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Is Medical Publishing Due for an Exorcism?

S

everal recent studies, including an influential Journal of the American Medical Association analysis last year, and a related study published just last month, underscore the need for some organizations and journals to continue to update their disclosure policies to more easily illuminate the ghosts lurking behind submitted manuscripts. The 2008 JAMA study (299:1800-1812) was startling enough to cause a surge of effort to enforce more authorship transparency. The researchers sifted through the paper trail related to the Merck drug rofecoxib (Vioxx). Although nearly all of the 24 clinical trial articles included in their analysis disclosed Merck’s financial support, only half of the 72 review articles contained such disclosures. And it was not uncommon for external experts to be recruited as authors and to receive honoraria for manuscripts written on their behalf. Rick Scheife, PharmD, FCCP, editor-in-chief of Pharmacotherapy, admitted that he was “absolutely sideswiped” by the JAMA findings. For journal editors, they constituted a bit of an earthquake, he said. “Given that wake up call, what you basically saw was

see GHOSTWRITING, page 26

Nuclear Pharmacists Fret Over Tech-99m Shortage Cancer diagnosis, treatment may be impacted

T

he continuing global shortage of an isotope used in medical imaging has cancer patients experiencing testing delays, clinicians worrying about degraded quality of care and members of the nuclear pharmacy community wondering if there is any relief in sight, given the chief source of the imaging agent— the world’s aging nuclear reactors. The shortage of the agent, technetium-99m (Tc-99m), was triggered this summer by the shutdown of two reactors—one in Chalk River, Ontario, and the other in Petten, The Netherlands. The Petten facility is scheduled for major repairs in March 2010. “If Chalk River can’t get back online this spring and relieve the pressure, we may be in for even worse shortages,” said Jeffrey Norenberg, PharmD, executive director of the National Association of Nuclear Pharmacies.

see SHORTAGE, page 10

#4

Volume me 36 • Number 11 • December 2009 ❃

Printer-friendly versions available online

Ghostwriting blasted by editors, clinicians

ou bo r ot h

McMahon Publishing

in this issue Medication Storage Tops List Up Front Reader Survey

Of Joint Commission Citations

Price, quality emerge as key factors influencing generic drug purchasing

3

Surveyor reveals 2009’s toughest challenges, offers tips for passing 2010 reviews

Clinical

Transplant Pharmacy The profession’s evolving role on patient-care team.

18

Policy

NEW! Spotlight on: Generics A new way to save on nonbranded drugs, a look at key biosimilars legislation, a pharmacy director Q&A, and more.

22

Q&A Exclusive interview with ASHP leadership.

32

Operations & Mgmt

Guest Editorial ‘White Bagging’ brings more patient meds to hospitals; are you ready?

38

Communications First of a three-part series on effective communication skills.

40

Technology

Critical Care Software helps community hospital achieve tight glucose control in ICU.

43

Educational Review Guidelines for the Management of Febrile Neutropenia See page

8

T

he Joint Commission’s Medication Management Update has outlined a plethora of troublesome medication management standards and medication-related National Patient Safety Goals (NPSGs), along with new recommendations for resolving these often-cited problems, to better prepare pharmacists for what lies ahead in 2010. Presented in a webinar by Darryl S. Rich, PharmD, a surveyor for the Joint Commission, the update highlighted two recent changes: those related to the 2009 Medication Management (MM) standards, which resulted from the group’s Standards Improvement Initiative (SII) project; and the MM standard changes that became effective in July 2009 for organizations seeking Medicare payments. The update also looked at more recent revi-

see MED MANAGEMENT, page 29

Obama Administration Eyeing Comparative Research Funding

T

he Obama administration has committed to spending $1.1 billion on comparative effectiveness research (CER), with funds expected to start flowing next spring. But the initiative is being met with mixed feelings by members of the medical community. Everyone agrees that, in the age of budget constraints, health care spending must be kept in check. But they also worry that it may be

impossible to sort through the huge volume of evidence to arrive at a completely accurate and impartial conclusion on any topic—with the task made even more difficult by the ambitious array of therapeutic areas to be tackled under very tight timelines—and that any conclusion favoring one treatment may well lead to other treatments being barred. John I. Allen, MD, MBA, councillor,

see COMPARATIVE, page 37

New Products MediDose/EPS introduces free PCA warning labels.

Sotalol Hydrochloride Injection from Bioniche Pharma and Academic Pharmaceuticals, Inc.

AHP launches new unitdose products. See pages

40, 46

29


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Up Front 3

Pharmacy Practice News • December 2009

Capsules For more information on generic drug trends, see our “Spotlight On…” section, which begins on page 22.

PPN Reader Survey:

surf

watch

Health Care Reform Spurs Interest in Generic Drugs

DECEMBER 2009

T

he pending health care legislation and potentially reduced reimbursements are leading many health systems to rethink their generic drug strategies. A full 70% of pharmacists participating in a Pharmacy Practice News online survey indicated that the proposed health care legislation has increased their interest in purchasing lower-cost generic drugs.

The five most-viewed articles last month on pharmacypracticenews.com: 1. Hospitals Hit With Propofol Shortage 2. New Study Shines Light on Vancomycin Toxicity

Percentage of Respondents

3. Pharmacists Help Minimize Delays to Proper Sepsis Care 4. First Pharmacist To Lead SCCM Says Team Approach Is Crucial 5. Compatibility of Commonly Used Intravenous Drugs [Educational Review] Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

1

50

2

40

3

30

4 5

20 10 0 Quality

Customer Service

Incentives

Volume Discounts

Return Policy

Figure. Factors influencing generic drug purchasing strategy. (rated on a scale of 1 to 5, with 1 indicating low influence and 5 indicating high influence)

Managing Anticoagulation Patients in the Hospital: The Inpatient Anticoagulation Service

When it came to which generic purchasing strategies to use, responses were more mixed. Nearly half (49.8%) of 253 respondents indicated that they would rely more on group purchasing organization (GPO)-negotiated contracts, 39.1% noted that they would attempt to buy generics directly from wholesalers, 31.6% noted that they would give more generics high market share in their hospitals/health systems and 8.7% reported that they would consider changing GPOs. Almost one-fifth of those responding indicated they would make no changes to their generic purchasing strategies at this point. When asked about factors that might influence their generic purchasing strategy, more than 93% of respondents reported that quality was a significant factor, giving it a 4 or a 5 (Figure). Cost came up big as well, being influential for more than 80% of respondents. Other factors that would play an influential role for pharmacists as they are choosing generics were contract pricing and other volume discounts (84%), the quality of suppliers’ customer service (71.7%), supplier or GPO incentives to promote brand-to-generic drug switches (60.8%) and suppliers’ return policy (60.2%).

41

—Sarah Tilyou

transplant pharmacy], it is a beautiful thing to see.’ —Lonnie Smith, PharmD

See article, page 18

The Book Page

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Continuity of care ‘doesn’t really happen in many practice settings, but when it does [in organ

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4 Clinical

Pharmacy Practice News • December 2009

Infectious Disease

Mysteries of C. difficile Infection Gradually Being Solved San Francisco—Scientists continue to make parallel and incremental steps in understanding Clostridium difficile, as evidenced by the numerous presentations on this challenging organism at the 2009 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in September. The latest progress in the field includes an increased understanding of how patients are colonized with C. difficile, how to rapidly and accurately detect C. difficile infection (CDI) and what factors are most important in the spread of the infection. During a well-attended presentation at ICAAC, Dale Gerding, MD, associate chief of staff for research at Hines Veterans Affairs Hospital, Hines, Ill., and professor of medicine, Loyola University Chicago Stritch School of Medicine, provided experimental support for the idea that the rate of transmission of CDI is affected by antibiotic pressure, an idea that has been accepted by many in the field but has never been proven. Also garnering attention from those present at the conference were a talk on the airborne dispersal of C. difficile from symptomatic patients, several posters on various diagnostic tests for CDI and a presentation on a common genetic mutation associated with an increased risk for recurrent CDI.

Selection Pressure and Transmission Rates To investigate the role of antibiotic selection in the transmission rate of CDI, Dr. Gerding performed a set of four experiments in hamsters. In the first experiment, he administered a nontoxigenic strain of C. difficile to a group of hamsters on day 1 and a toxigenic, normally fatal strain of C. difficile on day 3. He also administered intraperitoneal ceftriaxone—an antibiotic to which C. difficile is generally not susceptible—at a dose of 60 mg/kg per day on days 1 through 5. All of the hamsters became colonized by the nontoxigenic strain of C. difficile; after exposure to the toxigenic strain, all of the hamsters were alive on day 8, the end of the study. In the second experiment, Dr. Gerding administered a toxigenic strain of C. difficile on days 1, 3, 5 or 8. He also administered oral ampicillin—to which C. difficile is resistant to an intermediate degree—at a dose of 60 mg/kg per day on days 1 through 5. None of the hamsters that had been given the toxigenic strain concurrently with ampicillin became infected or colonized during the time that the antibiotic was being administered. However, administration

of C. difficile after the ampicillin was discontinued resulted in infection and death of the animals. In the third and fourth experiments, Dr. Gerding administered a nontoxigenic strain of C. difficile on days 3 through 7; the strain, known as M3, is susceptible to clindamycin. Additionally, he administered a toxigenic, clindamycin-resistant strain, known as B1, on days 5, 7 or 9. Clindamycin was administered on days 1 through 5. The hamsters that were given B1 on days 5 or 7 were colonized by the toxigenic, clindamycin-resistant strain and died within two days. However, those animals not given the toxigenic strain until day 9 were neither colonized

nor died; rather, they were colonized on day 9 by the nontoxigenic, clindamycinsusceptible strain M3. “This showed that M3 protected the animals from the toxigenic strain B1 if they were exposed to B1 only once [and if ] the level of clindamycin in the gut had declined sufficiently to allow colonization by the nontoxigenic C. difficile,” Dr. Gerding told Pharmacy Practice News. “Taken together, these studies support the notion that antibiotic selection pressure affects CDI transmission rates in situations in which the C. difficile strains are resistant to the antibiotic. The mechanism may be by enabling toxigenic, resistant C. difficile

Evidence that C. difficile spores can be in the air in rooms with CDI patients ‘further enhances our knowledge of the need to consider methods of isolation to contain such spread, [and of ] the well-known ability of the spores to survive for extended periods of time on environmental surfaces.’ —Robert C. Rapp, PharmD

strains to survive in the gastrointestinal tract and colonize it while the antibiotic is being given. Subsequently, the colonized patients can shed this toxigenic C. difficile into the environment.” Dr. Gerding is working to develop a live, nontoxigenic C. difficile intestinal vaccine against CDI. These “findings give a scientific basis to infection control and antibiotic stewardship programs to control case rates of C. difficile infection,” commented Thomas Louie, MD, professor of medicine at the University of Calgary Faculty of Medicine, and medical director of infection prevention and control for Calgary’s hospital. “An intestinal ‘vaccine’ would also be beneficial, should this approach be proven [effective] in clinical trials.”

Airborne Transmission The possibility of airborne transmission of C. difficile was explored in a preliminary study led by Mark Wilcox, MD, consultant/clinical director of microbiology/pathology, Leeds Teaching Hospitals National Health Service Trust, in the United Kingdom. Dr. Wilcox and three colleagues measured the concentration of airborne and environmental C. difficile spores in the immediate area surrounding four types of patients: 10 patients with suspected CDI, 50 with confirmed CDI (not all were symptomatic), 10 with symptomatic CDI and 10 control patients who did not have CDI. The investigators found that C. difficile spores were in the air and on the surfaces surrounding the majority of the symptomatic patients. “This may help to explain the widespread dissemination of C. difficile in the hospital environment,” said Dr. Wilcox. “The data also emphasize the importance of early, single-room isolation to limit the dissemination of C. difficile, especially to control the spread of epidemic strains. However, it remains unclear what may be the value of controlled ventilation or other decontamination systems to reduce C. difficile air counts.” According to Joe Dylewski, MD, director of microbiology and infectious diseases and chief of the Department of Laboratories at St. Mary’s Hospital, in Montreal, the implications of these findings to infection control practices are not clear. “Disinfecting rooms by a standard protocol appears to be an effective means to control C. difficile outbreaks, so I am not sure that there is a need to include disinfection of areas only affected by airborne spread,” commented Dr. Dylewski, who also presented research at the meeting.

see C. DIFFICILE, page 6


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6 Clinical

Pharmacy Practice News • December 2009

Infectious Disease

Multichamber PN Bags May Lessen Infection Risk A

mong the advantages touted for multichamber parenteral nutrition (PN) bags are extended shelf life and quick access to a near-complete standard nutritional premix. But could the bags also decrease the risk for PN-related bloodstream infections?

‘Touch contamination risk grows as the number of products you’re adding increases, so there are multiple points of contamination.’ —Todd W. Canada, PharmD Possibly, according to Todd Canada, PharmD, clinical pharmacy services manager and nutrition support team coordinator at the University of Texas M.D. Anderson Cancer Center in Houston. “We found that patients who received PN through multichamber bags had lower bloodstream infection rates and shorter hospital stays than those who received PN via conventional compounding.” PN-related bloodstream infections are a significant problem. According to Dr. Canada, the incidence ranges from 7.2% to 39%, and hospitalizations attributable to such infections range from 6.1 to 13.5 days. Although these infections don’t seem to have an effect on mortality rates, they do lengthen hospital stays. In a retrospective analysis of the Premier U.S. database of 196 hospitals, Dr. Canada and his team identified 68,984 adult patients (aged 18-89 years) who

C. DIFFICILE continued from page 4

ID Pharmacists’ Perspective Kevin Garey, PharmD, MS, associate professor and chair of the Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, in Texas, agreed that more research is needed to conclusively determine the implications of airborne spread. “But perhaps one thing we should do is wash farther up the walls,” Dr. Garey suggested. “The air ducts are also places where we should be looking for spores.” Dr. Garey also pointed to the need for continued research into genetic factors that could influence CDI. He was the lead investigator of a study presented

received PN during a two-year period. One group of 4,669 patients was treated with multichamber bags containing dextrose-amino acids (fat emulsion and micronutrients were added separately). The other group of 64,315 patients received PN from conventional compounding. Nearly 86% of patients were postsurgical and 73% were older than 55 years. The adjusted bloodstream infection rate was 26% higher for patients who received compounded PN than for patients given multichamber PN preparations (25.9% vs. 20.6%), and hospital length of stay attributable to bloodstream infection was six days longer (P<0.001). Patients in the compounded PN group also received more days of PN (8.1 vs. 5.3; P<0.001) and stayed in the hospital longer (19.1 vs. 15 days). Dr. Canada said that he can’t be certain as to why patients receiving compounded PN products experienced a higher rate of infection, but speculated that it may be because conventionally compounded solutions are more susceptible to touch contamination, particularly when the mixtures require numerous additives. “Touch contamination risk grows as the number of products you’re adding increases, so there are multiple points of contamination,” he said. “And if you look at any evaluation of bloodstream infections, patients on PN always have

at ICAAC that identified a common polymorphism in the interleukin-8 gene that is associated with a 3.1-fold increase in the risk for recurrent CDI (abstract K-1914).

higher rates of infection.” He acknowledged, however, that patients who require compounded PN are generally sicker than those who receive premixed PN, and are therefore more susceptible to bloodstream infections. “One of the things that obviously could have been an issue was patient acuity,” Dr. Canada said. “We can make some inferences that these patients were likely sicker because they had higher rates and durations of ICU [intensive care unit] stays and longer hospitalizations.” He added that he was somewhat surprised that bloodstream infection rates were lower at community hospitals than at teaching hospitals. “That’s the opposite of what I would expect,” he said because the latter are typically more accustomed to more complex cases and usually have greater staff expertise with compounding PN.

More Evidence Needed Vanessa Kumpf, PharmD, called the study interesting but said that she would need more evidence to convince her that the higher infection rates were linked to anything other than higher patient acuity. “I suspect that the patients who used multichamber bags were probably not as sick, and patients with lower acuity have less risk for infection,” said Dr. Kumpf, a nutrition support clinical specialist at

University of Kentucky Medical Center, in Lexington. Dr. Rapp commented that Dr. Gerding’s research “documents in an animal model the role of antimicrobial selection pressure on the rate of

‘Taken together, these studies support the notion that antibiotic selection pressure affects CDI transmission rates ….’ —Dale Gerding, MD As for Dr. Gerding’s animal model of C. difficile spread, the research is yet another example of the infectious disease physician’s “impressive breadth of knowledge and research agenda,” said Robert P. Rapp, PharmD, FCCP, professor of pharmacy and surgery emeritus,

transmission of CDI.” Dr. Rapp pointed out that Dr. Gerding’s use of ceftriaxone and ampicillin in his studies is significant because these agents “have been implicated as major contributors to hospital CDI.” Dr. Rapp also offered Dr. Wilcox kudos

Vanderbilt University Medical Center in Nashville, Tenn. Additionally, facilities that most often use multichamber bags tend to be smaller hospitals whose patient populations are less complex

‘To me, it wouldn’t make sense that the multichamber bag itself presents less risk for infection because a contaminated bag is pretty rare. It’s the type of patient you’re dealing with.’ —Vanessa Kumpf, PharmD

than those at referral centers. Dr. Kumpf said she also is skeptical about attributing the difference in infection rates to contamination that occurs during the compounding process. “That’s another reason why I’m leaning toward differences in patient acuity as an explanation for the study findings,” she said. “The risk for contamination during compounding is actually pretty low.” The source of bloodstream infection associated with PN, Dr. Kumpf added, rarely is from contaminated solutions, but rather from catheters and catheter hub sites. “To me, it wouldn’t make sense that the multichamber bag itself presents less risk for infection, because a contaminated bag is pretty rare. It’s the type of patient you’re dealing with.” —Steve Frandzel

for documenting the fact that C. difficile spores can be present in the air in rooms with CDI patients. The finding “further enhances our knowledge of the need to consider methods of isolation to contain such spread, [and of ] the well-known ability of the spores to survive for extended periods of time on environmental surfaces,” said Dr. Rapp. “Further work will be needed, however, to more fully understand the implications of airborne transmission in the role of CDI transmission,” he added. “All health care workers must realize the serious implications of this disease on our patients and on our hospitals.” —Rosemary Frei, MSc


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8 Clinical

Pharmacy Practice News • December 2009

Educational Review

Guidelines for the Management of

Febrile Neutropenia MICHAEL GABAY, PHARMD, JD, BCPS Director, Drug Information Group and Prior Authorization Services Clinical Assistant Professor

MARIA TANZI, PHARMD Clinical Assistant Professor, Drug Information Group University of Illinois at Chicago College of Pharmacy Chicago, Illinois

F

or patients receiving chemotherapy, febrile neutropenia often is associated with immediate hospitalization and institution of empiric broad-

spectrum antibiotic therapy.1 Although the condition remains

a major source of morbidity and mortality, improvements in treatment have significantly improved outcomes.2

Historically, mortality was extremely high— rates approached 90% in a 1962 study involving patients with gram-negative bacteremia and severe underlying disease.3 More recent data from the Surveillance and Control of Pathogens of Epidemiologic Importance Project found mortality rates of 33.4% with coagulase-negative staphylococci, 22.8% with methicillin-susceptible Staphylococcus aureus, and 17.7% with methicillin-resistant S. aureus (MRSA) bloodstream infections in 2,340 patients with underlying malignancies.4 Although the definition of febrile neutropenia varies within clinical studies, both the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN) define fever as a single oral temperature of at least 38.3˚C (101˚F) without any obvious environmental cause.5,6 In addition, a febrile state is defined as a temperature of at least 38˚C (100.4˚C) for at least 1 hour. An absolute neutrophil count (ANC) fewer than 1,000 cells/mcL or fewer than 500 cells/mcL often is used to define neutropenia.1 The lower the neutrophil count, the greater the risk for infection.5 Beyond the quantity of neutrophils, the duration of neutropenia also can impact infection risk. A protracted neutropenic state can significantly increase the potential for infection.

Causes of Neutropenia And Infectious Complications The neutropenia observed in patients with

malignancy usually is the direct result of cancer chemotherapy.7 Neutropenia can be so severe that subsequent cycles may be delayed or require dose reductions, thereby potentially impacting the efficacy of the chemotherapy regimen in the future.8 Certain single-agent and combination regimens carry a high (>20%) risk for febrile neutropenia. Table 1 contains examples of such chemotherapy regimens.9 In patients with malignancy who develop febrile neutropenia, a variety of pathogens may be responsible for infectious complications. Bacteria are the primary causes of initial infection early in the course of febrile neutropenia.6 The predominant categories of bacterial pathogens identified as the source of infection have changed over time.10 In the late 1950s and early 1960s, gram-positive organisms, such as S. aureus, commonly were recognized as causative agents. Since that time, the primary bacterial cause underlying febrile neutropenia has fluctuated back and forth from gram-negative organisms (ie, Escherichia coli, Klebsiella spp, and Pseudomonas spp) in the late 1960s and early 1970s to gram-positive organisms in the 1990s, to an emergence of gram-negative organisms again in the new millennium. Today, coagulasenegative staphylococci, S. aureus, viridans group streptococci, and enterococci are the most common gram-positive pathogens6 and E. coli, Klebsiella spp, Enterobacter spp, and P. aeruginosa are the most common gram-negative species.

Fungal infections such as Candida and Aspergillus can occur later in the course of prolonged neutropenia.

