentrate [human]) label leads to dosage errors

• When 4,500 units of Kcentra were ordered, pharmacy staff noted the “500 U” in the upper right corner of the carton and vial label and assumed each vial contained 500 units.

• Each vial actually contains a range (400-620 units) of factor IX, which is listed on the back panel or the carton and vial label.

• Nine vials were used to prepare an infusion labeled “4,500 units in 180 mL,” but the bag contained 5,026 units given the actual units in each vial.

• Use an auxiliary label or computer reminder to alert staff to verify the actual number of units in each vial listed on the back label panel on the carton and vial.

• We asked the company to modify the label so the range is better communicated.

• We also suggested that additional information is needed where “500 U” appears on the front label panel—perhaps specifying “500 Units Range” as a midpoint of dosages in each vial.

Unfamiliar concentration of DOCEFREZ (DOCEtaxel) increases risk for error

• The Docefrez brand of DOCEtaxel is available as a lyophilized powder that reconstitutes to a concentration different from most commercially available DOCEtaxel products.

• Instead of a 10 mg/mL or 20 mg/mL concentration, reconstitution results in 24 mg/mL (80 mg vial) or 25 mg/mL (20-mg vial) concentrations.

• List Docefrez along with the concentration after reconstitution in order entry systems.

• Have a process in place to review new products (particularly for replacement products on back order or during drug shortages) so that staff is aware of the differences, and make adjustments to the IT system (including strengths and concentrations) as needed for safe use.

5

“Once-Daily” designation on label of longacting ASTAGRAF (tacrolimus) leads to error

• A renal transplant patient who had been taking oral tacrolimus 3 mg every 12 h was converted to a once-daily product, Astagraf, and instructed to take 6 mg.

• Despite application of a pharmacy label, the manufacturer’s label was visible, which prominently displays “ONCE-DAILY” below the drug name and 1 mg strength.

• The patient took just 1 mg once daily.

• Properly label containers dispensed to patients and provide education to them about how to take the medicine.

• The ISMP reported this risk to the FDA for consideration of label modifications.

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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendation

Tragic NMB error should prompt risk assessment by all hospitals

• According to news reports, a preparation error occurred in which rocuronium was accidentally added to an IV bag that was supposed to contain IV fosphenytoin. The error was not caught before dispensing, and the preparation was administered to the patient.

• The rocuronium led to respiratory paralysis, cardiopulmonary arrest, and death.

• Use this tragedy as an opportunity to thoroughly examine the pharmacy IV compounding process.

• Identify NMBs in your organization and determine where and how they are stored.

• Consider limiting the number of NMBs on formulary and segregate or eliminate storage from active pharmacy stock when possible.

• Outside of the pharmacy, sequester NMBs wherever stored.

Methylene blue confused with VISIONBLUE (trypan blue), causing blindness

• A patient undergoing cataract surgery had the lens capsule stained with methylene blue. The error led to blindess.

• During the procedure, the surgeon asked for VisionBlue, but the nurse heard methylene blue. The surgeon did not hear the nurse tell him she retrieved methylene blue and the error occurred.

• Methylene blue may be stored in perioperative areas for use during endoscopies or for visualizing fistulae.

• Store each product in separate areas.

• Require repeat back of verbal orders before medications are obtained and transferred to the sterile field.

• Be sure all products are labeled on the sterile field.

• Alert ophthalmologists to the risk of a mix-up; they may not be familiar with methylene blue.

Confusion caused by “per liter” content on manufacturers’ small-volume IV bag labels

• A back order of 3% sodium chloride solution led a hospital to compound the solution, but an error occurred because the small-volume bags of 0.9% sodium chloride listed the sodium content as 154 mEq/1,000 mL, not 38.5 mEq/250 mL. • The listing of the content per liter led to an error when calculating the number of mEq needed for a 3% solution.

• Drug regulators should consider improvements to the labeling to reflect the strength per total volume (not per liter).

• Educate staff about the risk for calculation errors.

• If products become unavailable, preprogram necessary formulas in automated compounders immediately when an alternative product must be used.

cont’d

Technology

2,4

ISMP, S , Institute st tute for o Sa Safe e Medication ed cat o Practices; act ces; IT,, information o at o tec technology; o ogy; NMB,, neuromuscular eu o uscu a b blocker; oc e ; PN,, pa parenteral e te a nutrition ut t o

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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.

The Institute for Safe Medication Practices (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. The ISMP independently reviews medication errors that practitioners and patients have submitted voluntarily to the ISMP Medication Error Reporting Program.

