October 2013 by McMahon Group

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Volume 40 • Number 10 • October 2013

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in this issue UP FRONT

CDC: antibiotic resistance still on the rise; better stewardship efforts urged.

CLINICAL

7 9

New guidelines issued for postexposure HIV prophylaxis. Malnutrition often overlooked in cancer care.

OPERATIONS & MGMT

Leadership in Action: setting up healthy boundaries for yourself and your staff.

POLICY

22 25

In reimbursement, don’t let distractions lead to revenue loss. New labeling tightens use of opioids in chronic pain.

New IPPS Rule Keeps Focus On 30-Day Readmits

Doomsday for PharmD Grads Or Alarmist Over-Reaction? B

he Centers for Medicare & Medicaid Services (CMS) updated its payment policies and rates earlier this month under the Inpatient Prospective Payment System (IPPS), and some hospitals will take a financial hit as a result of the changes. But the update that seems to be triggering the most attention is CMS’s continuing push to bring down 30-day hospital readmission rates via the steepest payment cuts yet imposed under the initiative. CMS is reducing reimbursement rates by up to 2% for 2,225 hospitals beginning Oct. 1 (the beginning of fiscal year 2014) as part of a program designed under the Affordable Care Act (ACA) to curb readmission rates. In fiscal year 2013, the program withheld up to 1% of reimbursements for hospitals that had too many readmissions within 30 days of discharge because of heart attack, heart failure and pneumonia. Under the ACA, the penalty will rise to 3% by 2015 and

y 2018, 20% of new phaarmacy graduates will enter a job m market that has no positions for them, aaccording to a top education expert. However dire such a crisis may aappear, experts interviewed by Pha armacy Practice News disputed this find ding. In a commentary in the Am merican Journal of Pharmaceutical E Education ((AJPE 2013;77:90; doi: 10 0.5688/ ajpe77590), Daniel L. Brown, Ph harmD, the director of faculty development at the Center for Teaching Excellence, and a professor of pharmacy practice at th he Lloyd L. Gregory School of Pharmaccy, Palm Beach Atlantic University, in West Paalm Beach, Fla., based his bleak jobs forecastt on an analysis of trends in pharmacy em mployment and pharmacy education. In 200 01, “the pharmacy academy began a period of un nprecedented growth, fueled by a long-standing shortage of pharmacists and an outstanding job market for new pharmacy graduates,” Dr. Brown wrote. New w colleges and schools of pharmacy opened, and existing programs expanded. As a result, the number of new PharmD graduates is expected to reach about 15,000 annually by 2018 (compared with 7,000 in 2001),

see IPPS RULE, page 20

see DOOMSDAY, Y page 16

•

TECHNOLOGY

Apps and other high-tech tools for promoting medication adherence.

EDUCATIONAL REVIEW

Genotyping Test May Reduce Myopathy Risk

Contemporary Management of Hyponatremia See insert after page 18.

esearchers are using a new pharmacogenetic-based algorithm to predict patients who are abnormal metabolizers of statins and thus at risk for accumulating high blood levels of the drug, leading to debilitating, even fatal, cases of myopathy. “One of the common well-known side effects [of statins] is muscle aches, pains and weakness, which can occur in a large number of people—up

•

see GENOTYPING, page 8

From HOPA fall conference:

Launching Oncology IT System With Old + New Tech a Bad Idea

uccessfully implementing an electronic medical record (EMR) system requires, among other things, starting from scratch with a clean system, without importing databases from older systems in a misguided attempt to save time. That’s one of the lessons that Scott Soefje, PharmD, MBA, BCOP, the associate director of oncology pharmacy services at Smilow Cancer Hospital at Yale-New Haven Hospital (YNHH), in Connecticut, learned

Web Exclusive: Stakeholders debate merits of final sterile compounding bill. http://tinyurl.com/ppn-compounding

as YNHH went through the challenging process of implementing an EMR system that went live Feb. 1, 2013. Dr. Soefje was one of the team leaders during the implementation and also helped guide a second EMR rollout that went live last June at a sister hospital, the Hospital of Saint Raphael. (The hospitals have since combined into one location.) He shared some insights gleaned from both rollouts with

•

see NEW SYSTEM, page 29

New Product FDA Approves Enalapril for Children and Adults See page 33.