Patient Risk Assessment Assessments of the risk for neutropenia and infectious complications are important components in the care of patients with malignancy. These assessments not only evaluate which patients may be at risk for febrile neutropenia but also attempt to predict the probability of serious complications and whether a low-risk individual may safely receive outpatient treatment with oral antibiotics.6 A variety of risk models have been studied to identify patient-, disease-, and treatment-related factors associated with the risk for developing neutropenia and its associated complications.11 In addition to risk models, studies of individual risk factors also have been conducted to aid in identifying patients at greatest risk.12 Although there is no consensus nomogram for risk assessment, the NCCN has developed a risk categorization for patients based on disease, chemotherapy regimen, patient risk factors, and treatment intent (ie, curative vs palliative).9 This scheme categorizes patients as having either a high (>20%), intermediate (10%-20%), or low (<10%) risk for developing febrile neutropenia. Table 2 lists patient risk factors for experiencing a poor clinical outcome or infection-associated complications, as noted in the 2009 NCCN Myeloid


Clinical 9

Pharmacy Practice News • December 2009

Educational Review Growth Factor guidelines.9 The identification of patients at low risk who may be treated on an outpatient basis with oral antibiotic therapy is an important consideration in the management of febrile neutropenia. The Multinational Association for Supportive Care in Cancer (MASCC) risk scoring index (Table 3)13 accurately identifies those at low risk for complications associated with febrile neutropenia who may then be treated with a more convenient and cost-effective option. The MASCC index was validated in a prospective, multinational study where a MASCC score of at least 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%.13 In addition, the IDSA and the NCCN have identified various individual factors that favor a low risk for severe infection among patients with neutropenia (Table 4).5,6

Table 1. Chemotherapy Regimens at High Risk for Febrile Neutropeniaa

Management and Treatment Use of Antimicrobials As discussed previously, patients with neutropenia are at risk for developing serious infections that can have a substantial impact on morbidity and mortality. Therefore, therapies aimed at eliminating the most likely infectious pathogens are the primary treatments used for managing patients with febrile neutropenia. In 2002, the IDSA published guidelines on the use of antimicrobial agents in neutropenic patients with cancer.5 An update to these guidelines is expected in

Regimen

Bladder

MVAC (methotrexate, vinblastine, doxorubicin, cisplatin)

Breast

Docetaxel plus trastuzumab AT (doxorubicin plus paclitaxel or docetaxel) TAC (docetaxel, doxorubicin, cyclophosphamide

Esophageal and gastric

Docetaxel-cisplatin-fluorouracil

Non-Hodgkin’s Lymphoma

ICE (ifosfamide, carboplatin, etoposide) CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone) DHAP (dexamethasone, cisplatin, cytarabine) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

Clinical Presentation Febrile neutropenia should be suspected in any patient who has received chemotherapy in the prior 4 to 6 weeks and presents with a fever or a general feeling of malaise.14 An infection may be present in these patients even without fever because a lack of neutrophils may negatively impact the ability to mount a sufficient immune response. A thorough history and physical examination should be completed to identify the site of infection; however, a definitive infection site may never be discovered.14,15 This examination should include the skin, mucous membranes, fundi, sinuses, and the perianal area.15 All peripheral and central catheter sites should be inspected for signs of infection. The date and the medications involved in the most recent chemotherapy treatment should be obtained. In addition, any history of prior prophylactic antibiotics should be noted because this therapy could alter the patient’s microflora and influence subsequent antibiotic choice.14 Initial laboratory evaluations include a complete blood count with differential, liver function tests, lipase, a complete chemistry panel, and a full set of cultures (ie, sputum, blood, and urine).15 Cultures should be drawn from every peripheral and central access point. Chest radiographs should be obtained even in patients without obvious pulmonary symptoms. If local signs or symptoms exist, consider acquiring additional imaging studies or laboratory tests that may provide more information regarding symptom etiology. Although patients may present with only fever and malaise, signs and symptoms of sepsis, such as hypotension and cardiopulmonary compromise, also may occur during initial presentation.14,15

Cancer Type

Melanoma

Dacarbazine-based combinations

Myelodysplastic syndrome

Decitabine

Ovarian

Topotecan Paclitaxel or docetaxel

Pancreatic

Gemcitabine-docetaxel

Sarcoma

MAID (mesna, doxorubicin, ifosfamide, dacarbazine)

Small cell lung

Topotecan

Testicular

VeIP (vinblastine, ifosfamide, cisplatin) VIP (etoposide, ifosfamide, cisplatin) BEP (bleomycin, etoposide, cisplatin) TIP (paclitaxel, ifosfamide, cisplatin)

a

Does not contain all high-risk regimens.

Based on reference 9.

2010. More recently, the NCCN published guidelines on the prevention and treatment of cancer-related infections.6 Both sets of guidelines recommend that empiric antimicrobial therapy be initiated in all neutropenic patients at the onset of fever. The selection of empiric therapy should be based on a variety of factors such as a patient’s infectious risk, potential sites of infection, and local antimicrobial sensitivity and resistant patterns (Table 5).6 For patients at low risk for complications (Tables 4 and 5), oral antimicrobial therapy can be given.5,6 Both sets of guidelines recommend an oral regimen that contains ciprofloxacin plus amoxicillin-clavulanate. The NCCN recommends ciprofloxacin plus clindamycin for patients with a penicillin allergy.6 If fluoroquinolone prophylaxis was used, the NCCN guidelines recommend against oral therapy. Outpatient management may be appropriate for low-risk patients who meet certain criteria, such as consenting to home care, having a telephone, having access to emergency facilities, having an adequate and supportive home environment, and being within 1-hour travel time to a medical facility or physician’s office. Patients at high risk for severe infections should be treated in the hospital with IV antimicrobials, according to the IDSA and NCCN guidelines.5,6 Both guidelines recommend various monotherapy and combination regimens, with

Table 2. Risk Factors for Poor Clinical Outcomes or InfectionAssociated Complications Sepsis syndrome Age 65 y or older Severe neutropenia, defined as an absolute neutrophil count <100 cells/mcL Neutropenia lasting >10 d Pneumonia Invasive fungal infection Other clinically documented infections Hospitalization at the time of fever Based on reference 9.

vancomycin recommended for select patients (Table 6). Some of the monotherapy and combination regimens differ between the 2 sets of guidelines. For monotherapy, the NCCN guidelines state that ceftazidime has weak gram-positive coverage and is associated with increased breakthrough infections, suggesting that the utility of this agent is limited.6 With respect to

see NEUTROPENIA, page 14


10

Hem/Onc Pharmacy

Pharmacy Practice News • December 2009

In Focus

SHORTAGE continued from page 1

Dr. Norenberg said that repeated problems in getting Chalk River back online are not encouraging. And several news outlets have quoted sources who doubt whether the aging Canadian facility will ever return to service. “We really have nobody to blame for this crisis but ourselves,” said Dr. Norenberg, who is also associate director of the New Mexico Center for Isotopes in Medicine at the University of New Mexico, in Albuquerque. “The average age of the

five major sources of medical isotopes around the world is 47 years. But they’re only designed to last about 30 years, so all of these facilities are operating well past their planned senescence.” As a result, “we really are in a crisis, in terms of the lack of redundancy in facilities, the aging nature of the infrastructure and the cost to build a new facility (up to $150 million).” Cindy O’Bryant, PharmD, a board-certified oncology pharmacist at the University of Colorado Cancer Center, in Aurora, said the Tc-99m shortage already has had a troubling impact on patient care. “It’s

1

not a major issue in terms of the overall number of patients at our institution, but we have had to push back tests—mostly bone scans—in several cases. And if just one patient is negatively affected by a glitch in the Tc-99m supply, rather than an unavoidable worsening of their disease, well, that is really unfortunate.” Bone scans are the most common use for Tc-99m at most cancer centers, Dr. O’Bryant noted. The test is typically given to patients with metastatic disease, up to every six to eight weeks, to confirm that a given drug regimen is resulting in a response. Without such testing, “we’re

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unsure if this is the right therapy for that patient,” she said. “If the treatment is inappropriate and the patient doesn’t respond, we have to wait while the drug is cleared from their system and they recover from side effects. That delay could be critical; these patients may have aggressive cancers, and even a week or two can make a difference in survival.” Such delays are not an isolated event. The Society of Nuclear Medicine recently released the results of a survey designed to assess the impact of the Tc-99m shortage on several practice sites, including hospitals and outpatient imaging facilities. More than 90% of the respondents said they were affected by the shortages of the isotope. About one-third said they were only able to operate at 52% to 75% of their normal testing capacity. And 92% said they had to either cancel or postpone imaging procedures. Fortunately—at least for some facilities—the intensity of the shortages varies based on geographic location, Dr. Norenberg noted. He explained that Tc99m is a very short-lived radiotracer and thus needs to be delivered to facilities very quickly to remain effective. That’s easier to pull off in large urban areas than in rural locales, such as the University of Iowa Hospitals and Clinics (UIHC), in Iowa City, which has gone “without technetium for weeks at a time,” according to Dr. Norenberg. James A. Ponto, MS, RPh, chief nuclear pharmacist at UIHC, was more measured in describing the shortage’s impact. “On many days, we are just fine and can do a normal schedule,” he said. “But there have been rare days when we had zero Tc-99m on hand and could do no procedures.” In those cases, he added, “we have been fortunate to be able to get a few doses for emergency procedures from a private commercial nuclear pharmacy in Cedar Rapids, about 25 miles away. It’s not an ideal situation, but we’re coping.”

2 Line Tracing Label is easily removed and placed at the top of the line.

3 Second Tracing Label is placed at the bottom of the line.

There also has been an economic fallout from the Tc-99m shortage. “In the past, the average cost at our university was about $20 per dose,” said Michael M. Graham, MD, PhD, president of the Society of Nuclear Medicine. “The price has doubled in the last few months. With additional shortages, it is likely to go higher. The problem is that the margin on these studies is remarkably slim. With the prior arrangement, we were barely breaking even. Now this tips us over the edge.” Homer Macapinlac, MD, chair of the Department of Nuclear Medicine at the University of Texas M.D. Anderson Cancer Center, in Houston, said his facility has seen supplies of Tc-99m drop 20%. The hospital’s supplier does not rely solely on the Canadian reactor, he said. Dr. Macapinlac has worked with his supplier to get advance warning of


Hem/Onc Pharmacy 11

Pharmacy Practice News • December 2009

In Focus shortages, which can help with planning. Additionally, he has reduced dosing in some scans. He said such scans take longer, making them less comfortable and inconvenient for patients. Dr. Norenberg also cited several stopgap measures that can be taken to lessen the sting of the Tc-99m shortages, including the use of alternative imaging agents. Some bone scans for breast, prostate, lung and colon cancer patients, he noted, have been pushed over to positron emission tomography (PET), using sodium fluoride. “But it’s not reimbursable and it has limited distribution, so this does not enable a complete transfer of patients— maybe 10% can be serviced by PET.” For bone scans, Dr. Graham cited another alternative—a full-body computed tomography scan. But it involves a much higher radiation dose than Tc-99m and has a lower sensitivity, he said. Yet another stop-gap solution was offered by Dr. Macapinlac, who said he is using thallium, a different radioactive tracer, in patients who need myocardial perfusion imaging to detect cardiotoxicity from chemotherapy. “We might not be able to do the scan as optimally as we’d like, and we certainly do not like to switch techniques, but we need to deal with this on a daily or weekly basis,” he said.

Canada do it.’ But those reactors have a critical design flaw that makes it essentially impossible, or financially unfeasible, for them to fix,” Dr. Graham said. Now, some are trying to bring the solution to the United States. On July 21, Rep. Edward J. Markey (D-Mass.) introduced the American

Medical Isotopes Production Act of 2009, which calls for the creation of a program to evaluate and support production of molybdenum-99, a precursor to Tc-99m, in this country for medical use. Dr. Macapinlac said the bill is “our best hope to have a lasting solution to this shortage.” On Sept. 9, several experts testified on behalf of the bill to the House Committee on Energy and Commerce. One nuclear medicine specialist said the current crisis “is an acute exacerbation of a chronic problem with technetium99m supplies,” and is “the result of an unhealthy dependency on reactors

in other countries whose operational life expectancy is unpredictable. The development of a reliable domestic supply of technetium-99m is good public policy.” Dr. Norenberg agreed that the legislation is sorely needed. “What we’re currently doing to get through the shortage are really just short-term solutions. They’re not very sustainable, so we need to take measures to ensure a more reliable domestic supply of these agents for our patients.” —David Bronstein and David Jakubiak

building on our promises

Other Conditions Affected As for noncancer patients, the Tc-99m shortage is just as acute and potentially risky, Dr. Norenberg noted. In fact, “about 50% of all nuclear medicine involves cardiac procedures,” he said, with the bulk of the tests used for differentiating ischemia from myocardial infarction. “A lot of the workload has been taken up by thallium, but it’s an inferior technique, and that is why the industry moved towards a technetium agent.” He added that several other clinical areas have been negatively impacted. Acute cholecystitis, for example, is ideally diagnosed with Tc-99m. Since the advent of the shortage, “more invasive and less sensitive diagnostic techniques sometimes have to be used, even exploratory surgery in some cases. “So we have gone backwards not only in cancer but in cardiac and several other isotope imaging applications.”

A Crisis Years in the Making Although the dual shutdowns of the Petten and Chalk River reactors in July caught many nuclear medicine experts by surprise, the warning signs of such supply problems have been in place for years, according to Dr. Graham. About a decade ago, Canada announced it would build two new reactors to supply the world’s need for medical isotopes while replacing the production of the aging reactors. “That was supposed to be the solution for the whole world. Everybody was sort of standing back and saying, ‘let’s let

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12 Clinical

Pharmacy Practice News • December 2009

Events

SCCM Offers Snapshot of State-of-the-Art Critical Care Fluid management during surgery among pharmacy-focused topics on tap

S

ome 4,000 pharmacists, physicians and nurses are expected to descend on the Miami Beach Convention Center on Jan. 9-13, for North America’s largest gathering of medical professionals in critical care—the Society of Critical Care Medicine’s (SCCM) 39th Critical Care Congress. Emphasizing the theme “Commit, Transform, Improve,” the SCCM meet-

ing will feature dozens of educational sessions geared to the needs of critical care practitioners in cardiology, infectious disease, pediatrics and pharmacology, among other specialty areas. “Attendees can expect to come away from the SCCM Congress with a clear snapshot of the current state of the art in critical care medicine,” said Michael A. West, MD, PhD, co-chair of the

2010 meeting. Dr. West, who is professor and vice chair of the Department of Surgery at the University of California, San Francisco, and chief of surgery at San Francisco General Hospital, said attendees “will be able to learn about the latest advances in treatments, results from several pivotal prospective randomized trials, and hear from the experts about

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current controversies in the field.” Noting that “the SCCM Congress also emphasizes the human side of critical care,” Dr. West said the program would “feature numerous sessions on the socioeconomic aspects of health care that have dominated the news in recent months” and that attendees would also “be provided with up-to-the-minute information about the H1N1 pandemic and hear about the latest experiences with that disease.” Many of the educational sessions will feature presentations by clinical pharmacists, described by Dr. West as “crucial members” of the critical care team. “Numerous studies have documented the direct benefits that derive from involving clinical pharmacists in ICU [intensive care unit] rounds and decision making,” Dr. West said. “Pharmacists advise other members of the team about optimal drug treatments, maximize safety and minimize drug interactions, monitor drug levels and [perform] many other crucial functions.” On Sunday morning, Brian L. Erstad, PharmD, FCCM, FASHP, FCCP, BCPS, professor at the University of Arizona College of Pharmacy, Tucson, will moderate a session titled “Pharmacy Kitchen: Salt, Sugar and Protein.” “Blood loss is a common problem in critically ill patients,” Dr. Erstad said in describing the underlying theme of the program. “The blood loss leads to inadequate plasma volume and depletion of proteins such as immunoglobulins and clotting factors. “For repletion of plasma volume,” he said, “the standard resuscitation fluid is an isotonic crystalloid such as normal saline or lactated Ringer’s. Hypertonic sodium chloride solutions such as 3% hypertonic saline, and colloids such as albumin and starch products, have theoretical advantages over standard isotonic solutions.” Dr. Erstad noted, however, that “recent clinical trials involving hypertonic saline and colloid products have not found significant benefits over traditional isotonic fluids, and there is some data to suggest that they may cause harm in some situations.” Regarding proteins, he added, “the evidence supporting the use of immunoglobulins and certain clotting factors such as factor VII is limited.” He said the session would “present the pros and cons of these various therapies in the intensive care unit setting and provide the practitioner with practical information concerning their use.”

Factor Replacement in the ICU One of the session’s speakers, Asad Patanwala, PharmD, BCPS, clinical © 2009 Cadence Pharmaceuticals, Inc

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Pharmacy Practice News • December 2009

Clinical 13

Events

assistant professor in critical care/emergency medicine at the University of Arizona College of Pharmacy, in Phoenix, told Pharmacy Practice News that his talk will focus on factor VII and prothrombin complex concentrate, “the most common factor replacement products used in the intensive care unit or emergency care setting” for reversing elevated international normalized ratio in patients and helping to control life-threatening bleeding events. Dr. Patanwala said he will discuss “when it is appropriate to use these products” and the most cost-effective way of dosing them. On Saturday morning, two critical care pharmacists from the University of Pittsburgh Medical Center will lead a special four-hour session titled “Managing Pharmacotherapeutic Challenges: Learning Through Simulation.” Amy L. Seybert, PharmD, associate professor of pharmacy and therapeutics at the University of Pittsburgh School of Pharmacy and associate director, Pharmacy Programs, at the university’s Peter M. Winter Institute for Simulation, Education and Research, said the program will open with an overview of human patient simulation “in health care education, patient safety and potential for future use.” Dr. Seybert said the interactive, handson program will feature two electronically controlled simulated patients to demonstrate the effects of various pharmacologic strategies for emergency situations likely to arise in the critical care setting. “The audience will be able to see the actual consequences of an error on the physiology, including hemodynamics, of a patient,” Dr. Seybert said. “We will have the audience participate by responding via an audience response system to questions around patient care.” The program’s co-moderator, Sandra Kane-Gill, PharmD, MSc, FCCM, associate professor at the Pittsburgh School of Pharmacy and critical care specialist at the Center for Pharmacoinformatics and Outcomes Research, will look at how the use of human patient simulation can reduce the risk for medication errors in the ICU setting. Dr. Kane-Gill performed a study at the Pittsburgh Medical Center that showed a reduction in ICU medication errors through the use of simulation to educate

nurses on the appropriate way to administer medications. In one example she cited, pharmacists who were observing nurses in the medical ICU and cardiac care unit found that “the rate at which medication was being administered was often quicker than recommended. “We observed them and then helped correct [the error] by educating them through simulation on how they should do it,” Dr. Kane-Gill said. One of the session’s speakers, Joseph F. Dasta, MSc, RPh, FCCM, adjunct professor at the University of Texas College of Pharmacy, Austin, will employ a case study approach to show how simulation can educate practitioners on the use of medications to control hypertensive emergencies. The case study, he said, will involve “a patient with hypertensive emergency and underlying health conditions. The attendees will select their drug of first choice, prepare the IV and infuse the drug. They will see the resulting blood pressure [BP] response and may need to make further decisions based on their selection. If the patient’s blood pressure goes too low, for example, they will need to correct the overshoot. If the BP doesn’t respond, they will select another agent and dose the drug appropriately. Hopefully, they will achieve their goal BP.”

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Fighting Delirium On Sunday morning, John W. Devlin, PharmD, BCPS, FCCM, FCCP, associate professor at Northeastern University and clinical pharmacist in the medical ICU at Tufts Medical Center, Boston, will lead a sponsored symposium titled “Delirium Should ‘Never’ Occur, But If It Does …” “Increasingly,” Dr. Devlin said, “we’re realizing how prevalent delirium is in the intensive care unit. Institutions have really increased their screening efforts, which are predominantly nurse-driven. “At the same time,” he added, “we’re realizing the serious sequelae of delirium in the ICU. It is certainly associated with higher mortality, greater reintubation rates and higher costs related to longer lengths of stay in hospitals, and we’re also realizing some very substantial long-term cognitive sequelae where patients can develop dementia.” Dr. Devlin said he and his fellow presenters will focus on various treatment strategies. “There is substantial controversy on how we should treat delirium,” he said, adding that he and Richard R. Riker, MD, director of critical care research at Maine Medical Center in Scarborough, will detail some of the studies highlighting the benefits and risks associated with various medications used in treating patients with delirium. —Bruce Buckley

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14 Clinical

Pharmacy Practice News • December 2009

Educational Review Table 3. MASCC Risk Scoring Indexa

Table 4. Factors Favoring Low Risk for Severe Infection in Patients With Neutropeniaa

Extent of illness (choose 1)

IDSA 2002 Guidelines

NCCN 2009 Guidelines

No symptoms (5 points)

• Absolute neutrophil count of ≥100 cells/mcL

Mild symptoms (5 points)

• Absolute monocyte count of ≥100 cells/mcL

• No high-risk factorsa AND most of the following:

Moderate symptoms (3 points)

• Normal findings on a chest radiograph • Nearly normal renal and hepatic function tests

• Outpatient status at the time of development of fever • No associated acute comorbid illnesses

No hypotension (5 points)

• Duration of neutropenia is <7d

No chronic obstructive pulmonary disease (4 points)

• Resolution of neutropenia expected in <10 d

• Anticipated short duration of severe neutropenia, defined as <7d

• No IV catheter-site infection

• Good performance status

• Early evidence of bone marrow recovery

• No renal or hepatic insufficiency

Solid tumor or no fungal infection (4 points)

• Malignancy in remission No dehydration (3 points)

• Peak temperature of <39˚C

Outpatient at onset of fever (3 points)

• No neurologic or mental changes

Age <60 y (2 points)

• No appearance of illness

OR • A score of ≥21 on the MASCC Risk Index (see Table 3)

• No abdominal pain a

A score of 21 or higher indicates the patient is likely to be at low risk for complications. MASCC, Multinational Association for Supportive Care in Cancer Based on reference 13.

NEUTROPENIA

• No comorbid conditions such as shock, hypoxia, pneumonia or other deep-organ infection, vomiting, or diarrhea a High-risk factors are listed on page FEV-3 of v.2.2009 of the NCCN Practice Guidelines for the Prevention and Treatment of Cancer-Related Infections.