The ISMP is an accessible resource for any pharmacist or organization interested in implementing the actions recommended herein. Among the many products and services that the 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

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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 2014. 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

Table 2. Safety Issues Associated With Order Communication and Computerized Order Entry Title

Problem/Discussion Point

Recommendation

Technology

Use caution when “alternatives” are proposed with ambulatory electronic prescribing systems

• If a drug is not covered by a patient’s insurance provider, some ambulatory EMR systems (eg, Epic IT, Surescripts) may provide a list of “alternative” medications.

• However, the “alternatives” may not be appropriate. For example, cloNIDine (listed as an analgesic adjuvant drug) was recommended as a substitute for acetaminophen; fat-soluble vitamins K and A were listed as alternatives when cholecalciferol (vitamin D) was ordered; ALPRAZolam was listed as an alternative to clorazepate.

• Incorrect alternatives may be received by the IT vendor from a drug information vendor.

• Examine your electronic prescribing systems to see if this problem exists.

• Health systems may not have the ability to disable automatic “alternative” alerts.

• Educate providers to critically evaluate suggested alternatives when reviewing these alerts.

• We also encourage you to contact your IT vendor immediately about the problem.

• Please notify ISMP of any issues you may be having with this feature or other issues that result in the presentation of possible wrong information.

1

Posaconazole (NOXAFIL) dose depends on dosage form

• An order was placed for posaconazole 200 mg PO TID with meals, but no dosage form was specified. The prescriber thought an oral suspension would be used because, in the past, that had been the only dosage form available.

• In 2013, delayed-release tablets were made available (and now there is an injectable form).

• The order was transcribed as delayed-release tablets. This is clinically relevant because the new delayed-release, enteric-coated posaconazole tablet is not interchangeable with the oral suspension; the tablets have substantially higher bioavailability than the oral suspension.

• Three patients received overdoses when given the enteric-coated tablets in error.

• If both oral products (oral suspension, delayedrelease tablets) are available at your institution, you may want to install a clinical alert to appear at the time the drug is ordered as a reminder of the various dosage forms and their inability to be interchanged.

1

Misidentification of alphanumeric symbols

• Problems may arise during written or electronic communication because of similarities in appearance of the alphanumeric symbols we use.

• For example, the letter “l” can look like the numeral “1,” especially when the drug name and dose are close together like “Levoxyl25 mg.”

• There are similar issues with other letters and numerals that share similar characteristics.

• Promote visibility, legibility, and readability in written communication using the following methods: • Use lowercase or mixed-case letters to provide distinction; • Encourage prescribers to clearly print handwritten orders; • Provide lightly lined order forms to prevent interference with symbols; • Be selective about font and typeface; • Avoid italics and underlining; and • Ensure proper spacing between drug names and doses, and between numerical doses and the unit of measure.

1

Error with lomustine caused by dispensing more than a single course of therapy

• A patient with brain cancer was prescribed a single 150-mg dose of lomustine, followed by reassessment in 6 wk to evaluate the benefit of additional doses.

• A mail-order pharmacy dispensed a 3-cycle supply of the drug (3 doses). Expecting a single dose, the patient took all of the capsules totaling 450 mg.

• The overdose led to a slow and painful death 6 wk later. Similar errors with dispensing this drug have been published previously with fatal results.

• Order entry systems should not allow more than a single dose to be entered and should limit the quantity dispensed.

• Pharmacists should provide patient counseling, supply leaflets, and enhance labels (eg, CAUTION: TAKE A SINGLE DOSE ONLY ONCE EVERY 6 WEEKS).

• Nurses should reinforce education before discharge, and insurers should pay only for a single dose at a time.

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Table 2. Safety Issues Associated With Order Communication and Computerized Order Entry cont’d Title

Problem/Discussion Point

Recommendation

Technology

FDB OrderKnowledge System is useful but error prone

• FDB’s OrderKnowledge System allows clinicians to quickly choose from a list of “common orders” once the drug and route are selected.

• However, the “common orders” cannot be edited by the facility and may not be clinically appropriate. For example, “common orders” for several common doses of oral methotrexate only allow selection of “every day,” which is unsafe for the vast majority of patients receiving the drug for immune-mediated diseases.

• FDB has reportedly corrected the methotrexate order selection, but changes will only cross over if you update your system.

• Ensure that your default and “common orders” for methotrexate are weekly.

• This is in line with ISMP’s Targeted Medication Safety Best Practices for Hospitals.

• We also encourage facilities to educate users that all options available through FDB OrderKnowledge may not be clinically appropriate.

MARQIBO (vinCRIStine sulfate liposome injection) and conventional vinCRIStine mix-ups

• Fatal mix-ups have occurred between liposomal and conventional forms of drugs (eg, amphotericin B) due to vast dosing differences. Such a mix-up is possible with Marqibo and conventional vinCRIStine.