4 Up Front

Pharmacy Practice News • October 2013

Capsules

surf

CDC Calls for Antibiotic Stewardship In Report on Drug-Resistant Pathogens

OCTOBER 2013

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Tips for Surviving “The Unthinkable” in Patient Safety 2. Pharmacists Feeling Pain Over AMA Resolution 3. Are You Confident About Your Sterile Compounding QI Plan? 4. To Insource or Outsource? That Is the Question! 5. Getting Ready for Joint Commission Surveys Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘We docs can’t run the show by ourselves. Medical care is a team sport. We are all taking care

first

of patients and can’t do it right if our egos get in the way.’ —“drmfr” See article, page 34

Via website Aug. 8, 2013

ntibiotic-resistant pathogens infect at least 2 million people in the United States each year, according to a report by the Centers for Disease Control and Prevention (CDC). Clostridium difficile, carbapenemresistant Enterobacteriaceae (CRE) and drug-resistant Neisseria gonorrhoeae received the highest hazard level, “urgent,” under the CDC’s new classification system. “For the first time ever, we’ve had a snapshot of antimicrobial resistance threats that have the most impact on human health,” said Tom Frieden, MD, MPH, director of the CDC, in a Sept. 16 media briefing. Of the 2 million annual infections, the CDC estimates that roughly 23,000 are fatal. The organization stressed that these numbers are conservative approximations based on hospital infections, and did not include data from nursing homes, dialysis facilities, long-term care hospitals or assisted living facilities. The CDC ranked 18 common drug-resistant pathogens using the following criteria: clinical and economic impact, current incidence, 10-year projected incidence, transmissibility, availability of effective antibiotics and barriers to prevention. Pathogens were categorized as urgent, serious or concerning hazard levels. Of the urgent threats, CRE, which is resistant to almost all antibiotics, causes 9,000 infections annually, and there are an estimated 246,000 new cases of drug-resistant gonorrhea each year. Although C. difficile does not yet show significant antibiotic resistance, it frequently infects patients treated with other antimicrobials and causes 250,000 hospitalizations annually. The CDC classified multidrug-resistant Acinetobacter, r drug-resistant Campylobacter, r fluconazole-resistant Candida, extended spectrum β-lactamaseproducing Enterobacteriaceae, vancomycin-resistant Enterococci, multidrug-resistant Pseudomonas aeruginosa, drug-resistant non-typhoidal Salmonella, drug-resistant Salmonella typhi, drug-resistant Shigella, methicillin-resistant Staphylococcus aureus, drug-resistant Streptococcus pneumoniae and drug-resistant tuberculosis as serious threats. The concerning threats were vancomycin-resistant Staphylococcus aureus, erythromycinresistant Group A Streptococcus and clindamycin-resistant Group B Streptococcus. “When we’re dealing with untreatable infections, we no longer have the second-tier drug to rely on,” said Michael Bell, MD, deputy director of CDC’s Division of Healthcare Quality Promotion. “That’s when it becomes a life-or-death matter.” The CDC used the report as a call to action for better stewardship of antibiotics. “Up to half of antibiotic use in humans in this country is either unnecessary or inappropriate,” Dr. Frieden said. “We have a lot of room for improvement.” Patients must understand there is a difference between more medication and the correct medication, he said. In addition to improving antibiotic prescription and use, the CDC report also recommended preventing infections through immunization, handwashing and safe food preparation. “If we don’t take action urgently, the medicine cabinet may be empty for patients with lifethreatening infections in coming months and years,” Dr. Frieden said. “But we do see a real ray of hope in the effective interventions that can prevent and reverse drug resistance.” —Ben Guarino

EDITORIAL BOARD

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Volume 40 • Number 10 • October 2013 • pharmacypracticenews.com