IDSA, Infectious Diseases Society of America; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network Based on references 5 and 6.

continued from page 9

vancomycin as empiric therapy, the IDSA recommends that this agent be used for patients with clinically suspected serious catheter-related infections, known colonization with penicillinand cephalosporin-resistant pneumococci or MRSA, positive results of a blood culture for gram-positive bacteria before final identification and susceptibility testing, or hypotension or other evidence of cardiovascular impairment.5 The NCCN guidelines recommend that vancomycin be used for patients meeting any of the same criteria as the IDSA guidelines, in addition to patients with a soft tissue infection or those with risk factors for viridans group streptococcal bacteremia.6 The NCCN guidelines strongly recommend against the use of empiric vancomycin for patients not meeting these criteria because of concerns about resistance and breakthrough infections. These guidelines also comment on the use of agents such as linezolid (Zyvox, Pharmacia), daptomycin (Cubicin, Cubist), and quinupristin-dalfopristin (Synercid, Monarch) and state that use of these antimicrobials should be limited to specific situations involving infections caused by documented vancomycin-resistant organisms or for patients in whom vancomycin is not an option. Patients with febrile neutropenia who are clinically unstable, such as those with sepsis, should be initiated on combination therapy that includes a broad-spectrum β-lactam (eg, imipenem-cilastatin, meropenem, or piperacillin-tazobactam [Zosyn, Wyeth]) plus an aminoglycoside and vancomycin.6 The addition of antifungal therapy (eg, fluconazole or an echinocandin) also should be considered for patients not receiving antifungal prophylaxis. Alterations in the initial empiric regimen are needed for patients who are not responding to therapy.5,6 The NCCN guidelines recommend

assessing the appropriateness of antimicrobials for isolated pathogens in patients with documented infection who are not responding to empiric therapy.6 In addition, for patients with fever of unknown origin who are unstable, antimicrobials should be broadened to include coverage of anaerobes, resistant gram-negative rods and gram-positive organisms, and Candida. Empiric antifungal therapy is generally initiated after 4 to 7 days in patients who remain febrile. The NCCN guidelines state that the duration of antimicrobial therapy is determined by several factors such as the underlying site of infection, causative organisms, and the patient’s clinical condition, response to treatment, and time to neutrophil recovery.6 For patients with fever of unknown origin, antimicrobial therapy is generally continued until the ANC is at least 500 cells/ mcL, assuming the patient is afebrile for at least 24 hours before discontinuation. For patients with documented infections, the NCCN guidelines acknowledge that most clinicians treat patients until the ANC recovers to 500 cells/mcL or more, but they recommend using a defined course of therapy appropriate for the specific infection. The durations for antimicrobial therapies suggested in the NCCN guidelines are summarized in Table 7.6 The duration of antimicrobial therapy is treated differently in the IDSA guidelines.5 The IDSA guidelines state that if no infection is identified after 3 days of treatment, the neutrophil count is at least 500 cells/mcL for 2 consecutive days, and the patient has been afebrile for at least 48 hours, antimicrobials can be stopped. The guidelines also recommend that for patients with prolonged neutropenia, therapy can be stopped in low-risk patients who are clinically well and

Table 5. Factors Influencing Initial Antimicrobial Selection Infection risk assessment (ie, low vs high risk) Antimicrobial susceptibilities of pathogens isolated locally The most commonly potentially infecting organisms, including antimicrobial-resistant pathogens, such as ESBL-producing gram-negative rods or VRE Colonization or previous infection with MRSA Potential site of the infection Importance of broad spectrum antimicrobial coverage that includes antipseudomonal coverage Previous antimicrobial use Clinical instability such as organ dysfunction, hypotension Drug allergy ESBL, extended spectrum β-lactamase; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococcus Based on reference 6.

afebrile for 5 to 7 days. Antimicrobial therapy can be stopped after 2 weeks in patients with persistent fever on day 3 and prolonged neutropenia, as long as no documented infection is found and the patient is clinically stable.

see NEUTROPENIA, page 16


16 Clinical

Pharmacy Practice News • December 2009

Educational Review

NEUTROPENIA continued from page 14

Table 6. Empiric Antimicrobial Therapy for Febrile Neutropenia

Table 7. Suggested Durations Of Antimicrobial Therapy for Patients With Documented Infections

Prophylactic Antimicrobials Both the IDSA and NCCN guidelines comment on the use of antimicrobial prophylaxis for afebrile neutropenic patients.5,6 The IDSA guidelines recommend against the routine use of antimicrobial prophylaxis because of emerging resistance.5 Antimicrobial prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is only recommended to prevent Pneumocystis jiroveci pneumonitis in patients at risk for this infection. Antifungal prophylaxis with fluconazole and antiviral prophylaxis with acyclovir or ganciclovir are recommended for patients undergoing allogenic hematopoietic stem cell transplantation. The NCCN guidelines include a detailed discussion on antimicrobial prophylaxis, which is beyond the scope of this review; however, key recommendations include fluoroquinolone prophylaxis, with levofloxacin (Levaquin, Ortho-McNeil-Janssen) as the preferred agent for patients expected to have neutropenia for more than 7 days, and TMP-SMX for patients at risk for Pneumocystis jiroveci infections.

IDSA 2002 Guidelines

NCCN 2009 Guidelines

Monotherapy • Imipenem/ cilastatin • Meropenem • Cefepime • Ceftazidime

Monotherapy • Imipenem/cilastatin • Meropenem • Piperacillin/ tazobactam • Cefepime • Ceftazidime (limited utility)

Combination therapy • Aminoglycoside plus antipseudomonal penicillin • Aminoglycoside plus cefepime, ceftazidime, or carbapenem

Combination therapy • Aminoglycoside plus antipseudomonal penicillin with or without β-lactamase inhibitor • Aminoglycoside plus cefepime or ceftazidime • Ciprofloxacin plus antipseudomonal penicillin

Prophylactic Use of Colony-Stimulating Factors Reducing the incidence, severity, and duration of neutropenia is another important treatment strategy used for managing patients with febrile neutropenia. Colony-stimulating factors (CSFs) are used to prevent neutropenia in patients who are receiving myelosuppressive chemotherapy.16 These agents regulate the proliferation, differentiation, maturation, and functional activation of neutrophils. The CSFs are classified into 2 groups: granulocyte-CSFs (filgrastim [Neupogen, Amgen] and pegfilgrastim [Neulasta, Amgen]) and a granulocyte-macrophage CSF (sargramostim [Leukine, Genzyme]).17-19 The labeled indications for filgrastim, pegfilgrastim, and sargramostim vary; a summary of these indications is presented in Table 8.17-19 Filgrastim should be initiated 24 to 72 hours after completion of chemotherapy at a daily dose of 5 mcg/kg.17 Therapy should be continued through the post-nadir recovery to normal or nearnormal levels. Filgrastim should not be given the same day chemotherapy is administered. Pegfilgrastim should also be initiated 24 to 72 hours after the completion of chemotherapy and not administered on the same day chemotherapy is given.18 Pegfilgrastim is given as one dose of 6 mg per treatment cycle. Sargramostim is given at a dose of 250 mcg/m2 per day, also initiated 24 to 72 hours after the completion of chemotherapy, and continued through the post-nadir recovery period.19 The American Society of Clinical Oncology (ASCO) guidelines recommend that use of sargramostim is limited to its labeled indications.16 Recommendations for Use of CSFs In 2006, ASCO published an update to its 2000 recommendation on the use of CSFs.16 Data have shown that prophylactic use of CSFs reduces the incidence, length, and severity of chemotherapy-related neutropenia, and decreases rates of infection.20,21 Use of CSFs is recommended as primary prophylaxis of febrile neutropenia for patients at high risk based on

Vancomycin (for select patients) • Vancomycin plus cefepime, ceftazidime, or carbapenem with or without aminoglycoside

Vancomycin (for select patients) • Monotherapy or combination therapy

IDSA, Infectious Diseases Society of America; NCCN, National Comprehensive Cancer Network Based on references 5 and 6.

age, medical history, disease characteristics, and risk for myelotoxicity associated with a chemotherapy regimen. Available data support the use of CSFs with chemotherapy regimens that have a 20% or greater risk for febrile neutropenia

Infection

Duration of Therapy

Skin and soft tissue

7-14 d

Bloodstream infections Gram-negative Gram-positive

10-14 d 7-14 d

Sinusitis

10-21 d

Bacterial pneumonia

10-21 d

Fungal (mold and yeast) Candida

Mold (eg, Aspergillus) Viral Herpes simplex/ Varicella zoster Influenza

Minimum of 2 wk after first negative blood culture Minimum of 12 wk

7-10 d 5-10 d

Based on reference 6.

(Table 1). In addition, CSFs may be beneficial for patients undergoing nonmyelosuppressive therapy but who have risk factors for febrile neutropenia or infectious complications. A summary of ASCO’s recommendations is presented in Table 9.16 The CSFs are not recommended for routine treatment of afebrile neutropenia and use should be avoided in patients receiving a combination of chemotherapy and radiation. The 2009 recommendations from NCCN on the use of CSFs are summarized in Table 10.9 These guidelines, which are similar to the ASCO guidelines, also recommend the prophylactic use of CSFs with chemotherapy regimens that have a 20% or greater risk for febrile neutropenia. In addition, patients are considered to be at high risk if

Table 8. Labeled Indications for CSFs CSFs

FDA-Approved Indications

Filgrastim (Neupogen, Amgen)

• Cancer patients receiving myelosuppressive chemotherapy • Patients with AML receiving induction or consolidation chemotherapy • Cancer patients receiving BMT • Patients undergoing peripheral blood progenitor cell collection and therapy • Patients with severe chronic neutropenia

Pegfilgrastim (Neulasta, Amgen)

• Cancer patients receiving myelosuppressive chemotherapy

Sargramostim (Leukine, Genzyme)

• Patients with AML receiving induction or consolidation chemotherapy • Patients undergoing peripheral blood progenitor cell collection and therapy • Cancer patients receiving BMT • Use in BMT failure or engraftment delay

AML, acute myeloid leukemia; BMT, bone marrow transplant; CSFs, colony-stimulating factors Based on references 17-19.


Clinical 17

Pharmacy Practice News â&#x20AC;˘ December 2009

Educational Review Table 9. ASCO Recommendations on Use of CSFs As primary prophylaxis of febrile neutropenia for patients at high risk based on age, medical history, disease characteristics, and risk for myelotoxicity associated with a chemotherapy regimen.

Table 10. NCCN Recommendations on CSFs For Febrile Neutropenia

For patients undergoing nonmyelosuppressive therapy but who have risk factors for febrile neutropenia or infectious complications due to bone marrow compromise or other comorbidities. As secondary prophylaxis in patients who have previously experienced an episode of febrile neutropenia (without primary prophylaxis) when a reduction in dose of chemotherapy is not appropriate. Use can be considered as adjunctive treatment of febrile neutropenia for patients at high-risk for infectious complications.

Risk for Febrile Neutropenia

Use of CSF

High (>20%)

CSF

Intermediate May be (10%-20%) considered

To allow for a modest to moderate increase in dose-density and dose-intensity of chemotherapy regimens.

Low (<10%)

No CSFa

CSF

CSF

May be considered

May be considered

No CSF

No CSF

As an adjunct to progenitor-cell transplantation. For reduction of neutropenia in patients with AML with initial or repeat induction chemotherapy or completion of consolidation therapy. To increase ANC in patients with myelodysplastic syndrome. Following completion of initial induction therapy or first post-remission course of chemotherapy for ALL.

a

Only consider CSF if a patient is at significant risk for serious medical consequences of febrile neutropenia, including death. CSFs, colony-stimulating factors; NCCN, National Comprehensive Cancer Network Based on reference 9.

For limited use with refractory or relapsed AML (data suggest only a few shortened days of neutropenia can be expected). As prophylaxis in patients 65 y and older with diffuse aggressive lymphoma undergoing CHOP or more aggressive regimens. For patients being treated with lethal doses of total body radiotherapy. For pediatric patients, CSFs can be used for primary prophylaxis and as secondary prophylaxis or as adjunctive therapy for high-risk patients; the risk for secondary myeloid leukemia or myelodysplastic syndrome should be considered in children with ALL. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; ANC, absolute neutrophil count; ASCO, American Society of Clinical Oncology; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CSFs, colony-stimulating factors

Conclusion Febrile neutropenia remains a significant source of morbidity and mortality for patients receiving chemotherapy. Risk factors and models have been evaluated to aid in determining which patients may be at high risk for complications and which patients may be at low risk and therefore benefit from treatment with more cost-effective and convenient medication regimens. The IDSA and NCCN have developed guidelines for the prevention and treatment of infections associated with febrile neutropenia. In addition, the NCCN and ASCO have published guidelines regarding the appropriate

8. Lyman G. Risks and consequences of chemotherapyinduced neutropenia. Clin Cornerstone. 2006;8(suppl 5): S12-S18, PMID: 17379159. 9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Myeloid growth factors (v.1.2009). http://www.nccn.org/professionals/physician_gls/PDF/ myeloid_growth.pdf. Accessed November 11, 2009. 10. Ellis M. Febrile neutropenia. Ann NY Acad Sci. 2008;1138:329-350, PMID: 18837909. 11. Lyman GH. Risk assessment in oncology clinical practice. From risk factors to risk models. Oncology (Williston Park). 2003;17(suppl 11):8-13, PMID: 14682113.

Based on reference 16.

they experienced a previous neutropenic complication in the immediate previous cycle with no plan to reduce the dose intensity of the chemotherapy regimen. When deciding if CSFs should be used, clinicians are encouraged to consider the intent of the chemotherapy regimen. For example, is therapy curative or is it being used for symptom control? For patients in the intermediate-risk category (10%-20%), NCCN recommends that if the risk is based on patient-specific factors, then use of CSFs is reasonable. However, if the intermediate risk is based on the chemotherapy regimen, then use of less myelosuppressive therapies or a dose reduction should be considered.

its management. Cancer. 2004;100(2):228-237, PMID: 14716755.

use of myeloid growth factors for this condition. Appropriate therapy in selected patients can significantly improve outcomes and reduce complications of febrile neutropenia.

References 1.

Lyman G. Kuderer NM. Epidemiology of febrile neutropenia. Support Cancer Ther. 2003;1(1):23-35, PMID: 18628128.

2. Viscoli C, Vanier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis. 2005;40(suppl 4):S240-S245, PMID: 15768329. 3. McCabe WR, Jackson GG. Gram-negative bacteremia. II. Clinical, laboratory, and therapeutic observations. Arch Intern Med. 1962;110(6):856-864. 4. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis. 2003;36(9):1103-1110, PMID: 12715303. 5. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34(6):730-751, PMID: 11850858. 6. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related Infections (v.2.2009). http://www.nccn.org/ professionals/physician_gls/PDF/infections.pdf. Accessed November 10, 2009. 7. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for

12. Lyman GH, Lyman CH, Agboola O, for the ANC study group. Risk models for predicting chemotherapy-induced neutropenia. Oncologist. 2005;10(6):427-437, PMID: 15967836. 13. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18(16):3038-3051, PMID: 10944139. 14. Walji N, Chan AK, Peake DR. Common acute oncological emergencies: diagnosis, investigation, and management. Postgrad Med J. 2008;84(994):418-427, PMID: 18832403. 15. Adelberg DE, Bishop MR. Emergencies related to cancer chemotherapy and hematopoietic stem cell transplantation. Emerg Med Clin N Am. 2009;27(2):311-331, PMID: 1947314. 16. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205, PMID: 16682719. 17. Neupogen [package insert]. Thousand Oaks, CA: Amgen; 2007. 18. Neulasta [package insert]. Thousand Oaks, CA: Amgen; 2008. 19. Leukine [package insert]. Seattle, WA: Bayer; 2008. 20. Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008;(4):CD003189, PMID: 18843642. 21. Sung L, Nathan PC, Alibhai SM, Tomlinson GA, Beyene J. Meta-analysis: effect of prophylactic hematopoietic colonystimulating factors on mortality and outcomes of infection. Ann Intern Med. 2007;147(6):400-411, PMID: 17876022.


18 Clinical

Pharmacy Practice News • December 2009

Transplant Pharmacy

A Specialty Coming of Age T

hree decades ago, there were only a handful of pharmacists working in the field of solid organ transplant medicine. Today, hundreds of practitioners help care for patients in the nation’s 250-plus transplant centers. But has the specialty come of age? Recent signs are encouraging. Earlier this year, transplant pharmacy was recognized as a “community of practice”—that is, a specific group of caregivers—within the American Society of Transplantation.

And a survey released in April 2009 by researchers at the Vanderbilt University Transplant Center in Nashville, Tenn., suggests that up to 90% of the nation’s transplant centers rely on pharmacists for some aspect of patient care. Despite this, many questions about the practice remain. For example, should all transplant pharmacists complete postgraduate residency programs, or can onthe-job training suffice? (Both models exist.) Which stage of therapy should

transplant pharmacists focus on—hospital admission, inpatient or post-discharge care? And what is the best strategy for meeting federal practice requirements that could negatively impact reimbursement if they are not met? To gain insight into these questions, Pharmacy Practice News interviewed a wide range of organ transplant pharmacists who, collectively, have more than 50 years of experience caring for these complex patients.

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CLINICALLY RELEVANT SEARCH RESULTS MOST COMPREHENSIVE DRUG INFORMATION CLEAN, UNCLUTTERED INTERFACE

Who Should Be on the Team? One of the most basic questions facing an organ transplant center is exactly who to bring on board to manage the medication needs of patients. It’s an important consideration, because individuals who receive organ transplants are often taking 10 to 12 drugs. “If these agents are not dosed correctly, or some other mistake is made, you get into trouble really fast—organs can be rejected within a very short period of time,” said Kwaku Marfo, PharmD, a transplant pharmacist at Montefiore Medical Center, in New York City. Some guidance on transplant team staffing has come from the United Network of Organ Sharing (UNOS), which administers the Organ Procurement and Transplantation Network (OPTN), established by the U.S. Congress in 1984. In 2004, UNOS updated its bylaws to recommend that all transplant programs “should”—but not “must”—identify one or more pharmacists to provide pharmaceutical care to solid organ transplant patients. Three years later, the Centers for Medicare & Medicaid Services (CMS) issued its own “conditions of participation” for organ transplant centers. But instead of naming pharmacists specifically, those conditions require only that an individual “with expertise in organ transplant pharmacology” be a member of a multidisciplinary transplant team. Dianne LaPointe Rudow, DNP, a past member of UNOS’ Executive Committee Policy Advisory Group, said it may be interesting to parse the UNOS and CMS positions on who should provide pharmacologic care. “But it’s a bit of a moot point,” she said. “I doubt you could visit a single solid organ transplant center in the United States and not find that it is a pharmacist who fulfills that role.” Dr. Marfo agreed. “Across the board, when you look for someone to fulfill that CMS mandate, even though it does not specify our profession by name, it is, in fact, nearly always a highly skilled pharmacist. We’re clearly the pharmacology experts; the nation’s solid organ transplant centers recognize that and so they turn to us accordingly.” That strong role for pharmacy was underscored in the Vanderbilt survey. Of the 58 centers whose responses were evaluable, 90% said they had access to a pharmacist who provided support for adult organ transplant patients, according to coinvestigators Christie B. Truscott, PharmD, and Edward Y. Zavala, MBA. Nearly 70% of the centers said their pharmacists also provided pediatric transplant support, noted the researchers, who presented their results at the UNOS Transplant Management Forum in Seattle.


Clinical 19

Pharmacy Practice News • December 2009

Transplant Pharmacy The survey also offered a glimpse into the varying roles that pharmacists play as members of the organ transplant team. Fully 100% of the centers said pharmacists provided inpatient care; 81%, discharge medication counseling; 71%, outpatient care; 62%, pre-transplant education; and 36%, clinical research. That diverse practice pattern illustrates that transplant pharmacy “continues to expand and evolve into new roles despite the lack of a specific policy regarding the extent of [their] involvement,” the researchers concluded. Mr. Zavala, the transplant administrator at Vanderbilt, was one of several individuals who pushed hard to have the updated UNOS bylaws specify that pharmacists become part of the transplant team. “Clearly, the fact that we did not spell out every aspect of what they should do on that team has not been a negative,” he said. “Each center has the freedom to decide the best mix of duties, based on the needs of their patient population.”

‘We’re clearly the pharmacology experts in the field; organ transplant centers recognize that and so they turn to us accordingly.’

—Kwaku Marfo, PharmD

very seriously. But I wouldn’t enforce it for every transplant center.” Currently, there are 12 organ transplant residency programs that participate in the accrediting process of the American Society of Health-System Pharmacists, according to Janet Tee-

ters, RPh, MS, the society’s director of accreditation services. Five of those programs are fully accredited; seven are in candidate status. In March 2009, Ms. Teeters added, there were 10 slots for pharmacy residents open in those centers; nine filled

as a result of the resident matching process.

Outcomes Data Can Be Elusive There is yet another area of transplant pharmacy practice that is still evolving: the degree to which the profession has been able to document that outcomes actually improve when pharmacists join the patient-care team. There have been a few studies that one could point to, Dr. Marfo noted. He cited, as an example, a study of renal transplant centers that employed

see COMING OF AGE, page 20

In the treatment of VWD, Humate-P® stands alone

Accreditation, Training Still Evolving Each center also needs to determine the level of training it requires of transplant pharmacists. Many centers, for example, hire only pharmacists who have completed a postgraduate year 2 (PGY2) residency program in solid organ transplant pharmacy. Lonnie Smith, PharmD, manager of transplant services at the University of Utah, in Salt Lake City, has an interesting take on that issue. One might think, given the fact that Dr. Smith is the director of the university’s accredited PGY2 residency program in solid organ transplant medicine, that he would be in favor of such a mandate. In practical terms, he is—Dr. Smith said he hires only residency-trained transplant pharmacists. But would he advocate that this hiring strategy become a binding policy for all transplant centers? “How could I?” he told Pharmacy Practice News. “I’m not a graduate [of such a program] myself.” Dr. Smith explained that when he first became involved in transplant pharmacy nearly 12 years ago, there were only two or three PGY2 transplant residency programs in the United States. “I first got exposed to transplant medicine during my general practice residency, and really got hooked on this as a therapeutic area. I spent the next two years of my professional life doing nothing but getting trained on the job, as did a lot of very skilled, talented people who mentored me throughout my career.” Having said that, “there is a huge benefit to going through a PGY2 solid organ transplant residency program, and it’s something I’d encourage anyone with an interest in this practice area to consider

Humate-P® is the only von Willebrand factor (VWF) concentrate that: In over 20 years and more than one-half billion units infused, there is no documented evidence of viral transmission with Humate-P ®.1

Visit us at www.Humate-P.com

• Is approved for the treatment of von Willebrand disease (VWD) and d the prevention of excessive bleeding during and after surgery • Can be used for prevention of bleeding during and after surgery in all VWD types • Contains high molecular weight multimers of VWF—important for correcting the coagulation defect in patients with VWD1

Close as it gets to normal VWF

Important Safety Information Humate-P® is contraindicated in individuals with a history of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations, or to any of its components. Thromboembolic events have been reported in VWD patients receiving coagulation factor replacement, especially in the setting of known risk factors for thrombosis. Caution should be exercised and antithrombotic measures considered. Humate-P® 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 most common adverse reactions reported in patients receiving Humate-P® are allergic-anaphylactic reactions, including urticaria, chest tightness, rash, pruritus, edema, shock, chills and fever, and hypervolemia. For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding. 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 brief summary of prescribing information on next page. Reference: 1. Data on file, CSL Behring LLC. ©2009 CSL Behring LLC, 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901, USA | www.CSLBehring-US.com

IO#09-HUM-009

11/2009


20 Clinical

Pharmacy Practice News • December 2009

Transplant Pharmacy

COMING OF AGE continued from page 19

pharmacists to help patients and physicians reduce drug-related problems (Transplantation Proc 2008;40:2319-2323). More than 96% of the recommendations made by the pharmacists were accepted by the physicians on the transplant team, according to the study. Among the cases in which the pharmacists’ recommendations were accepted, nearly 95% of the patients improved clinically. Mr. Zavala said he was not surprised at that high level of physician acceptance.