• A pharmacist may receive an order for Marqibo but dispense the conventional product, not recognizing the higher dose recommendation for the liposomal product.

• Also, Marqibo requires a complex 26-step process for dose preparation.

• Review the differences between liposomal and conventional products during staff orientation.

• Orders for Marqibo are best communicated using the proprietary and generic names, indication for use, patient’s weight in kg, height in cm, mg/m2 dose, and final dosage calculation.

• Build dose-checking alerts in computer systems for both formulations to question all vinCRIStine doses that exceed agreed-on dosing limits.

• Separate the storage of Marqibo and conventional vinCRIStine

1, 5

ACTIQ (fentaNYL citrate oral transmucosal lozenge) mistaken as throat lozenge

• Three providers ordered Actiq to treat a sore throat, mistaking the powerful opioid for a typical throat lozenge.

• All of the patients were opioid-naive, but serious harm was avoided when pharmacists detected the error before dispensing the product.

• Prescribing Actiq should be limited to pain management specialists, anesthesiologists, oncologists, palliative care, and hospice providers who review an educational program and complete a knowledge assessment required by the drug’s REMS.

1, 5

Ambiguous course dosing of IVIG order led to error

• A telephone order for IVIG 150 g for 5 d was interpreted as 150 g daily for 5 d, but 150 g was intended to be divided over 5 d.

• The pharmacist misunderstood the “total dose of 1-2 g/kg, given over 2-5 days” as 2 g/kg/d.

• Similar errors have occurred with chemotherapy when course doses, not daily doses, are expressed.

• Doses should be prescribed as “dose/kg/day” for a set amount of days to avoid misinterpretation.

• Also, avoid telephone orders for these agents because these orders can sometimes be misinterpreted despite reading back the order to the prescriber.

1, 5

EMR, electronic medical record; FDB, First Databank; ISMP, Institute for Safe Medication Practices; IT, information technology; IVIG, intravenous immunoglobulin; REMS, Risk Evaluation and Mitigation Strategy

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Table 3. Problems Involving Drug Information, Patient Information, Patient Education, and Staff Education Title

Problem/Discussion Point

Recommendation

Technology

ISMP Canada identifies themes associated with fatal medication events in the home

• Analysis of fatal medication events in the home identified 3 categories of knowledge deficits: • Unrecognized risks associated with taking extra doses, sharing medications, and unsecured storage; • Unrecognized signs of toxicity, including unconsciousness mistaken as sleep, unreported changes in behavior, and a reluctance to seek help; and • Lack of knowledge about specific drugs including opioids, psychotherapeutic drugs, insulins, cardiovascular drugs, anticoagulants, and anticonvulsants.

• The themes identified in the analysis underscore the need to educate patients about the medications they take at home, particularly on these topics: • Importance of following instructions for use; seeking help if the directions for use are unclear; • Signs of toxicity, worsening symptoms, or sudden changes in behavior requiring intervention; and • Specific safeguards for the particular medication that is being taken.

Toxicity of topical anesthetics for teething infants

• One-year-old twins who were prescribed lidocaine viscous 2% for teething pain developed seizures and cardiac arrest.

• Toxic lidocaine blood levels were identified in both infants. Toxicity can occur with this and benzocaine-containing products used for teething pain.

• Well-meaning parents may use the products too often, or may add it to an infant’s formula or soak a pacifier in the gel thinking it is safe.

• The American Academy of Pediatrics discourages topical anesthetic use for teething pain, and viscous lidocaine is not FDA-approved for this purpose.

• Teach parents to avoid these products and to use safer alternatives including teething rings and pain medications such as acetaminophen and ibuprofen per directions from a health care professional.

Basal insulins incorrectly withheld

• Nurses have held doses of basal insulin when blood glucose levels were within the desired range, leading to elevated fasting blood glucose levels.

• Holding insulin for glucose levels within the desired range may be appropriate for mealtime or short-acting insulin products, but not basal insulins that can last up to 24 h, such as insulin glargine (LANTUS) or insulin detemir (LEVEMIR)

• Educate practitioners about the differences between rapid-acting and long-acting insulins.

• For long-acting insulin, consider adding the comment “Don’t hold without MD order” on labels and entries listed on medication administration records.

Some IV medications are diluted unnecessarily in patient care areas, creating undue risk

• An ISMP survey of nearly 1,800 nurses found that most dilute certain IV push medications for adults before administration.

• Even prefilled syringes containing a patientspecific dose are diluted by almost 25% of nurses. Unnecessary dilution often leads to unlabeled or mislabeled syringes, potential contamination of sterile IV medications, dosing errors, and other problems.