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

INTERNAL MEDICINE

EDITORIAL STAFF

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ONCOLOGY

CARDIOLOGY

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CNS/PSYCHIATRY

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6 Clinical

Pharmacy Practice News • October 2013

Infectious Disease

WHO Recommends Earlier Treatment for HIV T

he World Health Organization (WHO) has released updated guidelines on the use of antiretroviral therapy (ART) for the treatment and prevention of HIV. The most significant change, according to HIV experts, is the WHO’s recommendation to start ART at the CD4 threshold of 500 cells/ mm3 or less in all adults, adolescents and older children. This update is part of what the authors called “a consistent global trend toward expanding access and the earlier initiation of treatment.” According to a press release from the Joint United Nations Programme on HIV/AIDS, about 25.9 million people will now be eligible for ART—9.2 million more than the 2010 guidelines that recommended treatment at a CD4 count of 350 cells/mm3 or less. Additionally, the WHO advises the initiation of ART regardless of CD4 cell count for certain populations, including pregnant and breastfeeding women, children younger than the age of 5 years, HIV-positive partners in serodiscordant couples and individuals coinfected with active tuberculosis disease or hepatitis B virus with severe chronic liver disease. The WHO does recognize resource limitations inherent to low- and middle-income countries. While calling for a CD4 threshold of 500 cells/mm3, the guidelines state, “Priority should be given to individuals with severe or advanced HIV disease and those with CD4 count of 350 cells/mm3 or less.” According to the guidelines, the firstline regimen for adults should consist of tenofovir disoproxil fumarate (TDF) plus lamivudine or emtricitabine (FTC) plus efavirenz (EFV), as a fixed-dose combination. Stavudine should not be used in first-line regimens due to metabolic toxicity. Treatment failure and efficacy should be assessed using viral load monitoring. The guidelines consolidate a range of WHO clinical recommendations and resources, making them available for the first time in a single document. Other new aspects include suggestions to decentralize HIV treatment and care by shifting tasks to properly trained health care workers. Philippa Easterbrook, MD, MPH, a senior scientist in the HIV Department at the WHO, in Geneva, noted that raising the CD4 thresholds for ART initiation to 500 cells, and recommending one preferred first-line regimen—one pill as a daily fixed-drug combination—were among the most important changes in the new guidelines. “The recommendation of one preferred regimen of a fixed-dose combination … will make it easier to prescribe, easier for adherence, and it will

also simplify drug procurement and the supply chain. The cost of this regimen (TDF/FTC/EFV) has also decreased in recent years,” said Dr. Easterbrook, who helped coordinate the overall development process for the guidelines. Paul Volberding, MD, director of the AIDS Research Initiative and director of research for Global Health Science at the University of California, San Francisco, agreed that the updated CD4 treatment threshold set by the WHO is a major improvement. But Dr. Volberding, who has helped develop guidelines for the International Antiviral Society–USA and the U.S. Department of Health and Human Services, pointed out that the WHO’s position is not a major break from existing treatment policy. “Both major guidelines in the United States recommend ART for everyone with HIV, regardless of CD4 cell count. This is functionally not different than the WHO guidelines because the vast majority of those infected with HIV have CD4 counts below 500 cells/ mm3. There is a growing convergence between the guidelines of the resourcerich and -limited countries,” he told Pharmacy Practice News. There are, however, some differences between the WHO guidelines and those released in the United States. “Because I work in a setting where resources aren’t constrained,” Dr. Volberding said, “I’m in

‘With their next guidelines revision, [the WHO will] recommend treating all [HIV-] infected people.’ —Paul Volberding,MD

favor of pregnant women continuing to be treated after the baby is born.” That position, he noted, is supported by U.S. treatment recommendations. The WHO guidelines, in contrast, “say a woman may have treatment discontinued after the baby is born and after breastfeeding is complete if she does not meet local treatment guidelines,” he pointed out. “I think the WHO will come around to changing that. With their next guidelines revision, they’ll likely recommend treating all infected people.” Implementing the new recommendations in resource-limited settings will present challenges, however. For example, how will funding be obtained for these new patients? “This is the question of the moment,” Dr. Volberding said. “Countries are talking about this now. How high up can they afford to go without running out of drugs and having to

stop treatment?” He urged more affluent countries not to be too critical of poorer nations that balk at the added expense. “The guidelines [are] at least aspirational. We’ll see a trend upward.” Despite economic and resource advantages found in the industrialized world, Dr. Easterbrook believes these regions also face HIV-related challenges. In such locales, “the challenge is that a significant proportion of HIVinfected persons are unaware of their infection. As a result, these persons only present for care and are diagnosed when they are clinically unwell with already advanced disease. There is a need for improved access to and uptake of HIV testing.” —George Ochoa Drs. Easterbrook and Volberding reported no relevant conﬂicts of interest.

WHO HIV Treatment Guidelines: A Pharmacist’s Perspective Jennifer Cocohoba, PharmD, BCPS, AAHIVP Health Sciences Associate Clinical Professor Department of Clinical Pharmacy UCSF School of Pharmacy Clinical Pharmacist UCSF Women’s HIV Program San Francisco, Calif.