When he worked on the transplant administrator committee of UNOS, it took him about two years to get approval to add psychosocial support staff and transplant coordinators as team members under UNOS bylaws. Adding pharmacists to the bylaws, in contrast, “took about six months,” he said. Mr. Zavala explained that about half of the UNOS board members were physicians or surgeons. “Clearly, they already were aware of the huge value pharmacists bring to the transplant team.” Other studies have shown that organ transplant pharmacists can help boost

BRIEF SUMMARY OF PRESCRIBING INFORMATION

CSL Behring

Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized Humate-P Manufactured by: CSL Behring GmbH 35041 Marburg, Germany US License No. 1765

Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. INDICATIONS AND USAGE Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is indicated in adult patients for treatment and prevention of bleeding in hemophilia A (classical hemophilia). Humate-P is also indicated in adult and pediatric patients with von Willebrand disease for (1) treatment of spontaneous and trauma-induced bleeding episodes and (2) prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin is known or suspected to be inadequate. Controlled clinical trials to evaluate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Adequate data are not presently available on which to evaluate or to base dosing recommendations in this setting. CONTRAINDICATIONS Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is contraindicated in individuals with a history of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations. It is also contraindicated in individuals with a known hypersensitivity to any of its components. WARNINGS Thromboembolic events have been reported in VWD patients receiving Antihemophilic Factor/von Willebrand Factor Complex replacement therapy, especially in the setting of known risk factors for thrombosis.16,17,18 Early reports might indicate a higher incidence in females. In addition, endogenous high levels of FVIII have also been associated with thrombosis but no causal relationship has been established. In all VWD patients in situations of high thrombotic risk receiving coagulation factor replacement therapy, caution should be exercised and antithrombotic measures should be considered. See also DOSAGE AND ADMINISTRATION. Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Humate-P is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections and by inactivating and/or removing certain viruses during manufacture. Stringent procedures, utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction step of the Humate-P manufacturing process is the heat treatment of the purified, stabilized aqueous solution at 60 C for 10 hours (i.e., pasteurization). In addition, the purification procedure, which includes several precipitation steps and an adsorption step, used in the manufacture of Humate-P also provides virus reduction capacity (see DESCRIPTION section for virus reduction factors). Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-800-504-5434 (in the U.S. and Canada). The physician should discuss the risks and benefits of this product with the patient. PRECAUTIONS It is important to determine that the coagulation disorder is caused by factor VIII or VWF deficiency, since no benefit in treating other deficiencies can be expected. Thromboembolic events have been reported in VWD patients receiving coagulation factor replacement therapy, especially in the setting of known risk factors for thrombosis. In these patients, caution should be exercised and antithrombotic measures should be considered. As a precaution, the administration equipment and any unused Humate-P should be discarded after use. Information for Patients Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. Parvovirus B19 may most seriously affect pregnant women, or immune-compromised individuals. Although the overwhelming number of hepatitis A and parvovirus B19 cases are community acquired, there have been reports of these infections associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of parvovirus B19 and hepatitis A infections and inform patients under their supervision receiving plasma-derived products to report potential symptoms promptly. Symptoms of parvovirus B19 may include low-grade fever, rash, arthralgias and transient symmetric, nondestructive arthritis. Diagnosis is often established by measuring B19 specific IgM and IgG antibodies. Symptoms of hepatitis A include low grade fever, anorexia, nausea, vomiting, fatigue and jaundice. A diagnosis may be established by determination of specific IgM antibodies. Laboratory Tests Antihemophilic Factor/von Willebrand Factor (Human), Dried, Pasteurized, Humate-P , contains blood group isoagglutinins (anti-A and anti-B). When very large or frequently repeated doses are needed, as when inhibitors are present or when pre- and post-surgical care is involved, patients of blood groups A, B and AB should be monitored for signs of intravascular hemolysis and decreasing hematocrit values and be treated appropriately, as required. The Factor VIII levels of VWD patients receiving Humate-P should be monitored using standard coagulation tests, especially in cases of surgery. Strong consideration should also be given to monitoring VWF:RCo levels in VWD patients receiving Humate-P for the prevention of excessive bleeding during and after surgery. It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once daily in order to adjust the dosage of Humate-P as needed to avoid excessive accumulation of coagulation factors (see DOSAGE AND ADMINISTRATION). Pregnancy Category C Animal reproduction studies have not been conducted with Antihemophilic Factor/von Willebrand Factor (Human). It is also not known whether Humate-P can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humate-P should be given to a pregnant woman only if clearly needed. Pediatric Use Hemophilia A Adequate and well-controlled studies with long-term evaluation of joint damage have not been done in pediatric subjects. Joint damage may result from suboptimal treatment of hemarthroses. For immediate control of bleeding for Hemophilia A, the general recommendations for dosing and administration for adults, found in the DOSAGE AND ADMINISTRATION section, may be referenced. Von Willebrand Disease The safety and effectiveness of Humate-P for the treatment of von Willebrand disease was demonstrated in 26 pediatric subjects, including infants, children and adolescents but has not been evaluated in neonates. The safety of Humate-P for the prevention of excessive bleeding during and after surgery was demonstrated in 8 pediatric subjects (ages 3 through 15) with VWD. Of the 34 pediatric subjects studied for both treatment of VWD and prevention of excessive bleeding during and after surgery, four were infants (1 month to under 2 years of age), 23 were children (2 through 12 years), and 7 were adolescents (13 through 15 years). As in adults, pediatric patients should be dosed based upon weight (kg) in accordance with information in the DOSAGE AND ADMINISTRATION section. Geriatric Use Clinical studies of Humate-P® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. ADVERSE REACTIONS The most serious adverse reaction observed in patients receiving Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P®, is anaphylaxis. Thromboembolic events have also been observed in patients receiving Humate-P® for the treatment of VWD (see WARNINGS). Reports of thromboembolic events in VWD patients with other thrombotic risk factors receiving coagulation factor replacement therapy have been obtained from spontaneous reports, published literature, and a European clinical study. Early reports might indicate a higher incidence in females. In some cases, inhibitors to coagulation factors may occur. However, no inhibitor formation was observed in any of the clinical trials. Although few adverse reactions have been reported in clinical studies and in the postmarketing setting in patients receiving Humate-P® for treatment of hemophilia A and VWD, the most commonly reported are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock). For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding.

compliance with immunosuppressive medications, improve the control of hypertension—a condition that can cause organ rejection if left unchecked— and also lead to more cost-effective care (Ann Pharmacother 2007:41:1261-1263). At Montefiore, there is a transplant pharmacist who spends about one-third of her time conducting clinical research. (Some centers have pharmacists whose sole function is research.) “But a lot of what she focuses on is specific to transplant drugs,” Dr. Marfo said. When it comes to tracking improved outcomes, in contrast—ones that could be attrib-

Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. von Willebrand Disease Treatment of VWD Allergic symptoms, including allergic reaction, urticaria, chest tightness, rash, pruritus, and edema, were reported in 6 of 97 (6%) subjects in a Canadian retrospective study. Four of 97 (4%) subjects experienced seven adverse events that were considered to have a possible or probable relationship to the product. These included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus. In a prospective, open-label safety and efficacy study of Humate-P® in VWD subjects with serious life- or limbthreatening bleeding or undergoing emergency surgery, seven of 71 (10%) subjects experienced nine adverse reactions. These were mild vasodilation (1/9), allergic reactions (2/9), pruritus (1/9), and paresthesia (2/9); moderate peripheral edema (1/9) and extremity pain (1/9); and severe pseudothrombocytopenia (platelet clumping with a false low reading) (1/9). Humate-P® was discontinued in the subject who experienced the peripheral edema and extremity pain. VWD Subjects Undergoing Surgery Among the 63 VWD subjects who received Humate-P for prevention of excessive bleeding during and after surgery, including 1 subject who underwent colonoscopy without the planned polypectomy, the most common adverse events were postoperative hemorrhage (35 events in 19 subjects with five subjects experiencing bleeding at up to three different sites), postoperative nausea (15 subjects), and postoperative pain (11 subjects). Postoperative hemorrhagic adverse events are shown in Table 7. Table 7: Hemorrhagic Adverse Events in 63 Surgical Subjects Adverse Event

Surgical Procedure Category

Number of Subjects/ Events

Onset* (Number of Events) Post

Mild

Mod

Major

8/11

7

4

9

2

Minor Oral Major Minor

2/2 2/6 4/4 1/1

2 – 2 1

– 6 2 –

1 3 3 1

1 3 1 –

– – –

#

On Wound/injection site bleeding

Epistaxis

* # § +

Severity (Number of Events)

Severe

Cerebral hemorrhage/ subdural hematoma Gastrointestinal bleeding Menorrhagia Groin bleed Ear bleed Hemoptysis Hematuria

Major

1/2

2

2

Major

1/3

2

1

Major Oral Major Major Major

1/1 1/1 1/1 1/1 1/1

1+ – 1 1 1

– 1 – – –

– 1 1 1 1

1 – – – –

– – – – –

Shoulder bleed

Major

1/1

1

1

On = on-therapy; onset while receiving Humate-P or within 1 day of completing Humate-P administration. Post = post-therapy; onset at least one day after completing Humate-P administration Reported as serious adverse events after intracranial surgery Two of these events reported as serious adverse events occurring after gastrojejunal bypass Reported as serious adverse event requiring hysterectomy after hysteroscopy and dilation and curettage

Table 8 lists the non-hemorrhagic adverse events reported in at least two subjects, regardless of causality, and the adverse events that were possibly related to Humate-P . Pulmonary embolus that was considered possibly related to Humate-P occurred in one elderly subject who underwent bilateral knee replacement. Table 8: Non-Hemorrhagic and Possibly Related Adverse Events (AE) in 63 Surgical Subjects Body System

Body as a Whole

Cardiovascular

Digestive

Hemic and Lymphatic System Metabolic/Nutritional Nervous

Skin and Appendages Urogenital

Adverse Event

Pain Fever Abdominal Pain Infection Surgery Back Pain Facial Edema Chest Pain Pulmonary Embolus# Thrombophlebitis# Nausea Constipation Vomiting Sore Throat Anemia / Decreased Hemoglobin Increased SGPT Dizziness Headache Increased Sweating Insomnia Pruritus Rash Urinary Retention Urinary Tract Infection

Number of Subjects with an AE Possibly Related to Humate-P® – – – – – – – – 1 1 1 – 1 –

Number of Subjects with an AE Regardless of Causality* 11 4 3 3 3 2 2 3 1 1 15 7 3 2

2

1 1 1 – – – 1 – –

1 5 4 3 2 3 1 4 2

* Occurring in two or more subjects # These events occurred in separate subjects

Eight subjects experienced 10 postoperative serious adverse events: one with subdural hematoma and intracerebral bleeding following intracranial surgery related to an underlying cerebrovascular abnormality; one with two occurrences of gastrointestinal bleeding following gastrojejunal bypass; and one each with sepsis, facial edema, infection, menorrhagia requiring hysterectomy following hysteroscopy and dilation and curettage, pyelonephritis, and pulmonary embolus. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Humate-P®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Humate-P® exposure. Adverse reactions reported in patients receiving Humate-P® for treatment of VWD or hemophilia A are allergicanaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to Factor VIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia. Evaluation and interpretation of these postmarketing events is confounded by underlying diagnoses, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. Healthcare professionals should report serious adverse events possibly associated with the use of Humate-P® to CSL Behring at 1-800-504-5434 or FDA’s MedWatch reporting system at 1-800-FDA-1088. Adapted from October 2007 revision.

uted to pharmacists on the organ transplant team—“that is difficult,” he said. When there is an improvement in rates of rehospitalization, or a lowered cost of care, for example, “how do you reliably [link] that to the actions of pharmacists, when there are so many other providers on the patient-care team?”

Compliance Is Key There may be lingering questions about how best to track such outcomes. But empirically, at least, there’s little doubt as to the effectiveness of one pharmacist intervention: helping patients to comply with their transplant medications. In nearly all cases of organ rejection, Dr. Marfo said, “if you spend time with the patient and delve into their medication history, you’ll find some element of nonadherence.” Explaining to them the risks of not taking their medications—graft rejection, rehospitalizations, even death—can go a long way towards boosting compliance, he noted. Dr. Marfo also stressed that educating patients about their medications should not be left up to other caregivers. “At some centers, they let nurses counsel patients. They are very highly skilled caregivers, but pharmacists are the drug experts, and so we really need to be the ones providing this service.” Recently, one counseling point has come up that should be on the radar screen of all transplant pharmacists, he said: patient confusion over branded versus generic formulations of transplant medicines. This has become an issue with the recent approvals of generic tacrolimus and mycophenolate mofetil. “Sometimes patients will go to their community pharmacy, and because of insurance issues, they may be required to take a generic. Well, patients may not be aware that tacrolimus is the same as Prograf [Astellas], and mycophenolate mofetil is the same as CellCept [Roche], so there’s a risk that they will double up on their medications.” Currently, there is only one manufacturer of generic tacrolimus, but there


Clinical 21

Pharmacy Practice News • December 2009

Transplant Pharmacy are at least six makers of mycophenolate mofetil, “so the potential for confusion here is not something to overlook.” He added that although “we haven’t seen this occur yet, because these generic formulations have only been around for a few months, it’s been a problem with the other transplant-related drugs and will be an issue with the immunosuppressives as time goes on if you don’t educate patients about this.” Dr. Marfo and his colleagues have developed several strategies for avoiding such problems. “When we counsel patients, one of the things we tell them is that if you go to the pharmacy and there is ever a change in the color of your meds, you have to ask to speak with the pharmacist or call us first before

taking it,” he said. “That can avoid a lot of problems.” His team also counsels patients to obtain their medications from independent pharmacies that have expertise dealing with transplant medicines. “We’ve asked these pharmacies not to switch patients to generics without telling us. This way, we can prepare the patients and make sure they understand what they’re getting and how to take it safety.” About once a month, Dr. Marfo added, he visits the retail pharmacies in his community that service transplant

patients and asks for a list of patients who are being dispensed generic drugs. “It’s a great counseling tool,” he said. (For other counseling tips, see sidebar.)

A Lasting Contribution Dr. Smith said the practice of organ transplant pharmacy is rewarding on several fronts. One of its major attractions, he noted, is the ability to help patients at every stage of therapy. “I’ve had residents who counseled patients when they were first admitted to the hospital, helped care for them throughout their hospital stay, and then

provided detailed discharge counseling,” he said. “Months later, if any of these patients get readmitted—and trust me, many of them will come back to your clinic with complications—you have pharmacists in place who know them and can drop right back into providing a high level of clinical care.” That continuity of care “is something that the pharmacy profession has been striving to provide,” Dr. Smith said. “It doesn’t really happen in many practice settings, but when it does, it is a beautiful thing to see.” —David Bronstein

Patient Counseling Tips Don’t overlook food-drug interactions. Something as simple as grapefruit juice, for example, can interfere with the absorption of tacrolimus and cause problems, Dr. Marfo noted. Focus on side effects. Many transplant drugs cause significant side effects that can lead to noncompliance. Certain forms of cyclosporine, for example, can cause gingival hyperplasia, which is an overgrowth of gum tissue. In females, the drug can cause an overgrowth of facial hair. “These side effects are both especially troubling to younger patients, because they raise cosmetic issues,” Dr. Marfo said. “You need to work with the patients and parents to make sure these side effects don’t become reasons not to take their medications.” Stress the dangers of nonadherence. Many patients only come into the clinic once a month, Dr. Marfo said. “They may miss a dose for three weeks before you see them,” he said. “Then you do blood work, their creatinine has gone from 1.0 to 4 or 5, you suspect rejection, do a biopsy, and lo and behold, they’ve rejected their organ. It could really happen that quickly.” Warning patients about such outcomes, he said, can help boost compliance. Document discharge counseling. At discharge, pharmacists have “a wonderful opportunity” to counsel patients and family members about how to manage their medications and disease long after they leave the hospital, Dr. Smith said. But the counseling also has a compliance benefit. “CMS surveyors will look for documentation in the medical record that a pharmacist was an integral part of developing the discharge plan for your transplant patients.” —D. B.

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22 Policy

Pharmacy Practice News • December 2009

Spotlight on: Generics

P

harmacy Practice News introduces the “Spotlight On” feature, which will cover innovations in clinical care and hospital pharmacy operations. This first installment focuses on generic drugs and features a look at how a new purchasing program offered by Premier Inc., can help hospitals maximize savings and patient safety. Also on tap is a roundup of legislation affecting the availability of “biosimilars,” or generic biologic agents (page 24), and an inside look at generic drug purchasing at the Cleveland Clinic (page 25).

New Initiatives From Premier Focus on Cost, Safety P

harmacy directors know that group purchasing organizations (GPOs), like Premier Inc., negotiate better savings for member hospitals than practically any individual facility or even health system could get on its own. Indeed, pharmacy experts could name only one institution—Duke University Hospital—that even tries the do-it-yourself approach. With regard to generic drug pur-

chasing—just one of many services that GPOs provide—the volumes they represent are powerful hammers for wringing costs out of the supply chain. For example, Premier’s most recent generic bid effort produced 36-month contracts for 10,500 different drugs priced to deliver an average savings of 2.8% over the previous 36-month contracts—savings valued at $60 million to

‘For the vast majority of generics, it’s not an issue to switch manufacturers. However, with narrow therapeutic index drugs such as phenytoin, we have to make sure drugs are therapeutically equivalent when changing brands.’ —Fred Pane, RPh

The Role of GPOs

T

o clarify for pharmacists who haven’t been involved in drug acquisition, a GPO negotiates low prices for member hospital and health-system pharmacies, with member input. The GPO then turns that master agreement price list over to the nation’s wholesalers, which stock the contracted items for their pharmacy members and distribute to them. A pharmacy buyer accesses his wholesaler’s system and enters the drug name. The GPO-contracted drug usually pops up first. The buyer selects it, orders the necessary quantity and receives daily invoices for what is ordered. GPOs save a collective $6.8 billion annually on hospital pharmaceuticals, according to a study, The Value of Group Purchasing 2009: Meeting the Needs for Strategic Savings, by Eugene S. Schneller, PhD, principal, Health Care Sector Advances, Inc. The average hospital purchases 88% of its pharmaceuticals through a GPO, saving as much as 15% over what its own contracting would yield, the study found.

Innovations From Other GPOs

B

etween 96% and 98% of U.S. hospitals use GPO contracts for their purchasing functions—and GPOs range widely in their size and ownership and the services they offer to members, said the Health Industry Group Purchasing Association (HIGPA). The innovations they bring suit the needs of their memberships. A few examples follow: • Novation recently launched two distinct portfolios—one tailored to academic medical centers and the other to medical research departments. • Broadlane enhanced its BroadLink reporting suite to provide spending analytics based on up to 75% of a member’s purchase order transactions in real time. • MedAssets introduced Service Line Analytics that enables hospitals and health systems to compare their purchasing and performance with facilities that have a similar patient mix, and more. The GPO launched a separate program that helps hospitals develop defensible pricing strategies.

$70 million per year for its 2,200-member U.S. hospitals and more than 63,000 members from other health care sites. The new contracts run from July 1, 2009 to June 30, 2012. “In a year when prices are expected to increase by nearly 6%, these savings are urgently needed by hospitals struggling every day with a troubling economic outlook and declining reimbursements,” said Mike Alkire, president, Premier Purchasing Partners, LP.

Quality, Supply Outrank Price In Bidder Evaluation Yet Premier’s negotiation and bidder selection process involves more than low price. To be a winning single-, dual- or multiple-source bidder requires a nearly spotless record when it comes to drug quality, consistent supply and good manufacturing practices, according to Fred Pane, RPh, BSP, FASHP, senior director of pharmacy affairs at Premier Inc. Mr. Pane said that bidders are evaluated on several criteria. For example, has the company had any major recalls? If so, why? Any 483 (FDA inspection) reports? If the company ever failed to supply product, what were the reasons? Who owns the active ingredient? (It may be the manufacturer, or a supplier to the manufacturer.) Due diligence with respect to bidders and their suppliers narrows the list of candidates. Because some bidders seek to bundle 20 or so products together rather than offer single-line items, Premier Inc. runs utilization reports on specific medications and dosage sizes. This reveals what members actually use and pinpoints the most important products in a bid bundle. “A small community hospital might want a 10-mL size that’s ready to dispense, but a larger facility might prefer a bulk vial they can break down into individual doses,” Mr. Pane said. Premier Inc. also expanded its generic auto-substitution program to 350 injectable pharmaceutical products, giving an average added savings of at least 10% off Premier Inc.’s contract pricing. Under such a program, “for the vast majority of generics, it’s not an issue to switch manufacturers,” Mr. Pane said. “However, with narrow therapeutic index drugs such as phenytoin, we have to make sure drugs

are therapeutically equivalent when changing brands.”