• Many nurses also reported the often unnecessary practice of withdrawing a medication from a prefilled syringe and further diluting it in a larger syringe for patients with an implanted port or a peripherally inserted central catheter.

• Conduct a nursing survey to learn the extent and variability of dilution practices.

• Conduct educational programs to dispel myths and help nurses see the risk associated with unnecessary dilution.

• When possible, require pharmacy to prepare any IV push medications that must be diluted according to the manufacturer’s guidelines or hospital policy.

• If stability requires dilution immediately before administration, provide directions for dilution via written or electronic guidelines or checklists that provide standard diluent volumes and concentrations

Phenylephrine injection needs dilution for IV bolus

• Phenylephrine hydrochloride injection (10 mg/mL) 1-mL vials are often available for emergency use. However, bolus doses (50-250 mcg) cannot be drawn up accurately from a 10-mg vial, and, therefore, dilution is needed.

• Directions for dilution are not on the label, and the package insert may not be handy in an emergency.

• Create a dilution guideline or checklist for this drug according to the package insert for diluting 10 mg (1 mL) to yield a 100 mcg/mL concentration for bolus doses.

• If possible, have pharmacy attend codes to properly prepare this and other emergency medications as needed for bolus dosing.

Vancomycin injection for oral use given IM

• Due to the high cost of vancomycin capsules, the injectable form of vancomycin powder is often prepared as an oral solution to treat Clostridium difficile.

• In 2 LTC facilities, the pharmacy provided vials of vancomycin injection and diluent with directions for mixing and administering each dose.

• Nurses were unfamiliar with this practice and administered each dose IM, rendering it ineffective to treat C. difficile.

• Pharmacies should prepare the injectable solution for oral use and provide each individual dose in an oral syringe marked “FOR ORAL USE ONLY.” • Dispensing medications in the most ready-toadminister form should be the prevailing practice for all pharmacies that provide medications in hospitals and LTC facilities.

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Table 3. Problems Involving Drug Information, Patient Information, Patient Education, and Staff Education cont’d Title

Problem/Discussion Point

Recommendation

Leg lacerations following EPIPEN (EPINEPHrine) autoinjector use

• The directions for use say that the EpiPen must be held in place for 10 sec.

• The needle does not retract until the pen is removed.

• The needle can cut through the subcutaneous tissue and cause a laceration if the child moves during administration.

• Two children sustained leg lacerations while receiving EpiPen injections when they moved while the needle was still under the skin.

• Providers using EPINEPHrine auto injectors for children should pay close attention to patient restraint before injection, as the child may move if the needle remains in the thigh for 10 sec.

• If the needle is dislodged, reinsertion should never be attempted.

• If it was in place for at least 3 sec, the EPINEPHrine was likely delivered.

• Repeat doses only if clinically necessary.

ALIMTA (PEMEtrexed) vials contain overfill

• To prepare an 850-mg dose of Alimta, a total of 34 mL were needed using one 500-mg vial and four 100-mg vials after being reconstituted to obtain a final concentration of 25 mg/mL. • However, pharmacy staff was able to obtain 34 mL of Alimta without using the last 100-mg vial of drug.

• When contacted, Lilly confirmed that the vials contain overfill.

• In this instance, 1 vial was wasted, but the patient could have received a larger dose than prescribed.

• Overfill is mentioned in the package insert, but the details are not specified.

• Be sure staff is aware of vial overages with this drug, especially when a small difference could be clinically important.

New dantrolene (RYANODEX) product can improve safety

• Dantrolene, used to treat MH, is often available in kits containing 20-mg vials of the drug and a liter bag of sterile water to dilute each vial with 60 mL. • Preparation during an emergency takes time because multiple 20-mg vials often are needed.

• Accidental IV administration of the liter bag of sterile water has also occurred with catastrophic results.

• A new formulation of dantrolene, Ryanodex, is available in a 250 mg/20 mL vial, which requires further dilution with 5 mL of sterile water for injection.

• One vial provides a loading dose as opposed to ≥12 vials of traditional dantrolene, allowing quicker treatment of MH. • The new formulation also eliminates the need to stock liter bags of sterile water.

VARIZIG (varicella zoster immunoglobulin [human]) dilution issues reported

• A child was to receive 125 units of Varizig IM. A nurse used the entire 8.5 mL of the supplied diluent to reconstitute the drug instead of 1.25 mL as stated in the package insert.

• To administer this volume, the nurse needed to give the child 3 IM injections.

• Subtherapeutic doses are also possible if the entire diluent is used and staff believes this provides the labeled 100 units/mL concentration (the concentration when 1.25 mL of diluent is used).

• Consider adding an auxiliary label that reminds practitioners to reconstitute the drug with the correct volume (1.25 mL/125 unit vial, which provides 100 units/mL) and then to discard the remaining diluent.