June 2013 update brings the World Health Organization’s “Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection” into closer concordance with 2012 “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents” issued by the U.S. Department of Health and Human Services, as well as the 2012 “Antiretroviral Treatment of Adult HIV Infection” recommendations of the International Antiviral Society-USA. These guidelines recommend antiretroviral therapy (ART) for all HIV-infected persons irrespective of CD4-positive cell count, acknowledging that the level of supportive evidence for this varies at different CD4-positive cell count thresholds. Accordingly, the WHO has expanded its recommendations to include treatment for all HIV-positive persons with CD4-positive cell counts less than 500 cells/mm3 (with priority to those with advanced disease or CD4-positive cell counts <350 cells/mm3), all HIV-positive pregnant women, all patients coinfected with hepatitis B or tuberculosis and all persons in serodiscordant relationships (i.e., where one partner is HIV-positive and the other is HIV-negative, which poses a question as to what level of sexual activity can occur, given the fact that practicing safer sex reduces but does not eliminate the risk for transmission to the HIV-negative partner). Although the WHO recommendations do

not yet recommend treatment for all HIV-infected patients, these changes represent a significant step forward in the challenge to scale up ART to make it accessible to all. The 2013 WHO guidelines endorse tenofovir/lamivudine/ efavirenz or tenofovir/emtricitabine/efavirenz, both available as a single-tablet regimen, as the preferred combinations for initial treatment of HIV. This is in line with many other HIV treatment guidelines that recommend therapies balancing efficacy, toxicity and simplicity. Interestingly, the WHO guidelines also recommend the efavirenz-containing combinations for HIV-positive pregnant women, irrespective of the trimester of pregnancy, and for women of childbearing age. U.S. HIV perinatal guidelines tend to be more conservative and avoid the use of efavirenz in women of childbearing age or women in their first trimester of pregnancy. WHO guidelines allow more latitude concerning continuation of ART postpartum, whereas other guidelines recommend that women remain on ART after childbirth. Practicing pharmacists can take a strong role in helping their countries meet the challenge of scaling up ART. The WHO guidelines offer recommendations for expanding HIV testing to community-based locations that can provide linkage to prevention, care and treatment. They recommend initiation of therapy in hospitals or peripheral health facilities but promote the maintenance of ART in community-based settings. They recommend newer technologies and techniques, such as cell phone–based interventions, to improve adherence. They also support task-shifting to trained nonphysician clinicians to initiate, maintain and dispense ART. Pharmacists working in community pharmacies or in other community-based settings have the potential to fulfill many of these WHO-outlined roles to support testing, treatment and care for HIV-infected patients worldwide.

Clinical 7

Pharmacy Practice News • October 2013

Infectious Disease

New Guidelines Issued on Job-Related HIV Exposure T

he United States Public Health Service (USPHS) has released new guidelines on the management of occupational exposures to HIV and postexposure prophylaxis (PEP). Updated for the first time since 2005, the new guidelines include several important changes, most notably a recommendation that PEP regimens contain three or more antiretroviral drugs, as opposed to the two or three previously recommended, and that the regimen make use of newer, better tolerated medications. Raltegravir (Isentress, Merck), for example, an integrase inhibitor approved in 2007, has a better side-effect profile than the older drug zidovudine, which commonly causes nausea, vomiting, headache, insomnia and fatigue that can result in low adherence, the guidelines state. Due in part to its safer profile, raltegravir is now part of the preferred HIV PEP regimen, according to lead author David T. Kuhar, MD, a medical officer in

the Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC), in Atlanta. The preferred regimen also includes Gilead’s tenofovir (Viread) and emtricitabine (Emtriva), both of which were mentioned in the old guidelines, Dr. Kuhar noted. In addition to naming preferred agents, the updated guidelines also include important revisions regarding alternative HIV PEP regimens, Dr. Kuhar said. Janssen’s darunavir (Prezista), etravirine (Intelenc) and rilpivirine (Edurant), which were not available at the time of the previous guidelines, are now recommended. The new guidelines (Infect ( Control 2013;34:875-892) were a team effort, Dr. Kuhar added. They were developed by an interagency USPHS working group that included members from the CDC,

‘I think the changes that most of us would have liked have been included.’ —Cristina Gruta, PharmD

National Institutes of Health, FDA and the Health Resources and Services Administration, with contributions from an external expert panel.