New Tools Maximize Patient Safety, Member Savings In what it claims to be an industry first, Premier Inc. has designed a Scorecard Safety Tool that addresses core measures of patient safety, with product identifiers that instantly show: • Whether or not the manufacturer barcodes its medications, for hospitals that have bedside bar coding. Premier Inc. belongs to a GS1 subcommittee aiming to develop internationally standardized bar codes for medications. Hoping this will be achieved by 2011, Mr. Pane says the goal is “to develop an international pedigree, with end-toend tracing from country of origin to patient use.”; • If vaccines are free of thimerosal (a mercury-based preservative); • If an injectable is latex-free (due to

see INITIATIVES, page 24

NEW “Spotlight On” Sections

T

his new feature focuses on key clinical and operational aspects of hospital pharmacy practice. Each “Spotlight On” section includes: • Q&A with a key opinion leader • Meeting coverage, other late-breaking research news • Exclusive reader surveys • And more

2010 TOPICS • • • • • •

Cardiology Critical Care Hem/Onc Pharmacy Pharmacy Automation Blood Factors Generic Drugs


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24 Policy

Pharmacy Practice News • December 2009

Spotlight on: Generics

Bioengineered Generics Grind On L Table. Biosimilars Legislation At a Glance egislation is pending in Congress to create a regulatory pathway by which FDA could approve the marketing of follow-on biologic drugs, also called “generic biologics” or “biosimilars” (Table). Biologic drugs can be pricey: A year’s treatment of trastuzumab (Herceptin, Genentech) can cost $48,000 while imiglucerase (Cerezyme, Genzyme) can run $300,000. Although no one opposes the concept of making biologic drugs generic, battle lines have been drawn around marketing exclusivity—how long brandname drugs can be sold before generic competition is permitted. Health reform legislation (HR 3962), narrowly approved by the House of Representatives on Nov. 7, would grant innovator manufacturers 12 years of marketing exclusivity with an additional six months for pediatric applications. Brand-name manufacturers, patient groups and most lawmakers favor 12-year exclusivity, whereas generic drug makers, insurers and pharmacy benefit managers are pressing for five years. Anything more, they argue, and the whole idea should be scuttled. In the Senate, nearly identical provisions are included in the draft health reform bill (substitute to HR 3590) unveiled Nov. 18 by Sen. Majority Leader Harry Reid (D-Nev.). Similar provisions are also included in the reform bill passed in July by the Committee on Health, Education, Labor, and Pensions, but not in legislation (S 1796) approved by the Senate Finance Committee in October. As of press time, the timetable for full Senate consideration was uncertain due to the contentiousness of overall health care reform, and the matter may be put off until 2010. Finally, any differences between the House and Senate versions would need to be ironed out before a final bill can be sent to the White House. —Ted Agres

INITIATIVES continued from page 22

concerns about allergies); • If a medication is sugar-free (for patients with diabetes); and • If a medication is alcohol-free. In addition, Premier Inc. launched an Impact Analytics Tool in tandem with the generic bid roll, so members could easily validate their actual savings with the new contracts. A pediatric hospital versus a trauma center, for instance, has a different medication mix and different opportunities to save. Users conform the dashboard tool to their own relevant criteria, and compare new versus old contract prices; they multiply by units to

Favored Legislation

Who Supports It

Defining Quotes

12+ Years Exclusivity

“[A] base 12 years of data exclusivity, as proBrand-name drug manufacturers; vided in the House and Senate language, is Biotechnology Industry Organization critical to ensure the development of the (BIO); Pharmaceutical Research and next generation of therapies for patients, Manufacturers of America (PhRMA); lower costs for consumers, and continued job National Health Council; 50 patient advocacy groups including Alzheimer’s creation within the biotech industry.” Foundation, American Cancer —Biotechnology Industry Organization (BIO) Society and National Kidney Foundation; enough bipartisan lawmakers to pass the 12+ year legislation.

5 Years Exclusivity

“Reasonable exclusivity period means not Generic drug manufacturers; Generic granting innovator products unprecedented Pharmaceutical Association (GPhA); and unwarranted periods of market and Pharmaceutical Care Management data exclusivity, which serve only to extend Association; Coalition for a Competimonopolies by delaying competition from tive Pharmaceutical Market; pharmabiogenerics.” cies, health plans, pharmacy benefit managers, Aetna, CVS, Express Scripts. —Generic Pharmaceutical Association (GPhA)

7 Years Compromise

Obama administration

Financial Impacta

“Lengthy periods of exclusivity will harm patients by diminishing innovation and unnecessarily delaying access to affordable drugs.” Seven years exclusivity represents a “generous compromise.” —Nancy-Ann DeParle, Director of the Office of Health Reform, and Peter Orszag, director of the Office of Management and Budget in a June 24, 2009 letter to Rep. Henry Waxman (D-Calif.)

12 to 14 Years is too Long, But Prices Will Not Drop Regardless of What Happens

The Federal Trade Commission (FTC), which in a June 2009 report said follow-on biologic (FOB) competition is likely to resemble competition between competing brand-name products due to the high cost of developing biogenerics.

“[T]he 12- to 14-year regulatory exclusivity period is too long to promote innovation.” FOB “entrants are unlikely to introduce their drugs at discounts larger than between 10% and 30% of the pioneer product’s price.” Pioneer manufacturers are likely to “offer competitive discounts to maintain 70% to 90% of their market share and will continue to reap substantial profits, even after FOB entry.” —“Follow-On Biologic Drug Competition,” FTC report, June 10, 2009

a

A “thumbs up” symbol indicates that cost savings are likely to result from the legislation; “thumbs down” indicates drug expenditures will increase.

see the full net impact on savings. The tool is integrated with PharmacySpend, Premier’s program that members use to select purchasing tiers, view conversions/ generic equivalents, and evaluate performance programs and rebate offers. Premier Inc. is developing a marketshare savings maximization tool, which could be released this winter. “Members should constantly review that they are maximizing best-price opportunities on specific items they use. They may need to put an item through the [Pharmacy & Therapeutics] Committee in order to qualify for the deepest available contract savings,” added Mr. Pane. “This tool will help them identify savings more readily.” —Al Heller

GPO Resources Novation, Irving, Texas, serves 25,000 members and affiliates of VHA Inc. and the University HealthSystem Consortium (UHC), and more than 20,000 Provista members. http://www.novationco.com Broadlane, Dallas. http://www.broadlane.com MedAssets, Alpharetta, Ga. http://www.medassets.com AmeriNet Health Resource Services, Seattle. http://www.amerinet-hrs.com HealthTrust Purchasing Group, Brentwood, Tenn. http://www.healthtrustcorp.com Consorta, Schaumburg, Ill. http://www.consorta.com A Primer on Group Purchasing Organizations, from the Health Industry Group Purchasing Association (HIGPA). http://www.higpa.org/assets/1/workflow_ staging/AssetManager/230.PDF The Value of Group Purchasing 2009: Meeting the Needs for Strategic Savings, by Health Care Sector Advances, Inc. http://www.higpa.org/assets/ 1/workflow_staging/AssetManager/235.pdf


Policy 25

Pharmacy Practice News • December 2009

Spotlight on: Generics

5 Questions for the Cleveland Clinic F

or insights into how pharmacy departments approach generic drugs, Pharmacy Practice News interviewed David Kvancz, MS, RPh, FASHP, chief pharmacy officer, and two key members of his pharmacy team, Jeffrey Rosner, RPh, director, pharmacy contracting and purchasing, and Mandy Leonard, PharmD, RPh, BCPS, assistant director, Drug Information Center. Premier Inc. is Cleveland Clinic’s group purchasing organization (GPO), and Cardinal Distribution is its wholesaler.

Q

: How does today’s greater reliance on generic drug purchasing free up capital for hospitals and health systems? A: The use of generics has always been an important component in driving down costs. This is especially important with pending health care reform as we anticipate that third-party and government payers will pay us less for our combined services. This means we must identify every possible opportunity to switch from a branded medication to a generic, and we must execute conversion as quickly as possible. We monitor our compliance closely and we routinely achieve a 95% compliance rate on conversions across the entire health system within 30 to 45 days, where compliance is measured as not only using a generic, but also using the product from a manufacturer approved by our drug information and purchasing departments. At Cleveland Clinic, between 50% and 60% of our doses are multisourced generics, although they account for just 8% to 10% of the dollars spent.

Q

: How does collaboration help to maximize savings, patient safety and patient outcomes? A: Many hospitals and health systems are unable to commit the human resources that Cleveland Clinic has dedicated to

medication management review. Our clinical, finance and purchasing teams work closely to capitalize on opportunities to improve patient wellness first, while maximizing the fiscal strength of our health system. Our P&T [Pharmacy and Therapeutics] process is highly integrated; all clinicians review clinical implications and the financial side.

Q

: Do you have any clinical concerns about switching patients to generic narrow therapeutic index (NTI) drugs? A: We are always concerned with NTI medications, so we always start with the FDA’s bioequivalency ratings and search the professional literature to rule out any potential problems with bioavailability. In recent months, there have been more concerns expressed by professional organizations and others regarding the adequacy of the testing methodologies behind the FDA ratings for certain drugs or drug classes (e.g., antiepileptics). Our process is to scrutinize more closely the FDA’s testing requirements, to involve medical staff in generic brand selection decisions where such issues have been raised, and to make decisions regarding the use of specific manufacturer generic medications where these issues exist on a case-by-case basis. Broad, sweeping statements about the use of individual generic medications or within thera-

peutic categories without this type of individual product review process are a potential disservice to patients and to pharmaceutical science in general. The next significant opportunity for potential drug acquisition cost reductions with generic drugs will be the biosimilars. Several of these biological pharmaceutical agents are available in other countries, but not yet in the United States, as there is no FDA pathway for review and approval of these unique agents. There will be significant issues in determining equivalence between similar drugs that may contain different molecules, different active ingredient complexes and amounts, and different manufacturing processes—even though the clinical effect may be the same. As a result, there will need to be significant discussion at the federal and health-system levels regarding the true bioequivalency of these agents before the true value of these agents on both clinical use and cost reductions will be realized.

Q

: What is your due diligence with repect to generics suppliers? How do you protect against supply shortages? A: We get involved well before a manufacturer introduces a product. We meet with them to discuss products in their pipeline, as well as timelines, to get a sense of who will be players in

future markets. Because patent expiration dates of brands drive most generic launches, we create budgets based on the earliest time the generics would be available. Additionally, we monitor patent challenges and other legal issues to help sidestep any disruption from a possible product withdrawal. Additionally, we continually review all manufacturers for recall history, supply issues and FDA 483 inspection reports [issued by the agency after on-site inspections reveal manufacturing problems]. As for out-of-stocks and the inconsistency in product lines that follow, they definitely can create problems for practitioners and patients. In fact, we impose penalties if a manufacturer fails to supply product. In the case of marketplace shortages, we work closely with alternative suppliers to avoid any interruption in patient care. But we do a lot of up-front screening to avoid these types of issues. We also conduct site visits of API [Active Pharmaceutical Ingredient] suppliers and finished-product manufacturers when possible. When we learn a new generic is about to become available, we first examine the FDA’s therapeutic equivalency (Orange Book) for every dosage form. We also look into their suppliers of APIs. If we’re satisfied that there are no quality or service issues, we then look at cost.

Q

: Do you expect savings from a GPO’s generic bid roll process, when the organization puts all of its generic supply contracts up for bid at once and vendors compete for the business? A: Yes. We work very closely with our GPO as well as directly with manufacturers. —Compiled by Al Heller

FDA Studies Itself and Likes What It Sees Agency reaffirms its own methods for generic drug testing

A

cknowledging both the significant cost savings and ongoing controversies associated with generic drug substitution, the FDA has conducted a large analysis of generic drug bioequivalence and reaffirmed that its criteria for approval are appropriate and that generic drug formulations are therapeutically equivalent to their innovator counterparts. However, the study is not the last word on the safety of all drugs deemed bioequivalent by the FDA: Clinicians still must weigh carefully the risks and benefits associated with switching patients to generic versions of narrow

therapeutic index (NTI) drugs and other problematic medications, pharmacology experts stress.

Retrospective Analysis Scientists at the FDA’s Center for Drug Evaluation and Research (CDER) conducted a retrospective analysis of generic and innovator bioequivalence measures from 2,070 single-dose clinical studies of orally administered generic drugs approved from 1996 to 2007 (Ann Pharmacother 2009;43:15831597). In nearly 98% of the studies, the generic product plasma drug concen-

tration versus time curve (AUC) differed from that of the innovator product by less than 10% (mean ± SD of the geometric mean ratios was 1.00±0.06 for peak plasma concentration [Cmax] and 1.00±0.04 for AUC; average difference in Cmax and AUC between generic and innovator products was 4.35% and 3.56%, respectively). “The criteria used to evaluate generic drug bioequivalence studies support the FDA’s objective of approving generic drug formulations that are therapeutically equivalent to their innovator counterparts,” the researchers concluded.

Controversy, Cost Savings Use of generic drug products in the United States resulted in savings of $734 billion over the past decade, with $121 billion of these savings achieved in 2008 alone, according to the Generic Pharmaceutical Association, a trade association in Arlington, Va. Nevertheless, generic substitution remains controversial, especially for NTI drugs: • The American Academy of Neurology opposes generic substitution of anticonvulsant drugs for epilepsy without the attending physician’s

see FDA STUDIES, page 36


26 Policy

Pharmacy Practice News • December 2009

Ethics

GHOSTWRITING continued from page 1

pretty much every major pharmacy, medical and science journal, all of a sudden took a very strong stance and came up with their own policy to make certain that things like this were not going to happen,” he said. Soon after, the board at Pharmacotherapy (published by the American College of Clinical Pharmacy) created a revamped authorship policy, which went into effect in December 2008. The Pharmaceutical Research and Manufacturers of America (PhRMA) also has recently revised its principles on disclosure in clinical publishing; they went into effect this fall. The voluntary PhRMA principles cite their support of the authorship standards of the International Committee of Medical Journal Editors, including the disclosure of any ties—personal or financial—that might pose a conflict of interest. That includes the role of any company sponsors in designing, data collection or writing up the published results.

‘I can’t think of a time when [ghostwriting] ever would have been an accepted practice, even before the standards became more stringent.’ —Judi Jacobi, PharmD Underlying the recent discussion is a renewed focus regarding what constitutes authorship, along with strategies to better identify all of the hands and potential conflicts that touch a manuscript, according to clinicians interviewed by Pharmacy Practice News. Pharmacists must practice due diligence when evaluating research studies, review articles and other types of journal articles, said Cathy Rosenbaum, PharmD, MBA, RPh, a clinical effectiveness and safety officer at Bethesda North Hospital in Cincinnati. But there also should be inherent trust and transparency in the process itself, said Dr. Rosenbaum, who also is an editorial board member of Pharmacy Practice News. “I feel that there is, in research, a real need to eliminate as much variability as possible,” Dr. Rosenbaum said. “And I think accurate writing is a pivotal part of that element. It’s not just the design of the model that matters, but it’s all the collective hands and minds that touch the presentation of the results.” In addition to the variation in how authorship has been defined, there is

variation among journals with respect to disclosure practices, according to another JAMA study published last month (2009;302:2230-2234). The study, which scrutinized the policies posted online in 2008 for 256 medical journals, found that 89% included language requesting the disclosure of conflicts of interest. But only 54% of the journals evaluated required that each author involved sign a conflict-ofinterest statement. The questions asked in these statements were most likely to focus on direct financial relationships; more than 80%

of the journals asked about related stock investments or consultancies. Fewer of the journals asked about personal relationships (42%), paid expert testimony (42%) or travel grants (12%).

Revealing the Ghosts Regardless of the policy involved, transparency ultimately relies on the author’s integrity, said Arthur G. Lipman, PharmD, FASHP, professor of pharmacotherapy and anesthesiology at the University of Utah, Salt Lake City. Dr. Lipman, editor of the Journal of Pain & Palliative Care Pharmacotherapy, said he believes that

“99.5 percent of people are honest and appropriate. But frankly, I have a couple of colleagues who are very good people who I know have allowed papers to be published under their names that were almost exclusively written by outside editors.” At his own journal, authors are instructed to disclose any source of financial support along with the names of anyone involved with the manuscript’s preparation, he noted. The review articles are among the easiest to take apart, he said. “We’ve received numerous review articles that had a clear bias, in which the conclusions were not supported by the

The risks associated with cattle thrombin may stay with patients long after surgery

1

Patients with antibodies to cattle thrombin products should not be re-exposed due to the risk of developing postsurgical immune-mediated coagulopathy.22 In a recent clinical trial, 1 in 6 surgical patients with likely prior exposure to cattle thrombin had antibodies to cattle thrombin.33 Minimize these risks with RECOTHROM RECOTHROM, the only recombinant human thrombin, is 100% free 4,5 of cattle plasma and as effective as cattle thrombin.4,5 In a phase 3 study of RECOTHROM compared to cattle thrombin, adverse events were reported with similar frequency in both treatment groups, and no reported adverse events were considered causally related to antibody formation in either group. Limited data (n=6) exist regarding re-exposure to RECOTHROM.

Rethink your thrombin

Indication: RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. Important Safety Information: For topical use only—do not inject directly into the circulatory system. Potential risk of thrombosis if absorbed systemically. Do not use for the treatment of massive or brisk arterial bleeding or in patients with known

hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins. No speci¾c adverse events have been established as adverse reactions causally related to RECOTHROM administration. In a clinical study comparing RECOTHROM to bovine thrombin, adverse events were reported with similar frequency in both treatment groups. The most common event was incision site complication. Limited data (n=6) are available on repeat exposure to RECOTHROM.


Policy 27

Pharmacy Practice News • December 2009

Ethics [evidence provided]. We just rejected them based on the conclusions not being supported by the data.” It was unknown, Dr. Lipman added, whether the authors of the review articles were working with a vested interest. Similarly, original studies can be scrutinized for inconsistencies in the data or conclusions that aren’t supported, he said. But it’s more difficult, he added, to ferret out problems. “You have to assume the data are legitimate. There is no way to go back and check the source documents.” In its recent author policy up-

date, Pharmacotherapy more strictly defined the various guests and ghosts involved in manuscripts, including ghostwriting, ghostauthorship and guest authorship. It also has updated its conflict-of-interest policy several times in the last two years. Having an outside medical writer

Please see Brief Summary of full Prescribing Information on next page. References: References: 1. 1. Ness Ness P,P, Creer Creer M, M, Rodgers Rodgers GM, GM, et et al; al; the the Recognition, Recognition, Evaluation Evaluation and and Treatment Treatment of of Acquired Acquired Coagulopathy Coagulopathy Consensus Consensus (RETACC) (RETACC) Panel. Panel. Building Building an an immune-mediated immune-mediated coagulopathy coagulopathy consensus: consensus: early early recognition recognition and and evaluation evaluation to to enhance enhance post-surgical post-surgical patient patient safety. safety. Patient Patient Saf Saf Surg. Surg. 2009;3(1):8. 2009;3(1):8. 2. 2. Thrombin-JMI Thrombin-JMI [package [package insert]. insert]. Bristol, Bristol, TN: TN: King King Pharmaceuticals, Pharmaceuticals, Inc.; Inc.; 2007. 2007. 3. 3. Singla Singla NK, NK, Ballard Ballard JL, JL, Moneta Moneta G, G, Randleman Randleman CD CD Jr, Jr, Renkens Renkens KL, KL, Alexander Alexander WA. WA. AA phase phase 3b, 3b, open-label, open-label, single-group single-group immunogenicity immunogenicity and and safety safety study study of of topical topical recombinant recombinant thrombin thrombin inin surgical surgical hemostasis. hemostasis. JJ Am Am Coll Coll Surg. Surg. 2009;209(1):68-74. 2009;209(1):68-74. 4. 4. Chapman Chapman WC, WC, Singla Singla N, N, Genyk Genyk Y,Y, et et al. al. AA phase phase 3,3, randomized, randomized, double-blind double-blind comparative comparative study study of of the the ef¾ ef¾cacy cacy and and safety safety of of topical topical recombinant recombinant human human thrombin thrombin and and bovine bovine thrombin thrombin inin surgical surgical hemostasis. hemostasis. JJ Am Am Coll Coll Surg. Surg. 2007;205(2):256-265. 2007;205(2):256-265. 5. 5. RECOTHROM RECOTHROM [package [package insert]. insert]. Seattle, Seattle, WA: WA: ZymoGenetics, ZymoGenetics, Inc.; Inc.; 2009. 2009. RECOTHROM RECOTHROM isis aa registered registered trademark trademark of of ZymoGenetics, ZymoGenetics, Inc. Inc. ©2009 ©2009 ZymoGenetics, ZymoGenetics, Inc. Inc. All All rights rights reserved. reserved. RT264-00, RT264-00, July July 2009 2009

involved in preparation is not, in and of itself, problematic, Dr. Scheife said. H o w e v e r, t h a t individual should not be a ghost but rather should be listed as an author. That step not only reveals that writer’s involvement, he said, but also requires that, once the individual is identified as an author, they must disclose any related

To learn more, call 1-888-784-7662 or visit www.RECOTHROM.com

conflicts of interest. The line into the problematic “guest” authorship category is crossed when a “ghost” author creates the manuscript and then invites the “guest” author to put his or her name on it with little to no input, Dr. Scheife said. If they do so, “that can never be made right,” he said. Beyond updating its author policy, Pharmacotherapy’s board updated its conflictof-interest policy and revised it twice since, including this fall, when questions were added about any immediate family

see GHOSTWRITING, page 28


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION

28 Policy

Pharmacy Practice News • December 2009

®

RECOTHROM Thrombin, topical (Recombinant)

Ethics Rx Only The following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant). INDICATIONS AND USAGE RECOTHROM Thrombin, topical (Recombinant), is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. RECOTHROM may be used in conjunction with an absorbable gelatin sponge, USP. DOSAGE AND ADMINISTRATION For topical use only. DO NOT INJECT.

with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated. DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS Do not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding. any components of RECOTHROM, or hamster proteins. WARNINGS AND PRECAUTIONS Potential risk of thrombosis if absorbed systemically. potential for allergic reaction. ADVERSE REACTIONS

RECOTHROM to bovine thrombin,1 adverse events were reported with similar frequency in the two treatment groups, and the most common events reported were incision site complication, procedural pain, and nausea.

GHOSTWRITING continued from page 27

members who might pose a conflict, and about patent-related connections. The patent question asks about any patents— planned, pending or issued—either for products discussed in the manuscript itself or for a competing product.

Quality of Care at Risk For clinical practitioners, preserving the foundation of published research is of paramount importance, said Judi Jacobi, PharmD, FCCM, FCCP, BCPS. The critical care pharmacy specialist at Methodist Hospital/Clarian Health, Indianapolis, will become the president of the Society of Critical Care Medicine in January 2010. It’s “appalling” when clinicians submit an industry-designed and written paper as their own, she said. “I can’t think of a time when it ever would have been an accepted practice, even before the standards became more stringent,” said Dr. Jacobi, who is a member of the Pharmacy Practice News editorial advisory board. “We need unbiased information to make the best judgment for patient care, whether it’s for the patient in the bed in front of you or whether it is for a formulary decision for your organization.”