• A new liquid form of the product is under development that will not require reconstitution.

Dinoprostone (PROSTIN E2) suppository confused with progesterone

• A pregnant patient with asymptomatic uterine contractions was given a Prostin E2 vaginal suppository instead of a progesterone vaginal suppository.

• Both suppositories were available in the labor and delivery area. Prostin E2 suppositories are used for evacuation of uterine contents for missed abortion or IUFD. • The patient developed contractions and delivered a 1.1-kg baby.

• Remove the Prostin E2 suppository from stock in patient care areas and add a warning on the screens of pharmacy and electronic prescribing systems that Prostin E2 is indicated for IUFD, uterine evacuation, and end termination of pregnancy only.

• Barcode scanning verification at the point of care should be used when available.

Unlabeled bowls in procedure areas are still a problem

• A patient undergoing a breast biopsy in the radiology department was injected with formalin instead of lidocaine 1%.

• Both the tissue preservative and the local anesthetic were on the sterile field in unlabeled basins.

• In 1996, we wrote about a 7-year-old boy who died after receiving an injection of undiluted EPINEPHrine that was in an unlabeled container on the sterile field instead of lidocaine with EPINEPHrine. Since then, we have repeatedly published cases of similar mix-ups, many leading to death or permanent disability.

• In 2011, only 73% of hospitals reported consistently labeling containers of medications or solutions on the sterile field.

• Require labels on all products placed in the sterile field, even if only 1 product is present.

• Provide sterile markers and blank labels, or preprinted labels that can be opened onto the sterile field in all areas where procedures may take place.

• Confirm all medications and labels before pouring products into containers as well as when retrieving and drawing up into syringes.

• Label 1 product at a time before allowing another to enter the sterile field.

• Provide tissue preservatives only after tissue extraction, which may not require entry onto the sterile field if the cup is held outside the sterile field as the specimen is dropped in the labeled container.

Technology

1,2,4,5

Table 3. Problems Involving Drug Information, Patient Information, Patient Education, and Staff Education Title

Problem/Discussion Point

Recommendation

Technology

State drugtracking database can be useful in averting medication errors

• A patient with 100-mcg fentaNYL patches on a home medication list was prescribed the drug at hospital admission.

• A pharmacist checked the state’s electronic database (intended to reduce drug abuse) and discovered the patient had not filled a prescription for the drug in 4 months. He was currently opioid naive and thus not a candidate for a high-dose fentaNYL patch.

• The drug was discontinued.

• State databases can be useful resources for the inpatient pharmacist when a new patient is admitted with a controlled substance prescription.

• Pharmacists should use these databases but also ensure that once clarification is obtained, home medication lists are updated to reduce the chances that an error will occur again.

1,5

Caution with medication products outside of the pharmacy distribution system

• Medications not purchased by the pharmacy found their way into hospital supplies.

• These products included a heparin flush syringe brought in by a patient’s family, sample medications brought in by physicians, and lidocaine ampules from an IV line insertion kit. Safety is a concern when pharmacy has not assessed medications for adequate labeling, expiration dating, barcode scanning capabilities, and other aspects of drug therapy.

• Ensure you have policies in place to avert medications being brought from outside sources.

• The pharmacy should develop a list of manufacturers’ kits that contain medications, and before they are purchased, pharmacists should assess safety and test barcodes when possible.

• Saving unused medications from manufacturers’ kits should be prohibited.

• Be on the lookout for these products during routine medication storage assessments.

IM, intramuscular; IUFD, intrauterine fetal death; LTC, long-term care; MH, malignant hyperthermia

Table 4. Ad Addressing dd i C Concerns IInvolving l i IInfection f i C Controll Title

Problem/Discussion Point

Recommendation

New ISOVUE (iopamidol) IBP for use with power injectors

• Isovue is now packaged in an IBP approved for use with multiple patients in the CT suite in conjunction with an automated contrast injection system or syringe-based injection system.

• Use of the Isovue Multipack PBP (pharmacy bulk package), renamed Isovue PBP, is limited to the preparation of syringes in an ISO Class 5 environment in the pharmacy.

• The Isovue PBP and Isovue IBP products must be used exactly as described in the package insert to ensure sterility.

Wrong patient insulin pen injections occur despite barcode scanning

• A hospital implemented barcode scanning and other strategies to prevent the sharing of insulin pens.

• Although nurses knew not to share pens, the barcode system revealed that nurses had picked up the wrong insulin pen 400 times in 3 mo, and without an alert from the barcode system, might have administered a dose.