Assessing Risk Is Part Of Intervention Plan Previously, the USPHS recommended assessing the level of risk associated with an individual exposure to determine whether two or three drugs should be used. Now, in the new guidelines, three or more drugs are recommended as PEP in all cases. “There are two main improvements from a clinician’s standpoint,” said Julia Garcia-Diaz, MD, MS, the program director of the Infectious Diseases Fellowship at Ochsner Medical Center, in New Orleans, who was not associated with developing the guidelines. “One is that, with the previous guidelines, we used to try to assess risk, meaning we would have to ask ourselves, do we use two drugs or do we use three drugs? The USPHS updates now have made it simpler and easier: You use three drugs or more. From our standpoint, this is a big help. The other improvement is the new recommendations in terms of the drugs that can be given to patients. The new regimen is much better tolerated and easier to take.” Jennifer Cocohoba, PharmD, a health sciences associate clinical professor at the University of California, San Francisco (UCSF) School of Pharmacy, said that in her view, the addition of raltegravir is one of the more noteworthy aspects of the updated guidelines. The drug likely was added not only because of its better side-effect profile, but also due to the lower risk for resistance that comes with any new agent, noted Dr. Cocohoba, who also is a pharmacist in the UCSF Women’s HIV Program. The 2013 guidelines also include a new recommendation regarding HIV testing of an exposed health care worker: Such testing can be completed in as little as four months after exposure if a fourth-generation combination HIV p24 antigen-HIV antibody test is used. Otherwise, six months of follow-up test-

ing is recommended to rule out HIV, according to the USPHS. Other aspects of the guidelines are continued from the previous edition. For example, PEP should be started as soon as possible, preferably within hours of exposure, and should continue for four weeks, and expert consultation is recommended.

PEPline Offers Help One place where medical providers can obtain expert consultation, whether they are concerned about a needle stick or a splash of bloody fluid, is the PEPline ([888] 448-4911), one of three consultation services run by the National HIV/AIDS Clinicians’ Consultation Center (NCCC). Cristina Gruta, PharmD, a pharmacist specialist at the NCCC who works on the PEPline, said, “We already knew that the CDC/USPHS was updating the occupational exposure guidelines to HIV because our project director, Dr. Ronald Goldschmidt, served as a member of the expert panel convened by the authors. We’ve been using the spirit of the guidelines even prior to publication, because our organization is part of the expert HIV treatment community.” Asked about compliance with PEPline recommendations, Dr. Gruta said that when health care providers call back, “it’s rare that I would hear of a situation where they disagreed with what we recommended. I think our recommendations are pretty well received.” She noted that in 2012, the PEPline received approximately 10,000 occupational exposure calls, about 95% of which involved actual exposures as opposed to general informational questions. Asked what she would change in the guidelines if she could, Dr. Garcia-Diaz said, “I don’t think I would change anything. I think the changes that most of us would have liked have been included.” —George Ochoa Drs. Cocohoba, Gruta, and Kuhar reported no relevant financial conflicts of interest. Dr. Garcia-Diaz disclosed that she is on the speakers’ bureau for Pfizer.

Pharmacy Practice News TWEETS! Follow us @PharmPracNews And send your Twitter handle to editor David Bronstein at davidb@mcmahonmed.com so we can follow you.

8 Clinical

Pharmacy Practice News • October 2013

Pharmacogenomics

GENOTYPING continued from page 1

to 10% or 15% of the patients who take them,” senior author Richard B. Kim, MD, a professor of medicine at the University of Western Ontario, London, Canada, told Pharmacy Practice News. “Although the vast majority are able to take statins, a small subset of those patients can go on to have ... rhabdomyolysis that sometimes leads to kidney failure and, in very rare cases, death. So the question then comes down to [whether] there [is] a way

of predicting those who may experience these types of side effects.” In the study, the researchers prospectively recruited 299 outpatients taking atorvastatin or rosuvastatin (Circ Cardiovasc Genett 2013;6:400-408). Fortyfivefold interpatient variability in statin concentration was found among patients taking the same drug and dose. Nearly 90% of the explainable variability in rosuvastatin concentration could be accounted for by two reduced-function transporter polymorphisms, one in the uptake transporter gene SLCO1B1 and

the other in the efflux transporter gene ABCG2. Explainable variability in atorvastatin level was almost equally divided between two polymorphisms in SLCO1B1 and activity of cytochrome enzyme CYP450 3A4. From these findings, the investigators designed an algorithm that includes recommendations for maximum atorvastatin and rosuvastatin doses, based on the patient’s age and transporter genotype. The doses were predicted to result in plasma concentrations of statins that would be lower than the