Dr. O’Donnell said. “If your reputation is tarnished and questioned, then the information you are presenting is damaged as well,” he said. To prevent relying on misleading papers and studies, the pharmacy department in every health care organization should have at least one clinician experienced in evaluating drug literature, Dr. Lipman said. Along with assessing the findings and searching for any inconsistencies, clinicians should pay attention to where the article was published, whether the journal was peer reviewed and any sponsorship connections or potential conflicts of interest, he said. In short, clinicians should be savvy enough “to smell a rat,” he said. Dr. Lipman echoed the sentiment of several other clinicians interviewed, who said the problem was not industry-sponsored research per se. “Some of the work that I’ve done that I’m very proud of and was published in firsttier journals were industry-sponsored projects,” he said. But the sponsor was clearly stated and the manuscript was his creation, Dr. Lipman said. “The bottom line is that whoever’s name is on the paper as the author is responsible for what’s there. And the author can’t turn around and blame it on the ghostwriter.”

When a ghost author creates a manuscript and then invites a guest author to put his or her name on it with little to no input, ‘that can never be made right.’ —Rick Scheife, PharmD

human thrombin. Antibodies against bovine thrombin product were not tested either group did not lead to any adverse events such as excessive bleeding.

To report SUSPECTED ADVERSE REACTIONS, contact ZymoGenetics, Inc. at 1-888-784-7662, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS

In some cases, such as when many people are involved in a paper, the line might become blurred in terms of who is actually doing the work and who is doing the writing, Dr. Jacobi said. But the stated author must have been significantly involved throughout the process, she said. “I never would have participated in a paper where I wasn’t doing the writing and involved in selecting the content.”

Legal Implications REFERENCES 1

Clinicians who misrepresent themselves, by claiming authorship when it isn’t warranted, also may face potential legal risks, according to James O’Donnell, PharmD, an associate professor of pharmacology at Chicago’s Rush University Medical Center, who has written several books about drug development and drug regulations. For example, what if the stated authorship of a prominent paper is sufficient to land a contract or a consultancy? That clinician could be legally vulnerable for misrepresenting his or her expertise,

Because ghostwriting is by definition hidden, it’s difficult to know how much of a problem it truly was, according to clinicians interviewed. But the heightened scrutiny can only benefit research publishing, including the clinicians who rely on it to make formulary and other decisions, they said. “I think there is more awareness and, in all candor, I think that the awareness is going up sky high,” Dr. Scheife said. “And because of that, the frequency of infractions is probably going down.” —Charlotte Huff

What’s Your View? Is it ever appropriate not to disclose that a ghostwriter helped prepare a scientific manuscript for publication or a slide deck for presentation? Send replies to

ppneditor@mcmahonmed.com


Policy 29

Pharmacy Practice News • December 2009

Joint Commission

MED MANAGEMENT continued from page 1

sions—specifically, changes in the 2010 requirements for medication-related NPSGs and aspects of the newly implemented anticoagulation NPSG.

Changes Due to the SII Project The SII project involved rewriting some of the standards for clarity, and as a result, surveyors reported that there were more requirements for improvement (RFIs) on their surveys. “This is because there are less bullets and more Elements of Performance, so therefore it is easier to become noncompliant with the standard,” Dr. Rich explained during the webinar, which was sponsored by Pharmacy OneSource (www.pharmacyonesource.com). The Joint Commission also has eliminated supplemental findings, and this has added to the increase in RFIs. “Anything that previously would have been a supplemental finding is now a requirement for improvement and something that you have to fix. So there are no more items appearing on your report as consultative and which you do not have to fix,” said Dr. Rich. Another change is the classification of standards and Elements of Performance based on whether their impact on patient care is “direct” or “indirect.” Pharmacists now have 45 days after the survey to respond to any direct impact standards that are scored, and 60 days to respond to indirect standards. “Only the direct impact standards count toward your accreditation decision. You could literally have a ton of indirect impact standards scored and still pass your survey, because it’s only the direct impact standard scores that affect accreditation,” said Dr. Rich. “In the first part of 2009, organizations are getting approximately three times the number of RFIs that they got previously. The number of direct impact standards, however, is much lower—anywhere from one-fourth to one-fifth of the total number of standards scored—so most people have not had their accreditation in jeopardy as easily or as closely as they have [had] in the past.” “Subtle” MM changes for 2009 include new recommendations for medication storage and a requirement that policies for self-administration of medications, managing investigational drugs, and responding to and notifying prescribers of adverse drug reactions and medication errors, must all now be in writing. “We now say that medication storage has to be per the manufacturers’ recommendations. If there are none, then it has to be according to pharmacist instructions. We used to say according

‘I’ve been in places where a receptionist, or even the clerk at the registration desk, is dispensing [oral contrast] agents, and yet the law doesn’t allow it. That can result in conditional accreditation, so you have got to make sure that whoever is dispensing oral contrast agents can do so.’ —Darryl S. Rich, PharmD

to proper temperature, humidity and so forth,” noted Dr. Rich. In contrast, a big change is MM.05.01.01.

This standard now requires that medication orders be reviewed for variations from hospital-approved indications. “We

require you to approve drugs to the formulary based on an approved indication for use,” Dr. Rich explained. “So you have to decide which are the approved indications for drugs on your formulary.” Another change is MM.05.01.07, which now requires a defined time frame for dispensing sterile medications.

Medication ‘Deemed Status’ No Longer Automatic The Joint Commission no longer enjoys automatic granting of “Deemed Status”— a standard applied to organizations seek-

see MED MANAGEMENT, page 30

Your Single Source Solution

®

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Pharmacy Practice News • December 2009

Joint Commission

MED MANAGEMENT continued from page 29

ing Medicare payments—and has to apply “like everybody else,” said Dr. Rich. As a result, Joint Commission standards must align more closely with Medicare Conditions of Participation, and will have to follow their interpretations. “Therefore, a lot of our standards related to sedation and restraints and so forth are going to more closely parallel them, and where they are more prescriptive than we have been in the past, we are going to have to be more

prescriptive and follow their interpretation,” he said. As a result of this change, the Joint Commission has integrated some issues that were in the Conditions of Participation into new Elements of Performance. Now, IV medications must be approved by medical staff rather than nursing or respiratory policy and procedure. Also, the institution must now report abuses or loss of controlled substances not only to the director, but to the CEO of the organization. “I’ve been on surveys where there is no mechanism in place to inform a CEO of a narcotics loss. This is a process that you are going to have to establish within your organization,” said Dr. Rich. “It’s probably not a bad idea to do that anyway because the chances are that various investigating agencies, like the Board of Pharmacy and State Department of Health, will show up once the loss is reported.” Another requirement is to report any medication errors and adverse drug reactions deemed to be significant and reportable to the attending physician as soon as the error is discovered.

Medication Storage: No. 1 on the Hit List Medication storage issues, especially security, topped the noncompliant standard list for 2009. Surveyors found that no action was taken when refrigerator temperatures went out of range, usually due to power outages. Nor was there a policy on medication handling after removal from floor stock until the medication was administered or returned. Dr. Rich said that the Joint Commission wants to stop scoring refrigerator temperatures. “I don’t think there is any hospital that can monitor all their refrigerators to make sure every one is working properly if they are using a manual system, and we don’t want to force people to use automated ones. So we really are trying to get away from scoring whether you actually record the temperature or not.” However, the Joint Commission does want someone in the pharmacy to evaluate whether the drugs can still be used, or whether they must be thrown out. “If the temperature is out of range for a very short period of time, you could call the manufacturer. If they tell you not to worry, then nothing has to be done. But if the refrigerator has been out for 24 hours and they say you have to throw out the drugs, then that’s what you have to do,” said Dr. Rich. [For tips on how to improve monitoring of cold-storage medications, see Pharmacy Practice News, June 2009, page 46.] Also new are updated requirements for

see MED MANAGEMENT, page 34


Q & A 31

Pharmacy Practice News • December 2009

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32 Policy

Pharmacy Practice News • December 2009 This article originally appeared on pharmacypracticenews.com

Q&A

ASHP Executive Team Looks to the Future Rosemont, Ill.—Tweeting at pharmacy conferences, convening a summit meeting to explore the future of the profession and creating a payment scale for the provision of clinical pharmacy services are among the initiatives that will gain varying degrees of traction in the coming year, executives of the American Society of Health-System Pharmacists (ASHP) said during an exclusive interview with Pharmacy Practice News. Sitting down with PPN during the ASHP Summer Meeting were Henri R. Manasse Jr., PhD, ScD, ASHP executive vice president and chief executive officer; Lynnae M. Mahaney, MBA, FASHP, incoming ASHP president and chief of pharmacy services at the William S. Middleton Memorial Veterans Hospital in Madison, Wis.; and Kevin J. Colgan, MA, FASHP, outgoing ASHP president and senior vice president of Health Economics and Outcomes Research at EPI-Q, Inc. in Oak Brook, Ill. (In the next issue, we’ll publish a Q&A from the Midyear Clinical Meeting, held last month.) PPN: The Pharmacy Practice Model Initiative (PPMI) is getting a lot of attention, with a summit meeting to discuss the concept planned. Why focus on this now? Dr. Manasse: It’s being driven, at least in part, by recent developments in health care, especially with respect to medication use, its increasing complexity and

Hilton Head conference, held by ASHP in 1985. That was a crucial meeting that brought together leaders in pharmacy who envisioned a future in which most health-system pharmacists would be focused on the direct care of patients. So what we’re now aiming for is Hilton Head II, if you will, where we bring together the stakeholders in the profession who can do a careful examination and a reality check of pharmacy practice, and from that, begin to envision a new future. PPN: Will the focus still be on clinically oriented pharmacy services? Dr. Manasse: Absolutely. During a PPMI advisory committee meeting, chaired by Dan Ashby, the pharmacy director at Johns Hopkins, [in Baltimore], it was made clear that pharmacists need to be prepared to be held more accountable, if not totally accountable, for the safety and effectiveness of medication therapy. That means using people in the workforce—for example, pharmacy technicians—who are best suited for drug dispensing, so we can tap into the clinical talents of our pharmacists every day and directly impact patient care. Once that happens on a more widespread basis, then we can begin to really assert ourselves in areas where pharmacy traditionally has not had great penetration, and where there are thus some real risks for medication errors. In radiology, for example, contrast

‘Pharmacists need to be prepared to be held more accountable, if not totally accountable, for the safety and effectiveness of medication therapy.’ —Henri R. Manasse Jr., PhD, ScD the increasing pressure for safety and quality at the institutional level. There now are policies in place, such as CMS’s [Centers for Medicare & Medicaid Services] decision not to reimburse hospitals for preventable medication errors, that put at least some of the responsibility for compliance directly with the pharmacist. Kevin Colgan’s leadership on this issue has led us to ask the questions: “Do we have the right practice model in our institutions to meet these challenges?” “Can we continue the evolution of the pharmacist as a clinically focused member of the health care team?” After discussing this at the executive and board levels, we decided that we needed something like the landmark

media agents often are administered without any pharmacist involvement. That’s becoming a practice area that we’re really concerned about in terms of the potential for medication errors, and it’s an area that needs a much better partnership between pharmacy and physicians. In terms of financial support for the initiative, we need to raise sufficient funds as quickly as we can, so that we can have a meeting that does justice to the legacy of the Hilton Head conference. Of course, it’s a very difficult climate in which to raise money, but one of our past presidents met [during the ASHP Summer Meeting] with our Foundation executive and myself,

and his strong feeling was that if we articulate this very clearly to our membership, they will give beyond what they normally would contribute—that is, in addition to membership dues—to make sure we could have this meeting. I found that very encouraging. PPN: Given that you’re asking ASHP members to have a financial stake in this, are you taking any measures to get those members involved in shaping the practice model? Dr. Manasse: We’ve spent a fair amount of time talking about that. We’ve already gotten many members engaged in the concept, but we want to keep that momentum going through social networking. After this [ASHP

than the future focus of their practice? Think about it: We are graduating PharmD students with advanced clinical skills and residency training. How do you think they want to practice? There’s really no question: They want practice models that challenge their clinical skills and enable them to use the knowledge they’ve gleaned during pharmacy school. Well, that won’t happen if we don’t keep evolving the profession to ensure that dispensing is not the primary practice model. The other key issue here is medication safety, which Henri touched on. The efficient, safe and effective use of medications is on every hospital administrator’s plate because of the cost associated with not meet-

‘We can’t deliver all of the clinical services we’re capable of, and, just as importantly, we can’t get paid for delivering those services, without [provider status].’ — Lynnae M. Mahaney, MBA, FASHP

Summer] meeting, we are going to launch some major initiatives in the social networking space, such as Twitter, Facebook and LinkedIn, with the goal of continuing to seek membership feedback on what the future practice model should be. And at the PPMI summit itself, what we’d like to do is have almost real-time communication with all of our members. So as the meeting is going on, if people want to tweet, for example, they can do so and we can send that information out to a much larger audience of pharmacists who are following the proceedings via Twitter. We also need to think about how we get our state societies engaged in dialogue at the local level, and how to get individual hospitals to contemplate moving this practice model into their strategic planning, because I think most institutions want to be thoughtful; they want to move into directions that are going to be better for patients and their profession. Social networking may be one part of our strategy for reaching out to those stakeholders. Mr. Colgan: What makes this social networking approach so powerful is that it’s a grassroots effort. In fact, it’s already happening, and we need to put some structure around it. The other benefit is that social networking is a very accepted communication tool for younger pharmacists, and for them, is there any other, more critical issue

ing that challenge. They want pharmacists in positions where they can impact the quality of patient care and drug therapy. I hear this from my colleagues all over the country: when they start a new service in a hospital, they want team-based, collaborative care, with a pharmacist on that team. So those pressures already are present at the grassroots level, and basically, we’re trying to put some structure behind it and help the profession move forward. PPN: What is the end goal for the PPMI white paper or similar document? A demonstration project? Dr. Manasse: Most of our effort is going to be focused on energizing our members and providing them with tools for revamping and improving their practice. Now, the typical diffusion curve for new concepts is likely going to occur. You’re going to get a small number of highly energized people who are going to get into this and really start moving, and then you’re going to have another group that’s going to take a while and then you’re going to have some real stragglers. So I think we’ve come to recognize that the vision isn’t going to be done in one year or two years. But my concern is that I don’t think we have another 20 years to play around with this, because the political pressures, payment pressures and patients’ pressures for safe care are just not going to wait.


Policy 33

Pharmacy Practice News • December 2009

Q&A PPN: Is the growing debate over health care reform also putting pressure on the pharmacy profession to redefine itself? Ms. Mahaney: Absolutely. The very first thing that comes to mind is provider status—we can’t deliver all of the clinical services we’re capable of, and, just as importantly, we can’t get paid for delivering those services—without it. Provider status is our legislative foot in the door to start building a framework for direct patient care services. It also can provide a basis for being accountable for quality and safety. It’s really the fast road to getting what we need. Mr. Colgan: I can’t agree more—we need provider status, and yes, we also need accountability for that status. I do believe pharmacists will step up and [accept] accountability, but they have to be recognized as providers first; that’s the key issue. Dr. Manasse: Our profession has always taken its social responsibilities very, very seriously, and we have a history of being willing and able to provide patient care services in the absence of getting reimbursed. As a result, hospitals actually are financing pharmacists’ positions because they need that skill base, even though there’s no service revenue coming to the hospital. Yes, they’re getting margins on products, but they’re not getting reimbursed for all of the clinical services rendered. That has to change, because there’s all kinds of published studies showing both the clinical and economic benefits of investing in pharmacists. The key here is to build a financing infrastructure, and that starts with an enablement in law—that is, establishing provider status for pharmacists. But that battle is not going to be won only by getting pharmacists inserted in the public health law. The next important initiative is to create a financing mechanism for getting pharmacists paid. It might be a relative value scale, similar to the scale set each year for physician payments. Or it could be some mechanism by which you grade the levels of services provided and then you drive a financing scheme [based on clinical outcomes]. You also need an appropriation, so this is going to be a long slog. The grants that are being included in the Senate Health, Education, Labor and Pensions Committee, for example, those recommendations will all provide us with the steam that’s going to be necessary for moving the law forward on this. If I were king, and we could just sprinkle stardust on all of this, I would put the financing mechanism in place right now, because we know how serious these issues are and how important reimbursement is. Mr. Colgan: There’s another reason why we need to strengthen our posi-

tion on the health care team: There aren’t enough primary care providers in this country. Too many physicians are specializing, and it’s a concern that I have heard voiced by many physicians in leadership positions. If you’re going to solve the problem of access to affordable primary health care, you’re going to have to turn to alternative providers. Well, here we are! Pharmacists are natural extensions of primary care position services. But if we don’t step up to the plate and fill this need, someone else will, and we will have lost a golden opportunity to enhance our professional standing and improve access to high-quality, affordable patient care. PPN: I assume this is part of the message that you convey when meeting with legislators who have a stake in health care. Are they responsive?

where you have to work through some initial roadblocks. The first I encountered was during a meeting with William Turner, who was a Robert Wood Johnson Health Policy Fellow working in the office of then-Sen. Barack Obama. I began talking about the value of pharmacists, and Dr. Turner’s first response was, “You’re not talking about the pharmacists at CVS and the chains, are you?” That’s a fairly common hurdle we have to overcome— the perception that we’re primarily a dispensing-based profession. Once we articulate what happens in the hospital, then they begin to understand that pharmacy practice is often at a much higher level and they see our value to the health care team. But perception isn’t our only challenge. We also have to look at the credentials associated with the individuals who provide clinical services, and that’s why, if you look at our policy

‘Once we articulate what happens in the hospital, then [legislators] begin to understand that pharmacy practice is often at a much higher level [than dispensing] and they see our value to the health care team.’ —Kevin J. Colgan, MA, FASHP Dr. Manasse: They do respond. It takes a while to tell the story because if you think about it in the big scheme, drugs account for only 10% of health care expenditures, and the bigger financial issues often relate to the cost of building hospitals and financing equipment. But once we begin to chat about the challenges of medication management, they begin to listen. We stress how many drugs patients are taking, what the proportion of the population is that gets admitted to emergency rooms because of problems with those medications, or the increase in length of stay when you’ve had a poor response to poorly managed drug therapy, whether it be problems with medications or the problems with adherence—remember, 50% of people never even fill their prescriptions. And when we get them to focus on the downstream financial impact of those poor outcomes, then they begin to get the picture. That’s why our major legislative focus has been strictly on education. Once we convey our message, we get traction. In fact, I’ve never had any conversations in Washington where this approach did not work. Mr. Colgan: There are instances

statements, we are in favor of a credentialing process, a privileging process, for pharmacists to provide a high level of clinical care. Ms. Mahaney: I would echo the importance of credentialing as a way to really underscore the expertise of pharmacists. Health-system pharmacists need to start building a framework for what the credentialing requirements are for the various types of clinical services that we provide. My easy example is always the anticoagulation pharmacist. This is a highly complex area of care, with narrow therapeutic index drugs and other difficult-tomanage aspects of patient care. Studies have shown that when pharmacists play an integral role in anticoagulation therapy management, both clinical and economic benefits result. But are we doing enough to delineate the training and credentialing requirements for pharmacists who provide those types of services? Certainly, you need the letters behind your name or the training you had in order to provide those services in a hospital, so that’s the first step that we need to take. The other important component is addressing an individual

pharmacist’s accountability for quality and safety—there’s probably more we can do to delineate how we are going to encourage and maintain accountability. PPN: What is the best way of accomplishing those goals? Ms. Mahaney: An important step is to get our membership to acknowledge their personal responsibility. That can be accomplished primarily through education. You can’t force the issue, but if we’re going to continue to push for provider status, then we are going to have to be accountable for what we do, and both of those goals go hand in hand. In my personal practice, I’m fortunate enough to work in a VA [Veteran’s Affairs] hospital, and it’s one of the best places to practice pharmacy in the world because we have such autonomy and accountability. Of course, it helps that we are not constrained by state law. PPN: What other goals or initiatives will you be focusing on as ASHP president? Ms. Mahaney: I’d like to open up the world of possibility to our members, in terms of providing high-quality and cost-effective patient care because we really can do it; this is not just theory. In fact, when we talk about the [PPMI], it’s important to remember that we already have wonderful demonstration projects in place, showing that hospital pharmacists can make a huge difference when they’re an integral part of the health care team. So we don’t have to reinvent the wheel, but we do have to increase awareness that these initiatives are out there, they’re successful and they should be encouraged to spread. If I can help accomplish that during my presidency, that is something I could take away from my experience and really be proud. PPN: Kevin, what were some highlights for you as outgoing ASHP president? Mr. Colgan: I would point to the fact that we have been able to work with the other pharmacy organizations to get some consensus on pharmacy technicians. ACCP [American College of Clinical Pharmacy], for example, is about ready to release a paper with guidelines on technician education, training and certification, how that’s done, how those tests are put together, and so on. Second, they are going to work next on harmonizing the PharmD degree with residency training and board certification. We started that dialogue in the fall, so to be able to collaborate with other organizations and get movement behind two major issues in pharmacy—that would be the highlight of my year.


34 Policy

Pharmacy Practice News • December 2009

Joint Commission

MED MANAGEMENT continued from page 30

a proper expiration date for all drugs, as well as a policy for medication handling. “The expiration date must be on all stored products, and it has to be the correct expiration date,” Dr. Rich explained. “You cannot use the date opened; the standard says it has to be the last date the product [can] be used, sometimes called the beyond use date. This has to be on the label.” The commission also took hospital staff to task for illegible handwriting. “We are

Failing to include all approved anticoagulants in a hospital’s compliance efforts ‘is, in my mind, doing a half-hearted job; hospitals are doing just what is needed to get accreditation, they’re not really out to give optimal care for patients.’ —Stuart T. Haines, PharmD seeing a lot of organizations that were being cited for failure to clarify unclear, illegible or incomplete orders. So you get an order that says morphine PRN

and there’s no clarification of that. Or it’s illegible. Those are the kinds of things that are going to be cited,” said Dr. Rich. He also warned that dispensing oral

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Introduction Coagulopathy may result in hemorrhagic disorders, thrombotic disorders, or abnormal laboratory coagulation parameters. Coagulopathy in the postoperative surgical patient may be associated with multiple underlying causes, such as anticoagulant and/or antiplatelet medications, various factor deficiencies, disseminated intravascular coagulation, and liver disease.1 Less commonly, immune-mediated coagulopathy (IMC) may result from the development of cross-reacting antibodies to naturally occurring coagulation factors

following patient exposure to nonhuman therapeutic proteins.2 Topical thrombin, derived from various sources, is commonly used during surgical procedures as an aid to hemostasis.3 However, bovine thrombin-containing preparations have been associated with IMC in some patients following exposure.4 Bovine thrombinassociated IMC appears to be related to the formation of antibodies to bovine thrombin (factor IIa) or bovine factor V (an impurity in bovine thrombin preparations) that cross-react with the corresponding native human coagulation factors, ultimately rendering the

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contrast agents to outpatients must be done by a qualified, licensed pharmacist or physician. “I’ve been in places where a receptionist, or even the clerk at the registration desk, is dispensing these agents, and yet the law doesn’t allow it. That can result in conditional accreditation, so you have got to make sure that whoever is dispensing oral contrast agents can do so.”