• Even with barcode scanning, 7 patients received an insulin dose from another patient’s pen during that time, due in part to mixing up pens carried in pocket; retrieving the wrong pen from a proximal medication bin; and other reasons.

• Even with implementation of barcoding, hospitals are still vulnerable to pen sharing.

• Weigh the benefits of using insulin pens against the risks associated with their use to determine the safest way to dispense and administer insulin to hospitalized patients.

• Although the ISMP cannot call for a moratorium on using insulin pens in hospitals, we still lean toward their use only under special circumstances, such as pens that may become available for concentrated U-200, U-300, and U-500 insulin.

• Otherwise, small vials of insulin dispensed for individual patients may be a safer alternative.

Technology

CT, computed tomography; IBP, imaging bulk package; ISMP, Institute for Safe Medication Practices

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Table 5. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

Issues with Medtronic MiniMed Revel insulin pump

• Patients using this insulin pump have presented with low blood glucose after rolling over onto the pump at night and accidentally activating a bolus dose of insulin.

• Another patient entered a blood glucose value (eg, 200) into the dosing “wizard,” in the field reserved for grams of carbohydrate consumption (eg, 60).

• Review the pump settings and ensure that the pump’s keypad is locked out to prevent inadvertent release of bolus doses, especially at night.

• Ensure patients use the glucose meter that communicates directly with this insulin pump so that patients do not have to manually enter blood glucose results into the pump.

Disrespectful behaviors

• Disrespectful behaviors in health care persist unchecked and are found at all levels of the organization and among all disciplines.

• According to ISMP’s 2013 survey, practitioners frequently encounter disrespectful behaviors that are clearly learned, tolerated, and reinforced in a culture that considers a certain degree of disrespect to be a “normal” style of interaction.

• Productivity demands, cost containment, and hierarchies that nurture a sense of status and autonomy have been the most influential factors.

• Disrespectful behaviors cause the recipient to experience fear, vulnerability, anger, humiliation, uncertainty, and self-doubt.

• The behaviors erode professional communication and collaboration, and have been linked to adverse events, even patient mortality.

• Establish a committee and educate members about the causes and impact of disrespectful behavior.

• Encourage reporting of disrespectful behaviors and establish a “no retribution” policy for reporters.

• Create a code of conduct or professionalism that serves as a model of interdisciplinary collegial relationships and collaboration.

• Establish a communication strategy for staff that must convey important information to enhance approachability and reduce intimidating behaviors.

• Establish an escalation policy to manage conflicts about the safety of an order when the standard communication process fails.

• Develop an intervention policy that has leadership support to consistently address disrespectful behavior.

Luer type connectors and enteral tubing

• Currently, Luer type connectors on medical tubing, ports, and catheters have a universal design that allows misconnections between devices that serve completely different functions (eg, enteral tubing connected to a tracheostomy tube inflatable cuff or an IV line).

• Tubing misconnections are rare, but when they occur, patient injuries can be serious, life-threatening, and even fatal.

• New enteral feeding device connectors that will not allow connectivity to any other type of connector will be introduced later this year.

• New enteral-specific administration sets became available in the last quarter of 2014.

• Enteral syringes for flushing and boluses will be available with the new connector in the first quarter of 2015, and new enteral feeding tubes will be available in the second quarter.

• Visit Stay Connected 2014 (www.stayconnected. org) to prepare for these changes.

Health systems need to plan for changes in enteral connectors

• Early in 2015, manufacturers will distribute administration sets with the new enteral-only connector, called ENFit, at the end that connects to the feeding tube.

• The new feeding tubes will not be available until later in 2015. Thus, a temporary transition adapter will be attached to the administration set.

• Once new enteral feeding tubes are in place, ENFit syringes will be required to flush or administer enteral liquid medications via a feeding tube.

• An oral or Luer syringe will not connect to the port.

• Convene an interdisciplinary team to assess the existing systems and processes that may need to change during and after transition to the new enteral connectors.

• The team should specifically focus on how the change will be communicated, how the enteral medications will be dispensed, how the connectors and sets will be stored, and how to transition to the new connectors.

• To stay updated, visit this website frequently: www.stayconnected.org.

Possible dosing dilemma for infants prescribed REVATIO (sildenafil)

• The FDA has clarified situations where Revatio may be acceptable for certain children with pulmonary arterial hypertension.

• Pediatric dosing is based on mg/kg.

• The 10 mg/mL liquid formulation comes with a 2-mL oral syringe with 0.5-mL (5-mg) and 2-mL (20-mg) dose markings, which may not correspond to the child’s dose and make accurate dose measurement difficult.

• Dispense Revatio oral suspension with a 1-mL oral syringe to correctly administer doses that do not conform to the scale on the provided oral syringe.

• It is unlikely that Pfizer will consider changing the dosing device provided.

Injection technique error with the LANTUS SOLOSTAR (insulin glargine) insulin pen

• Two patients dialed a Lantus Solostar insulin pen to the prescribed units of insulin. The pens failed to administer any insulin because the patients dialed the pen back down to zero, believing the twisting mechanism released the insulin, instead of pushing the button at the end of the pen.

• This error could also occur with other insulin pens with a similar design.

• Health care providers who educate patients about insulin pen use must adequately explain how each dose is programmed and delivered, and have the patients demonstrate how they will use the pen to confirm proper technique.

• Be alert to potential confusion regarding how to administer a dose.

Technology

Table 5. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

Technology

Scanning issue during Meditech bedside barcode verification

• Using a Meditech Bedside Medication Verification system to administer an IV admixture, a nurse scanned the IV base solution barcode instead of the barcode on the pharmacy-generated label, and the system verified the product although it did not match what was actually ordered.

• The admixture was documented in the patient’s eMAR as given but not recorded as being scanned, making it impossible to monitor scanning compliance rates accurately.

• Initially, Meditech told inquiring hospitals to activate a “compounding verification” function in the eMAR at the point of care and in the pharmacy when preparing IV admixtures (work with the vendor to turn the function on). The company has now made changes to the systems that have resolved the problem.

• Clients will receive the changes with their next update but can contact the company to schedule delivery of the changes sooner.

e eMAR, ,e electronic ect o c medication ed cat o ad administration st at o record eco d

Table 6. ISMP’s 2014-2015 Targeted Medication Safety Best Practices for Hospitals Title

Problem/Discussion Point

Recommendation

Technology

Still outside the bull’s-eye: 2014-2015 Targeted Medication Safety Best Practices for Hospitals

• The ISMP launched the 2014-2015 Targeted Medication Safety Best Practices for Hospitals to mobilize widespread adoption of best practices related to specific error-related issues that continue to harm patients.

• A survey suggests low levels of full implementation: dispensing IV vinCRIStine in minibags—53%; weekly default for oral methotrexate with a hard stop if overridden to daily—28%; pharmacist education of patients on weekly oral methotrexate—11%; patient weights measured and expressed in metric units—33%; dispensing oral liquids in oral syringes—52%; using oral liquid dosing devices that display only in metric units—39%; and elimination of glacial acetic acid—74%.

• Hospitals experiencing difficulty with gaining support for implementing these practices should view our Frequently Asked Questions at: www. ismp.org/sc?id=338.

• A free consumer leaflet to standardize and support education regarding methotrexate can be found at: www.ismp.org/sc?id=316.

• Pound to kg or g conversion charts should be available for nurses and other health care personnel to use when discussing measured weights with the patient and family.

• Education regarding the purpose and use of oral syringes should be provided during orientation of all professional staff that administers medications.

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VinCRIStine in a minibag

• Results from the 2012 ISMP International Medication Safety Self-Assessment for Oncology revealed that only 54% of US hospitals dispense vinCRIStine in a minibag of compatible solution to prevent accidental intrathecal administration.

• To date, there are 120 published cases of accidental administration of vinCRIStine by the intrathecal route when the drug was dispensed in a syringe, and zero cases of such misadministration when dispensed in a minibag.

• When vinca alkaloids are injected intrathecally, destruction of the CNS occurs.

• Despite repeated warnings by various national and international safety agencies, deaths from this type of error still occur.

• The goal of this best practice is to ensure that vinca alkaloids are administered by the IV route only.

• Dispense IV vinca alkaloids in a minibag of a compatible solution and never dispense and/or administer these drugs using a syringe.

• Dilute the drug in a minibag that contains a volume that is too large for intrathecal administration (eg, 25 mL for pediatric patients and 50 mL for adults).

• Prohibit IV vinca alkaloids in areas where intrathecal medications are administered and/or stored.

• Confirm that any prescribed intrathecal medications have been administered before dispensing IV vinca alkaloids.

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Methotrexate dosing regimen

• Since early 1996 and as recently as 2013, fatal errors have been reported to the ISMP about the accidental daily dosing of oral methotrexate that was intended for weekly administration.

• Prescribing errors occur when physicians, who are familiar with prescribing many medications for daily administration, erroneously prescribe this medication daily instead of weekly.

• Dispensing errors occur in much the same way, when pharmacy technicians and pharmacists inadvertently select/approve daily instead of weekly administration during order entry or verification.

• The goal of this best practice is to prevent errors involving inadvertent daily dosing of oral methotrexate both in the inpatient setting and after discharge.

• Use a weekly dosage regimen default for oral methotrexate.