National Patient Safety Goals on Anticoagulation Management With so many patients being treated with anticoagulation therapy, it became imperative to create NPSGs for anticoagulation medication management. These drugs can be quite dangerous and the potential to cause harm for patients is huge if their use is not subjected to rigorous standards, according to experts. The only anticoagulant drugs included are warfarin, unfractionated heparin and low-molecular-weight heparins, but other anticoagulants may be added to the list in the future, Dr. Rich said. Stuart T. Haines, PharmD, BCPS, a professor at the University of Maryland School of Pharmacy, in Baltimore, stressed that other anticoagulants now on the market should be included in a pharmacy’s anticoagulation monitoring policies and procedures. “Excluding those is, in my mind, doing a half-hearted job; hospitals are doing just what is needed to get accreditation, they’re not really out to give optimal care for patients.” One new NPSG Element of Performance requires that all the care ordered for a patient must be based on best practices identified in the literature and be a medical staff protocol, not a pharmacy protocol. This can be in the form of standing orders, a critical pathway or a written protocol. “From a pharmacist’s perspective, it can’t be something that is just developed by the pharmacy department, but this does not mean that the pharmacists shouldn’t be involved in the development,” said Dr. Haines. “In fact, we’re often a critical element to help in the protocol’s development. But in the end it has to be approved and reviewed by the medical staff. I would say most hospitals already use this mechanism.” The requirement for notification of the dietary service when a patient is on anticoagulation therapy has been deleted from the NPSG. However, there still needs to be some policies and procedures in place to avoid food and drug interactions, said Dr. Haines. “Hospitals should not be putting patients on very restricted vitamin K diets. What you want is consistent vitamin K intake. Restricting vitamin K can end up being more harmful for patients because once they leave the hospital and go home, they often start


Policy 35

Pharmacy Practice News • December 2009

Joint Commission eating some vitamin K–rich foods; this can throw off their therapy. But we still must have policies and procedures in place to address this potential negative consequence.”

Patient Teaching Urged The Joint Commission also insists that patients on anticoagulation therapy be taught about their medication, and not simply asked if they want to be educated. This is a crucial point, said Sheila Wilhelm, PharmD, BCPS, clinical assistant professor of pharmacy practice at Wayne State University, in Detroit. “Often, when a patient is in the hospi-

come up quite often on pharmacy listservs. “Many institutions didn’t have

a system in place for educating their patients when they were inpatients,

and so there are a lot of questions about how we are doing this.” Dr. Haines added that it is important to record in patients’ charts that they have, indeed, been educated in their medication use. “Look for gaps in their knowledge. If there are none, I would document in the chart that the patient knows how to take the medication properly, understands potential adverse effects and what to do about them, and knows about potential drug interactions.” —Fran Lowry

‘From a pharmacist’s perspective, it can’t be something that is just developed by the pharmacy department, but this does not mean that the pharmacists shouldn’t be involved in the development.’ —Stuart T. Haines, PharmD, BCPS, tal, someone will come in and ask if they would like to be told about their anticoagulation and the patient says, ‘No, I think I understand.’ That’s not adequate. You need to actually provide the education,” she told Pharmacy Practice News. This is an issue that her institution has been addressing, using pharmacy students to educate patients who are being discharged about their anticoagulant use. “We found that we weren’t getting all those patients educated because of time constraints and staff constraints. We’ve put into place a new teaching service using our pharmacy students to make sure we capture these patients, and we have greatly increased the number of patients we are teaching.” Dr. Wilhelm said they are in the process of assessing how effective the teaching has been. She added that education issues

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36 Policy

Pharmacy Practice News • December 2009

Spotlight on: Generics

FDA STUDIES continued from page 25

approval, citing instances of breakthrough seizures and increased seizure frequency in patients who switched to generic antiepileptic drugs (Neurology 2008;71:525-530). • The American Society of Transplantation recommends that generic immunosuppressive medications be clearly labeled and distinguishable from innovator drugs, and that patients should be educated to inform their physicians of any switch to or

among generic alternatives (Am J Transplant 2002;3:1211-1215). • A retrospective analysis showed that when 975 Israeli patients were switched from Coumadin (warfarin sodium, Bristol-Myers Squibb) to generic warfarin sodium clathrate, higher doses of the generic formulation were needed to maintain previously stabilized international normalized ratio (INR) values in some patients (Clin Pharmacol Ther 2003;74:215-221). “There are a lot of case reports and other nonrandomized controlled trial

data out there suggesting a cause for concern. Case reports are useful for helping generate hypotheses, but are not useful to prove an association,” said Aaron S. Kesselheim, MD, JD, an instructor in medicine at Harvard Medical School and associate physician in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, in Boston. “That being said, if you have an NTI drug like an antiseizure medication or an antiarrhythmic medication with a very tenuous patient, you may wish to consider whether [it is appropriate] to

Now Available on CMEZone.com Emerging Parenteral Therapies for Multimodal Postoperative Analgesia To participate in this FREE CME/CE activity, log on to www.CMEZone.com and enter keyword “SR0953” Release Date: October 1, 2009

This activity expires on October 31, 2010

Faculty Eugene Viscusi, MD

Chair

Associate Professor Department of Anesthesiology Director, Acute Pain Management Services Jefferson Medical College Thomas Jefferson University Philadelphia, Pennsylvania

Keith Candiotti, MD Associate Professor of Anesthesiology, and Internal Medicine Vice Chairman for Clinical Research Chief, Division of Perioperative Medicine University of Miami Miami, Florida

Raymond Sinatra, MD Professor of Anesthesiology Director, Yale University Pain Service Yale-New Haven Hospital New Haven, Connecticut

Accreditation Statement

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Physician: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc. and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Pharmacist: AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. AKH Inc. approves this knowledgebased activity for 1.0 contact hour (0.1 CEU). UAN 077-999-09-048-H01-P.

This activity is intended for anesthesiologists, surgeons, pharmacists, and other clinicians involved in postoperative pain management.

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Jointly sponsored by AKH Inc. and Applied Clinical Education. Distributed via:

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‘If we see scientific evidence that there is a problem with a generic, we will take action.’ —FDA statement to Pharmacy Practice News switch that patient from a brand-name drug to a different brand-name drug or to a generic formulation. Every physician needs to make his or her own decision about it,” Dr. Kesselheim told Pharmacy Practice News. Brien Smith, MD, medical director of the Comprehensive Epilepsy Program at Henry Ford Hospital, in Detroit, was critical of the FDA’s bioequivalence criteria. “The FDA believes that therapeutically equivalent drug products can be substituted with the full expectation that both products will produce the same clinical response. This is an example of disconnect between physicians who manage epilepsy patients and federal regulators,” he told Pharmacy Practice News. “Many of these patients have a narrow therapeutic index and they have not experienced the same clinical response when switching to another formulation,” said Dr. Smith, who is also chair-elect of the Epilepsy Foundation’s professional advisory board. “There have been numerous publications now demonstrating these effects [Epilepsia 2006;48:464-469]. Of course, none of these are listed in this [FDA] publication.” After consulting with the study’s lead author, Barbara M. Davit, PhD, JD, acting director of FDA’s Division of Bioequivalence II, Office of Generic Drugs, CDER, the agency issued this statement to Pharmacy Practice News: “We would like to see ... not anecdotes from random patients, but actual data that show that the generics are not performing the way they performed in the bioequivalent study that we have on file. If we see scientific evidence that there is a problem with a generic, we will take action.” Dr. Kesselheim, who is lead author of a separate meta-analysis that found no clinical or safety superiority for brandname cardiovascular drugs compared with generics (JAMA 2008;300:25142526), said it was important that the FDA demonstrate its procedures are working. “I hope it will help make patients and physicians more comfortable with prescribing generic drugs because in nearly every case, it’s appropriate and improves adherence to medications by lowering costs.” —Ted Agres

To participate in this FREE CME/CE activity, log on to www.CMEZone.com and enter keyword “SR0953”


Pharmacy Practice News • December 2009

Policy 37

Research

COMPARATIVE continued from page 1

American Gastroenterological Association Institute, and clinical associate professor of medicine, University of Minnesota, Minneapolis, noted that most people are “on board” with the concept of evidence-based medicine. “But I think skepticism comes from the fact that it’s an extraordinarily complicated and costly proposition to arrive at evidence-based medicine in general, and to arrive at decisions about every area of medicine at once will compound the complexity and cost to an unobtainable level,” Dr. Allen said. “We’re concerned that this is going to be superficial and not reflect the complexity of real-world patient care. We’re also concerned that comparative effectiveness analysis will lead to decisions that might restrict choices for patient care and development of new technologies and treatments.” Douglas Blayney, MD, president of the American Society of Clinical Oncology (ASCO), in Alexandria, Va., expressed a similar view. “I think that it is valuable to call attention to the fact that comparative effectiveness research is important for doctors’ and patients’ decision making,” Dr. Blayney said in an interview with Pharmacy Practice News. “But, in general, ASCO also wants to have the decision making remain in the hands of physicians and patients.”

The Top 100 The CER initiative is part of the rolling out of the American Recovery and Reinvestment Act of 2009. The legislation, signed into law on Feb. 17 by President Barack Obama, allocated $400 million to the Office of the Secretary of the Department of Health and Human Services (HHS), $400 million to the National Institutes of Health (NIH) and $300 million to the Agency for Healthcare Research and Quality (AHRQ). The law also called for the creation of the Federal Coordinating Council for Comparative Effectiveness Research, whose objectives are outlined in a June 30 report to the president and Congress (available at www.hhs.gov/recovery/programs/cer/cerannualrpt.pdf ). The council’s report sketched out a framework for arriving at priorities for research, investment of human and scientific capital, assembly of data and infrastructure, and dissemination and translation of CER. Additionally, the American Recovery and Reinvestment Act of 2009 called for the Institute of Medicine (IOM) to form a committee to recommend

priorities for the funding of CER. The IOM solicited input from the public, health care professionals and medical organizations before voting on the results and recommending 100 priorities for CER (available at www.iom. edu/CMS/3809/63608/71025.aspx). “The report is meant to address the fear that if one treatment comes out ahead, the other treatments will be denied,” remarked Sheldon Greenfield, MD, professor of medicine at University of California, Irvine, and cochair of the IOM committee that produced the report. “If one treatment is found to work well, and another treatment works only somewhat better, then both treatments will be available. CER isn’t about denying treatments, it’s about making sure all types of patients are appropriately treated.” AHRQ is expected to publish solicitations for research projects later this year, and funding will commence in spring 2010. The agency announced that it is suspending the appeals procedure for investigators applying for grants “due to the time sensitivity of the Recovery Act granting process.” At press time, neither the HHS nor the NIH had revealed when grant solicitations would be made or when funding will start to flow.

No dextran or modified dextran No test dose • No black box warning In pre-dialysis CKD anemia

trusted

for so many reasons

What Does This Mean for You? While the particulars of the grant solicitations are being worked out, there is little for clinicians across the country to do but wait. Gary Lyman, MD, MPH, examined oncology CER in the July issue of Cancer Investigation (2009;27:593-597). In the article, Dr. Lyman, who is editorin-chief of the journal, chair of four ASCO guidelines committees and a member of the FDA’s Oncology Drug Advisory Committee, laid out how systematic reviews, prospective clinical trials, longitudinal registries, comparative effectiveness simulations and clinical practice guidelines can deliver the apparent intent of the Obama initiative, which is to optimally inform clinical decisions. “But first, we have to carefully define what comparative effectiveness research is,” said Dr. Lyman, who is also professor of medicine and director of Health Services, Effectiveness and Outcome Research at Duke University School of Medicine, in Durham, N.C. “And second, he said, “let’s make sure there’s no hidden issues here. Let’s make sure there’s no subterfuge for rationing drugs, or for funding your research.” —Rosemary Frei, MSc

IMPORTANT SAFETY INFORMATION: Venofer® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.

Millions prescribed. Millions treated.

page 38. pages. Please see brief summary of full prescribing information on following Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

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VENFA2 Iss.8/2009


38 Operations & Management

Pharmacy Practice News • December 2009

Guest Editorial

White Bagging: A New Challenge for Your Hospital M While this new model, dubbed “white bagging,” is superior to the “brown bagging” model, it presents new and similar challenges for hospital pharmacists. In the more common “brown bag” model, a patient brings a medication, sometimes a self-administered medication, to the hospital or physician’s office to be administered. Private and state payers are continuing to expand the brown bag model, moving drugs from a medical benefit to a prescription

any payers are looking at the physician and hospital “buy and bill” model and looking to take cost out of the equation by purchasing drugs and sending them directly to the physician or hospital for administration to patients. Although some hospitals in states such as Florida that require drug “pedigrees” have been successful in blocking this process for the short term, many Premier member hospitals are encountering this new drug distribution/payer model.

Fred J. Pane, RPh, BS Pharm, FASHP Senior Director of Pharmacy Affairs Premier Inc.

Reference: 1. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856. 2. Data on file. American Regent, Inc., Shirley, NY.

(Table 2 continued)

Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection, USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer. See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®. Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Venofer® is excreted in milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established. Geriatric Use: The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition, over 2,000 patients treated with Venofer® have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDD-CKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0

Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term) Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia

NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 75.2 80.0 0.9

6.7

0

0

1.8 3.7 6.4 9.2 9.2 5.5

0 6.7 10.0 3.3 6.7 3.3

0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9

0 3.3 3.3 0 0 3.3 0 13.3 0

0 0.9 0 0 0.9

0 0 0 3.3 0

1.8

0

2.8 1.8

0 0

1.8 1.8 3.7 0.9

0 6.7 0 0

0.9 1.8 0 2.8

3.3 3.3 3.3 6.7

(Table 3 continued)

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

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified

2.2 0.7 3.6 4.3

3.6 0.7 0 0

6.5 2.9 0.7

1.4 0.7 0.7

2.2 3.6 2.2 1.4 0 0.7

0.7 0.7 0.7 2.2 0 2.2

2.2 1.4

4.3 2.2

6.5 2.2

4.3 0.7

NDD-CKD 200 mg 500 mg (N=109) (N=30) % %

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS

4.6

3.3

5.5 3.7

10.0 0

0.9 1.8 0

6.7 10.0 0

0.9

6.7

6.4 0.9

6.7 6.7

*NOS=Not otherwise specified

Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

NDD-CKD Adverse Events (Preferred Term) Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS

200 mg (N=109) % 23.9

500 mg (N=30) % 20.0

0 7.3 2.8

0 3.3 0

3.7 2.8 1.8

0 0 6.7

2.8 2.8

6.7 0

0

6.7

*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients In the pivotal study of 182 NDD-CKD patients, 91 were exposed to Venofer®. Adverse events, whether or not related to Venofer®, reported by 5% of the Venofer® exposed patients were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer® patient). Two patients experienced possible hypersensitivity/allergic reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer® group), three Venofer® patients had events that were considered drug-related (hypotension, dyspnea and nausea). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration. OVERDOSAGE leading to hemosiderosis. Periodic monitoring Dosages of Venofer® (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation, hypoactivity, pale eyes, and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin response and to replenish iron stores (ferritin, TSAT). Administration: Venofer® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer®, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS, Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL). Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F). [See the USP controlled room temperature]. Do not freeze. Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE: [1] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37: S182-S238, (suppl 1) 2001. BS2340 Rev. 10/08 Venofer® is manufactured under license from Vifor (International) Inc., Switzerland.

VENJA Rev 10/2008 © 2008 American Regent, Inc

benefit, and are requiring patients to either pick up their drugs at an in-network pharmacy or have them delivered to their homes from their specialty/ mail order pharmacy. However, most hospitals have a policy and procedure in place to not accept medications that come through the brown bag distribution model because of several downsides, including a lack of any mechanism to track supply chain integrity and pedigree of the drug. Moreover, there is some liability with having a hospital employee administer a medication that was not ordered by the normal hospital pharmacy supply chain, and in most cases, the hospital will not be reimbursed for compounding or administering the drug. White bagging addresses some of those issues. With white bagging, patients are being contacted directly by the insurance company through their pharmacy benefits manager or in-network pharmacy and asked where they would like to have their drug sent for administration. Because many of the drugs identified for white bagging are infusional, such as chemotherapy drugs, the insurance company asks if a physician’s office or hospital is where the patient wants the drug to be administered. The white bag model ensures more product integrity than the brown bag model, because medications can be sent directly from a licensed pharmacy to a licensed clinician (physician or hospital pharmacist), shipped at the correct temperature and tracked during shipping. If required, pedigree documentation may be sent with the drug. However, this model presents challenges for hospital pharmacies. One issue relates to storage. The hospital pharmacy would have to receive the medications for the patient and store them until the patient comes in for treatment. Hospital pharmacies would need to designate inventory space for “patient’s own medications,” separate from general hospital stock. In addition, hospitals would need to establish policies under which to administer “patient’s own medications” and would need to verify the white bag medications under that policy, prior to administration. There is also the question of liability with administering a “white bag” medication that was not purchased directly by the hospital. Many hospitals have developed policies, with input from their risk management/legal departments, to not administer medications not purchased through the hospital supply chain. If the hospital or health system owns physician office practices, a health system policy is in place and the physician offices also would not be allowed to accept the patient’s white


Operations & Management 39

Pharmacy Practice News • December 2009

Guest Editorial

With white bagging, patients are being contacted directly by the insurance company through their pharmacy benefits manager or in-network pharmacy and asked where they would like to have their drug sent for administration. month, up to 30% of their drugs came in from one payer via the white bag model; they addressed the issues with the payer and put a stop to it. In Pennsylvania and Massachusetts, hospitals have worked with their state hospital associations to bag medications, nor to compound or administer them. Another consideration relates to laboratory work that may be needed before administering a drug. This issue was exposed with the Centers for Medicare & Medicaid Services’ Competitive Acquisition Price (CAP) model. If the drug is sent to a physician office or hospital and the blood work indicates it is not appropriate to administer the drug—for example, white blood cell or platelet counts are low—what do you do with the chemotherapy that was sent for the patient? It is incumbent on hospital pharmacies to consider these practicalities because the white bagging model is likely to expand. Payers are offering this model to patients with a lesser copay under a prescription benefit than they would have to pay if they received the drug as a medical benefit based on the hospital charges or even a percentage of the average sale price model. If a patient is contacted directly by the payer and the payer tells the patient he or she will have a smaller out-of-pocket charge if it is administered as a prescription benefit, the patient will choose the lower out-of-pocket copay. Under the white bagging model, the drug administration model (physician office or hospital) would not change. I recently spoke with a neurologist who stated that intravenous immunoglobulin was being sent from a local plan’s specialty/infusion pharmacy to his office for him to administer to patients in the plan. In addition, a Premier hospital member reported that during one

What’s Your View? =?6;A

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Has your hospital had any experiences handling medications of incoming patients sent directly to your facility? Send replies to

ppneditor@mcmahonmed.com

petition against and address this model with private payers. Payer changes will affect the pharmacy drug budget and also hospital revenues. Hospital pharmacists and finance staff need to be actively engaged in

private payer contract negotiations and have frequent meetings with payers, quarterly if possible, to stay on top of changes and to discuss the best methods to provide optimal patient care (clinical and financial). Patient drug delivery changes, such as white bagging or brown bagging, need to be discussed as part of payer discussions. Payers need to be educated about the complexity of the hospital pharmacy drug distribution model and the need to comply with regulations and requirements of the state Department of Health, state boards of pharmacy and the Joint Commission.

®

Gelfoam + Human Thrombin In one kit. ®

®

Gelfoam Plus...

• Provides cost savings compared to items purchased separately1 • Offers additional savings opportunities with inclusion in the Baxter Value Incentive Program • Allows easy management of thrombin use • Helps consolidate inventory of multiple products And FLOSEAL [Hemostatic Matrix] are part of a complete hemostasis product line from Baxter. For more information please contact your local Baxter BioSurgery Representative or call 1-800-423-2090.

www.baxterbiosurgery.com GELFOAM PLUS Hemostasis Kit Indications GELFOAM PLUS is intended as a hemostatic device for surgical procedures when control of capillary, venous, and arteriolar bleeding by pressure, ligature, and other conventional procedures is either ineffective or impractical. Thrombin (Human) used without the Gelfoam Sterile Sponge is not indicated for hemostasis. Important Safety Information GELFOAM PLUS should not be used in closure of skin incisions, because it may interfere with the healing of the skin edges. GELFOAM PLUS should not be placed intravascularly, because of the risk of embolization. GELFOAM PLUS is not recommended for use other than an adjunct for hemostasis. GELFOAM PLUS contains thrombin, which is made from human plasma. It may carry the risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. While packing a cavity for hemostasis is sometimes surgically indicated, GELFOAM PLUS should not be used in this manner unless excess product not needed to maintain hemostasis is removed. Whenever possible, GELFOAM PLUS should be removed after use in laminectomy procedures and from foramina in bone, once hemostasis is achieved. This is because GELFOAM Plus may swell to its original size on absorbing fluids, and produce nerve damage by pressure within confined bony spaces. GELFOAM PLUS is not recommended in the presence of infection. There have been reports of fever associated with the use of Gelfoam Sterile Sponge, without demonstrable infection.

FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical. Important Safety Information FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result. Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges. Do not use FLOSEAL in patients with known allergies to materials of bovine origin. FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation. RX only: For safe and proper use of these devices, please refer to full device Instructions For Use. 1. 2006 IMS Hemostat and Sealant Revenue, Unit, and ASP Sales Data. Baxter, FLOSEAL and ADVANCING SURGERY,ENHANCING LIFE are trademarks of Baxter International Inc. Gelfoam is a registered trademark of Pharmacia & Upjohn Company LLC., used under license. BS1889 4/2008


40 Operations & Management

Pharmacy Practice News • December 2009

Communications

Open Body Language: Optimizing Your Nonverbal Communication

O

ur words convey what we are thinking, but our eye contact, gestures, facial expressions and tone of voice express what we are feeling in any given situation. Whether you are speaking in a clinical setting, delivering a formal presentation to a group of your peers or discussing medical findings with a patient, there may be a significant difference between what you say and how others hear you. This difference arises from how your nonverbal communication—your “body language”—is interpreted. Most people are largely unaware of how others view them and what messages their body language projects. The power of body language is illustrated by the emotional response it elicits from listeners. Feelings drive our reactions in virtually every situation, including when we are listening to someone present information. A listener’s interpretation of nonverbal cues can either strengthen or undermine the overall impact of the speaker’s information. The listener will receive mixed messages when the speaker’s gestures are not in alignment with verbal content. In an ideal world, we would be able to control every nonverbal message we transmit when speaking. Although this level of control may not be possible, increasing our understanding of the signs and signals we exhibit while speaking will strengthen our awareness of what we communicate to others. The best way to improve nonverbal communication is to learn open body language, which is characterized by four main components: direct eye focus, open body posture, open and purposeful hand gestures and a favorably expressive voice.

The key feature of open body language is eye contact. The ability to connect with the audience is enhanced if you slow the shift of your gaze to incorporate the time it takes to impart complete, discrete ideas. This technique helps regulate the flow of information. Slower-paced eye movement gives the audience an impression of confidence, interest, credibility and sincerity. Conversely, poor eye contact, such as scanning the audience or staring at only one spot, projects an image of nervousness, deception and tension. To provide a strong base for effective communication, adopt an overall open body posture. This communicates a

Part 1 of a 3-Part Series Be sure to watch for more articles on effective communication skills in future issues: PART 2: “Five Steps to Delivering an Effective Presentation” PART 3: “The Other Side of a Two-Way Street: Active Listening is Essential for Conversation”

Poor eye contact, such as scanning the audience or staring at only one spot, projects an image of nervousness, deception and tension. sense of authority while also projecting approachability, confidence and comfort. An open body posture features: • keeping movement away from the body’s vertical center line; • placing your feet hip-distance apart with your weight equally distributed; • keeping your hands open and down at your sides; • relaxing your shoulders; and • leaning forward slightly. The ability to connect with your listeners, capture their attention and facilitate their understanding strengthens with the use of open and purposeful hand gestures. Hand gestures act as a

visual aid that can demonstrate the size of an incision, the shape of a medical device or even the distance among stages of disease development; they also can subtly express emotion about the topic under discussion. Failure to use gestures gives the impression that you are stiff, uncomfortable and anxious. The qualities of your voice as you deliver your presentation also greatly affect how the audience perceives the spoken information. The sound and

timbre projected by your voice will convey how you feel about the information being shared. By controlling the speed, volume, tone, pitch and energy of your voice, you can alter the way the audience interprets and understands your messages. Regardless of whether the information being communicated is a complicated clinical discussion or a simple conversation, it is important to understand what nonverbal messages reveal. When our words have one meaning but our body language conveys another, our intended message suffers. By consciously using direct eye focus, open body posture, open and purposeful hand gestures and a favorably expressive voice to reinforce your words, you will increase the impact of your communication and decrease the likelihood of miscommunication. —Dalli Simmons Dalli Simmons, certified school psychologist, is a consultant at Exec|Comm LLC, a New York City-based communications consulting firm, where she coaches medical professionals, scientists and senior-level executives in a wide array of communication skills. She can be reached at dsimmons@exec-comm.com.

NEW PRODUCTS

Sotalol Hydrochloride Injection Introduced

B

ioniche Pharma and Academic Pharmaceuticals, Inc (API) announced that Sotalol Hydrochloride (HCl) Injection for intravenous use is now available. Sotalol hydrochloride tablets are available under the brand name Betapace (Bayer Schering Pharma). “Bioniche Pharma is very pleased to launch Sotalol HCl Injection,” said George Zorich, president, US Operations for Bioniche Pharma. “We partnered with API due to their knowledge of anti-arrhythmic treatment options and patient needs. This product expands Bioniche Pharma’s growing portfolio of branded products and demonstrates our commitment to aggressively expanding

our product line.” Sotalol HCl Injection has a black box warning relating to life-threatening proarrhythmia. Please refer to the Bioniche Pharma Web site for the complete prescribing information, including the boxed warning. For more information, visit www.bionichepharmausa.com

Medi-Dose, Inc. Announces New Label for ‘PCA by Proxy’ Errors

T

he Joint Commission has issued a warning regarding the administration of patient-controlled analgesia (PCA) medication by those other than the patient or authorized health care professionals. As stated in a recent Sentinel Event Alert, serious adverse events can result when family members, caregivers or clinicians who are not authorized

become involved in administering the analgesia for the patient “by proxy.”1 To alert all who come in contact with patients receiving PCA, MediDose/EPS has introduced a series of free auxiliary label images calling attention to the vital fact that only the patient is to control the PCA medication. The labels can be printed using the company’s MILT 3.0 software and its Mini-LiquiDose laser & thermal labels. “Well intentioned as people may be, PCA by proxy can result in catastrophic events. Our auxiliary labels help trained health care practitioners warn patients, staff and family members about this hazardous practice,” said Bob Braverman, Medi-Dose/EPS’s Director of Mar-

keting. “Other warning labels, including bar codes, graphics, special fonts, tall man lettering, shapes and logos can be created with the MILT 3.0 software, making it a vital part in promoting safety, increasing awareness and reducing the potential for medication error.” For more information on PCA by Proxy and other auxiliary images, contact Robert Braverman at 800-523-8966 or visit www.medidose.com/auxiliary.aspx.

Reference 1. The Joint Commission Sentinel Event Alert. Issue 33: Patient controlled analgesia by proxy. 2004. Available at: http://www.jointcommission.org/sentinel events/sentineleventalert/sea_33.htm. Accessed November 24, 2009.


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Technology 43

Pharmacy Practice News • December 2009

Critical Care For improved blood glucose control ...

Community Hospital ICU Turns to Software Program

No test dose or 30-minute observation period required In pre-dialysis CKD anemia

W

ithin a year of incorporating an FDA-approved software system into their blood glucose management protocols, staff at the 188-bed Kadlec Regional Medical Center (KRMC) in Richland, Wash., were able to provide improved blood glucose management to patients in the adult intensive care unit (ICU) without raising the risk for hypoglycemia. The journey started in 2001, when staff reviewed the literature and saw the need to balance good blood glucose management with the risk for hypoglycemia. What follows is an account of KRMC’s experience implementing the new protocol—along with an analysis of its impact on key patient outcomes— authored by Pamela W. Renard, PharmD, pharmacy clinical coordinator at KRMC. Benton Ricci, a PharmD student at Washington State University in Pullman, assisted in preparing the manuscript.

Due Diligence In the past, blood glucose management had not been a main focus area in most ICUs. Then in 2001, a seminal study by Van den Berghe et al revealed that maintaining blood glucose levels between 80 and 110 mg/dL in critically ill adult patients leads to an overall reduction in morbidity and mortality.1 With this study in mind, our staff set out to provide a level of care that would bring patients’ blood glucose within that range. However, managing individual insulin infusions outside of a clinical research setting can be time-consuming for physicians, nurses and pharmacists. Stress-induced hyperglycemia causes frequent fluctuations of blood glucose levels and insulin resistance, making blood glucose management in this patient population very difficult.2 In 2002, a study by Umpierrez et al compounded the issue by revealing that new-onset hyperglycemia may have more detrimental effects in patients without a history of diabetes than in those with an established history of the disease.3 The study showed that patients with newonset hyperglycemia had a higher rate of in-hospital mortality (16%) than patients with a known history of diabetes (3%; P<0.01), no matter where in the hospital they were admitted. These same patients also were more likely to be admitted to the ICU, to have a longer hospital length of stay and to be discharged to an extended-care facility. These new data prompted interest in the question of whether blood glucose management through intensive insulin treatment could improve patient prognosis in the ICU. The data also raised other concerns: How do we effectively manage blood glucose levels in a community hospital ICU? Is intensive insulin therapy safe for our patients? These are important questions, because a continuous infusion of insulin to achieve a relatively low blood glucose

level could put our patients at risk for hypoglycemia. Then in 2003, Van den Berghe et al published another important study of blood glucose management, indicating an increased risk for hypoglycemia with intensive treatment. In the study, the rate of hypoglycemia (blood glucose <40 mg/dL) was 5.2% in the intensive treatment arm compared with 0.8% in the conventional treatment arm.4 Although the authors characterized the hypoglycemic episodes as “brief ” and “clinically harmless,” the side effect nevertheless has the potential for causing serious patient harm and is as much a concern as hyperglycemia. If blood glucose falls low enough, a patient may lose consciousness or go into a coma, which may lead to longterm health complications.5 In March 2009, the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation)6 trial was released. This large, randomized study enrolled 6,104 patients who were expected to stay 3 or more consecutive days in the ICU, with the primary outcome being 90-day mortality. Again patients were given either intensive insulin treatment (81-108 mg/dL) or conventional treatment (blood glucose ≤180 mg/dL). The researchers concluded that intensive insulin treatment increased mortality (829 deaths with intensive treatment, 751 deaths with conventional treatment) and severe hypoglycemia (6.8% vs. 0.5%, respectively; P=0.02).6

safe

play it go proven

IMPORTANT SAFETY INFORMATION: Venofer® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.

Millions prescribed. Millions treated.

Methods Over the past 5 years, clinicians at KRMC has struggled with how best to treat the hyperglycemic patients in their ICU. With the evidence in mind, staff attempted to develop continuous insulin infusion protocols for blood glucose management in critical care patients.

see BG SOFTWARE, page 46

Please see brief summary of full prescribing information on following page 38. pages. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

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VENFA3 Iss.8/2009


A trusted source brings Tacrolimus Capsules to your shelf.

WARNING Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Tacrolimus Capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. 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 brief summary of full prescribing information including boxed warning on following pages. Prograf® is a registered trademark of Astellas Pharma Inc.

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Tacrolimus Capsules WARNING Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. INDICATIONS AND USAGE Tacrolimus capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that tacrolimus capsules be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that tacrolimus capsules be used in conjunction with azathioprine or mycophenolate mofetil (MMF). The safety and efficacy of the use of tacrolimus capsules with sirolimus has not been established. CONTRAINDICATIONS Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. WARNINGS (See boxed WARNING) Post-Transplant Diabetes Mellitus Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of tacrolimus-treatedkidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post transplant, in the U.S. and European randomized studies, respectively. Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS). Nephrotoxicity Tacrolimus capsules can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus capsules in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus capsules may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Hyperkalemia Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus capsules in the U.S. and European randomized trials, respectively, and may require treatment (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during tacrolimus capsules therapy (see PRECAUTIONS). Neurotoxicity Tacrolimus capsules can cause neurotoxicity, particularly when used in high doses. Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in tacrolimus capsules-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus capsules (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus. Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression. Malignacy and Lymphoproliferative Disorders As in patients receiving other immunosuppressants, patients receiving tacrolimus capsules are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus capsules following longterm immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution. Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including latent viral infections. These include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus. These infections may lead to serious, including fatal, outcomes. PRECAUTIONS General Hypertension is a common adverse effect of tacrolimus therapy (see ADVERSE REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating tacrolimus-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions). Renally and Hepatically Impaired Patients For patients with renal insufficiency some evidence suggests that lower doses should be used. The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients. Myocardial Hypertrophy Myocardial hypertrophy has been reported in association with the administration of tacrolimus capsules, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years). In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered. Information for Patients Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving tacrolimus capsules. They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician. Patients should be informed that tacrolimus capsules can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger. As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Laboratory Tests Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metbolic and hematologic systems should be performed as clinically warranted.

Drug Interactions Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus capsules with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with the co-administration of tacrolimus and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to tacrolimus should receive the first tacrolimus capsules dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels. Drugs that May Alter Tacrolimus Concentrations Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly. Drugs that may increase tacrolimus blood concentrations: Calcium Channel Blockers: diltiazem, nicardipine, nifedipine, verapamil; Antifungal Agents: clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole; Macrolide Antibiotics: clarithromycin, erythromycin, troleandomycin; Gastrointestinal Prokinetic Agents: cisapride, metoclopramide; Other Drugs: bromocriptine, chloramphenicol, cimetidine, cyclosporine, danazol, ethinyl estradiol, methylprednisolone, omeprazole, pretease inhibitors, nefazodone, magnesium-aluminum-hydroxide. Drugs that may decrease tacrolimus blood concentrations: Anticonvulsants: carbamazepine, Phenobarbital, penytoin; Antimicrobials: rifabutin, caspofungin, rifampin; Herbal Preparations: St. Johnâ&#x20AC;&#x2122;s Wort; Other Drugs: sirolimus This list is not all-inclusive. St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving tacrolimus capsules could result in reduced tacrolimus levels. Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with tacrolimus. Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided. Following co-administration of tacrolimus and sirolimus (2 or 5 mg/day) in stable renal transplant patients, mean tacrolimus AUC0-12 and Cmin decreased approximately by 30% relative to tacrolimus alone. Mean tacrolimus AUC0-12 and Cmin following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and efficacy of tacrolimus used in combination with sirolimus for the prevention of graft rejection has not been established and is not recommended. Other Drug Interactions Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus capsules, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1 At a given MMF dose, mycophenolic acid (MPA) exposure is higher with tacrolimus capsules co-administration than with cyclosporine co-administration due to the differences in the interruption of the enterohepatic recirculation of MPA. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MMF or MPA. Carcinogenesis, Mutagenesis, Impairment of Fertility An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in tacrolimus recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress. No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area. No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of preimplantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations. Pregnancy: Category C In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting Cardiovascular Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital (see WARNINGS) Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain Endocrine (see PRECAUTIONS) Cushing's syndrome, diabetes mellitus Hemic/Lymphatic Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia Miscellaneous Abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, mobility decreased, pain, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Respiratory Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration Skin Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating POST MARKETING Post Marketing Adverse Events The following adverse events have been reported from worldwide marketing experience with tacrolimus. Cardiovascular Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation Gastrointestinal Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease Hemic/Lymphatic Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura Metabolic/Nutritional Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Nervous System Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses Blindness, blindness cortical, hearing loss including deafness, photophobia

No reduction in male or female fertility was evident. There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus capsules should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus. Nursing Mothers Since tacrolimus is excreted in human milk, nursing should be avoided. Pediatric Patients Experience with tacrolimus in pediatric kidney patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus capsules. Two randomized activecontrolled trials of tacrolimus capsules in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus capsules to maintain blood trough concentrations of tacrolimus similar to adult patients.

Urogenital Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder. There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus therapy (see PRECAUTIONS-Myocardial Hypertrophy). Please see current package insert for complete adverse events information. OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

ADVERSE REACTIONS Liver Transplantation The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of tacrolimus and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

REFERENCE: CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42(RR-4):1-18.

1

Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS). Kidney Transplantation The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia. Less Frequently Reported Adverse Reactions The following adverse events were reported in either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials. Nervous System (see WARNINGS) Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia,

Manufactured in India by Sandoz Private Limited for Sandoz Inc; Princeton NJ 08540 Issued: August 2009


46 Technology

Pharmacy Practice News • December 2009

Critical Care successful protocol. Too narrow a range may require more frequent monitoring, and too low a range may increase the incidence of hypoglycemic events. Evidence seems to suggest that the threshold for mortality benefit may be around 145 mg/dL.7 The Surviving Sepsis Campaign recommends keeping blood glucose levels less than 150 mg/dL.8 Because the available research is conflicting, research continues to be done in this area. Having gone through 3 versions of a paper protocol, we have found our computer-based protocol to be a safe and effective method for managing blood glucose in critically ill patients.

BG SOFTWARE continued from page 43

In 2004, an interdisciplinary team consisting of a pharmacist, a physician and several nurses was organized. This team collaborated to develop our first intensive insulin protocol, which is a nurse-driven strategy. The ICU previously did not have a set goal for blood glucose levels. Clinicians usually only became concerned and initiated treatment when an ICU patient’s blood glucose level rose above 200 mg/dL. In September 2004, KRMC established its first paper protocol for intensive insulin infusion, with a desired blood glucose range of 80 to 110 mg/dL. This required a drastic, labor-intensive change in nursing care. Seeing that this protocol was not effective for many of our patients and we were documenting several episodes of hypoglycemia, in August 2006 our team changed the protocol and set the goal blood glucose range to 60 to 130 mg/dL. However, after several months it became clear that this version had its own challenges. The nurses found it hard to follow and our patients still were experiencing hypoglycemic episodes. Therefore, the team revised the protocol again in February 2008 with a wider blood glucose range of 60 to 150 mg/dL. Although the results improved with time and practice, it was evident that even this protocol was not ideal; it was hard to follow and susceptible to human error. Therefore, in October 2008 we revised the protocol again, with a new blood glucose target range of 100 to 150 mg/dL. Our ICU staff also started using a software system to manage blood glucose. This FDA-approved system, called EndoTool (Hospira, Inc.), helps clinicians determine an appropriate insulin dosage for each individual patient based on input from hospital staff.

References Education and Training The staff received extensive educational training before and after each protocol was initiated. The ICU nursing educator organized the education, held classes, spoke at staff meetings, and provided hands-on computer training for each revision. Staff also received one-on-one training. Before EndoTool went live, we had two days of training in our computer lab, so the nurses could learn how to use the software. Education and training is ongoing, and nurses continue to receive feedback at staff meetings. Pharmacists developed pre-printed orders for using EndoTool in the ICU, which make it easy for the nurses and physicians to know exactly how to use the system. Feedback from the nurses has been positive. They say they like using EndoTool far more than anything else they have worked with because they feel it is both safe and effective for their patients.

Results In the first year that the new protocol

was implemented, EndoTool recorded 24,180 blood glucose readings among 646 patients. The average blood glucose value after 4 hours of treatment was 133 mg/dL; 62.1% of the blood glucose readings were within the target range. To date, we have recorded 10 readings lower than 40 mg/dL (0.04% of the total). These 10 readings involved 8 patients, 1 of whom was inappropriately started on EndoTool after being admitted to our ICU with a blood glucose value below 40 mg/dL. If this patient is excluded, there have been 9 hypoglycemic events in 7 patients.

Conclusion Patients in the ICU are vulnerable to stress-induced hyperglycemia, which can be an independent risk factor for future complications. This brings the challenge to adult ICUs to establish insulin infusion protocols that are practical for staff to administer. Whether this is a paper- or computerbased protocol does not matter, as long as it works. A carefully selected blood glucose range also is essential for a

1. Van den Berghe G, Wouters P, sWeekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. 2. Tight glycemic control: reducing complications in the hospitalized patient. Therapeutic Insights and Review (a supplement to Hospital Pharmacy). 2006 (suppl): S1-12. 3. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitavchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87(3):978-982. 4. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med. 2003;31(2):359-366. 5. American Diabetes Association. Hypoglycemia. Diabetes Forecast Online 2009. http:// forecast.diabetes.org/diabetes-101/hypoglycemia. Accessed November 18, 2009. 6. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. 7.

Finney S, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA. 2003;290(15):2041-2047.

8. Dellinger RP, Carket JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3): 858-873.

NEW PRODUCT

American Health Packaging Launches New Unit-Dose Products

A

merican Health Packaging recently launched three new products to its growing unit-dose line, the company announced: • Ethambutol HCl Tablet 400-mg tablets (ABrated to Myambutol) • Rifampin 150- and 300mg tablets (AB-rated to Rifadin) • Sotalol HCl 80-mg tablet (AB-rated to Betapace) These unit-dose launches are part

of an ongoing commitment to support health systems’ vital patient safety and bar-coding initiatives, the company noted in a press release. All American Health Packaging unit-dose items are bar coded to the dose level and are stability tested to support extended shelf life. In addition, the company’s packages feature color-coded labels and “tall man” lettering to more easily distinguish products when they are being selected for dispensing.

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Midazolam Hydrochloride Injection CIV Brief Summary See package insert for full prescribing information Adult and Pediatric Intravenous midazolam HCl has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam HCl should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, i.e., pulse oximetry. Immediate availability of resuscitative drugs and age- and sizeappropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. (See WARNINGS.) For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure and route dependent (see DOSAGE AND ADMINISTRATION in full prescribing information). Neonates Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION in full prescribing information). INDICATIONS AND USAGE Midazolam HCl Injection is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting. Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY in full prescribing information). CONTRAINDICATIONS Injectable midazolam is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with openangle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Midazolam HCl Injection is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form. WARNINGS Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY in full prescribing information) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. See DOSAGE AND ADMINISTRATION in full prescribing information. Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic. Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients. Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY in full prescribing information). Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered. Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided. The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY in full prescribing information) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation. Usage in Pregnancy An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).

Usage in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration. The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources. PRECAUTIONS General Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS above and DOSAGE AND ADMINISTRATION in full prescribing information). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia. Use with Other CNS Depressants The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient’s underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see BOX WARNING, WARNINGS above and DOSAGE AND ADMINISTRATION section in full prescribing information.) Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal, see DRUG ABUSE AND DEPENDENCE section. Drug Interactions The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION in full prescribing information). Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. For additional drug interaction information, refer to full prescribing information. Pregnancy Teratogenic Effects – Pregnancy Category D (see WARNINGS) Labor and Delivery In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug. Following intramuscular administration of 0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum concentrations were lower than maternal concentrations. The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use. Nursing Mothers Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman. ADVERSE REACTIONS See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, e.g., upper endoscopy and dental procedures. Adults: The following additional adverse reactions were reported after intramuscular administration: headache (1.3%); Local effects at IM injection site included: pain (3.7%), induration (0.5%), redness (0.5%), muscle stiffness (0.3%). Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION in full prescribing information). The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), “oversedation” (1.6%), headache (1.5%), drowsiness (1.2%); Local effects at the IV site included: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), induration (1.7%), phlebitis (0.4%). Pediatric Patients The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent. Neonates For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, see BOX WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections. DRUG ABUSE AND DEPENDENCE Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970. Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam. Withdrawal symptoms similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting and tachycardia are prominent symptoms of withdrawal in infants. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient’s needs. In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days. Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) BAXTER is a trademark of Baxter International Inc. 462-051-06 4/2009


Midazolam HCI Injection

Now available with Distinctive Labels. To learn more, contact your Baxter representative at 1-888-229-0001. Please see preceding page for brief summary of full Prescribing Information including boxed warning.

Baxter, Committed to a Safer Healthcare Environment, and the distinct product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111198B 09/09


Pharmacy Practice News - December 2009 - Digital Edition