• If weekly default is overridden to daily, require a hard stop verification of an appropriate oncologic indication.

• Provide patient education by a pharmacist for all weekly oral methotrexate discharge orders.

• Ensure written drug information leaflets are given to patients that contain clear instructions about the weekly dosing schedule.

• Have the patient repeat back the instructions to ensure that the patient understands the weekly dosing schedule and that the medication is not to be used “as needed” for symptom control.

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Table continues on next page

Table 6. ISMP’s 2014-2015 Targeted Medication Safety Best Practices for Hospitals cont’d Title

Problem/Discussion Point

Recommendation

Technology

Patient weight

• Official product labeling for medications provides weight-based dosing using only the metric system (eg, mg/kg). Significant medication errors have occurred when the patient’s weight is documented in nonmetric units of measure (eg, pounds) and it has been confused with kilograms (or grams).

• Numerous mistakes have been reported when practitioners convert weights from one measurement system to another, or weigh a patient in pounds but accidentally document the value as kilograms in the medical record, resulting in more than a 2-fold dosing error.

• The goal of this best practice is to standardize the measurement and communication of patient weight using only metric units of measure (g and kg).

• Measure and express patient weights in metric units only.

• Ensure that scales used for weighing patients are set and measure only in metric units.

• Replace current scales that measure in pounds with new scales that only measure weight in grams or kilograms.

• If scales can measure in pounds and grams/kilograms, modify the scale to lock out the ability to weigh in pounds.

• Ensure that computer information systems and medication device screens (eg, infusion pumps), printouts, and preprinted order forms list or prompt for weight only in grams (for neonates) or kilograms.

• Discontinue the documentation of a patient’s weight in pounds in all locations, instead document patients’ weight using only metric designations.

• Use measured weight rather than a stated, historical, or estimated weight.

1,3,5

Oral liquid preparation

• The ISMP continues to receive reports in which patients were inadvertently given an oral liquid medication by IV. This happens most often when an oral liquid is prepared extemporaneously or dispensed in a parenteral syringe that connects to vascular access lines.

• Such errors have resulted in patient death.

• Fatalities have also occurred when the contents of liquid-filled capsules (eg, niMODipine) were withdrawn for oral administration via a nasogastric or other tube with a parenteral syringe and then inadvertently administered by IV. • The oral syringe tip is designed to be incompatible with vascular lines so it cannot be inadvertently attached.

• The goal of this best practice is to prevent the unintended administration of oral medications via the IV route.

• Ensure that all oral liquids that are not commercially available as unit-dose product are dispensed by the pharmacy in an oral syringe.

• Use only oral syringes marked “Oral Use Only.”

• Ensure that oral syringes used do not connect to any type of parenteral tubing used in the hospital.

• Use of an auxiliary label “For oral use only” is also preferred, since the print on the oral syringe is small, if it does not obstruct critical information.

Oral dosing devices

• The ISMP has received more than 50 reports of mix-ups between milliliter (mL) and household measures such as drops and teaspoons, some leading to injuries requiring hospitalization. Use of the apothecary system has also caused confusion with mix-ups between drams and milliliters and other nonmetric measurements such as ounces and tablespoons.

• ISMP first reported confusion in 2000, and has continued to receive reports of medication errors because of mix-ups between metric and nonmetric units of measure.

• The goal of this best practice is to use liquid medication dosing devices (specifically oral syringes, cups, and droppers) that only display volume using the metric scale.

• Purchase oral liquid dosing devices (oral syringes/cups/droppers) that only display the metric scale.

• Additionally, if patients are taking an oral liquid medication after discharge, give them (or provide a prescription for) oral syringes, to enable them to measure oral liquid volumes in milliliters.

“Glacial” acetic acid

• Patient harm has occurred when toxic chemicals have been misidentified as oral products, or when a very concentrated form of a chemical has been erroneously used in treating patients.

Of particular concern is glacial acetic acid.

• Accidental topical application of “glacial” (≥99.5%) acetic acid has repeatedly resulted in serious patient harm, including severe pain and serious tissue damage, third-degree burns, and in one case, bilateral leg amputation.

• Often in these cases, this item was either accidentally purchased or used in place of a much more diluted form of acetic acid, such as vinegar or a commercially available 0.25% acetic acid solution.

• The goal of this best practice is to prevent harm from the use of glacial acetic acid applied directly to patients.

• Eliminate glacial acetic acid from all areas of the hospital.

• Remove and safely discard this product from all clinical areas of the hospital (including the pharmacy, clinics, and physician office practices), and replace it with vinegar (5% solution) or commercially available, diluted acetic acid 0.25% (for irrigation) or 2% (for otic use).

• Laboratory use excluded if the lab purchases the product directly from an external source.