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‘A Great Paper’ “I think it’s a great paper,” said Jasmine Talameh, PharmD, PhD, a postdoctoral researcher at Ohio State University, in Columbus, who was not associated with the study. “There’s a lot of data in the literature on genetic variants associated with statin-induced myopathy. But a model combining those genetic variants for predicting statininduced myopathy hasn’t been established yet. This paper takes a step forward in doing that.” Asked whether the algorithm is ready to be used clinically, Dr. Kim said, “We do think the information provided in our published research can be [applied to patients]. What our algorithm does is serve as a statin selection and dosing decision-support tool for clinicians.” Dr. Talameh countered that “more research is needed. Concentration predictions need to be validated prospectively in an independent patient population. The gold standard after that would be prospectively validating the algorithm for association with not just concentration, but the clinical outcome of statin-induced myopathy.” Clinical use of the algorithm requires genotyping of the patient, which Dr. Kim said would cost $100 to $300. In the future, he noted, as a result of advances in the development of next-generation sequencing technology, “statin genotyping will be included as a part of a [large diagnostic] panel that could be done at once. So you basically buy the whole encyclopedia, and this [statins] would be just a chapter.” Insurers might pay for genotyping, but only “if there is increasing evidence that this is cost-effective.” Limitations of the study include a focus on only two of several commonly used statins and a predominantly white patient population, Dr. Kim noted. He added that he would like to see “a larger multicenter trial using our predictive algorithm versus standard care,” as well as research exploring the prevention of adverse reactions and severe muscle injury, overall health care costs, and noninferior or better cardiovascular outcomes and cholesterol lowering. —George Ochoa

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90th percentile, a value that reflects the fact that 10% of patients taking statins have statin-related muscle complaints. The researchers also retrospectively genotyped 579 patients from primary and specialty care databases in Canada and the United States. Genotypes associated with statin concentration were not differently distributed by statin dose, suggesting that clinicians had not optimized each patient’s statin serum level and that use of the algorithm thus might be beneficial.

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Drs. Kim and Talameh reported no relevant ﬁnancial conﬂicts of interest.

Clinical 9

Pharmacy Practice News • October 2013

Hem/Onc Pharmacy

Malnutrition Often Overlooked in Cancer Patients Washington—When it comes to providing enteral or parenteral nutrition to patients with cancer, the evidence shows the sooner an intervention is implemented, the better the outcomes. However, according to experts, malnutrition remains all too common. “A significant number of cancer patients have already experienced weight loss by the time they are diagnosed,” said Noreen Luszcz, RD, MBA, CNSC, the national home nutrition support program director at Walgreens Infusion Services in Deerfield, Ill.

fied as being at risk for malnutrition, the nurse and a dietitian make recommendations to the treating physician to improve the patient’s nutritional status. “The clinician may provide guidance to the patient as to how to increase calories and protein, as well as recommending use of oral supplements,” she said. “If the patient continues to deteriorate nutritionally, enteral [EN]

or parenteral nutrition [PN] may be indicated.”

Screening Tools Available Nutritional assessment tools such as the Patient-Generated Subjective Global Assessment and the Malnutrition Screening Tool are widely available to clinicians, so it is not the absence of screening tools that accounts for untimely malnutrition screening and intervention.

Furthermore, Ms. Luszcz said clinicians who find these tools too cumbersome can simply use observed weight changes to decide on the necessity for a nutritional intervention and how aggressive it should be (Table).

Barriers to Best Practice One way to improve detection and intervention could be to educate

•

see MALNUTRITION, page 10

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‘A significant number of cancer patients have already experienced weight loss by the time they are diagnosed.’

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—Noreen Luszcz, RD, MBA, CNSC

Table. Changes in Body Weight as Nutritional Intervention Triggers

Time

Significant Weight Loss, %

Severe Weight Loss, %

1-2

1 mo

3 mo

7.5

>7.5

6 mo

>10

Source: Luszcz N, ONS abstract 363, adapted from Blackburn GL et al. J Parenter Enteral Nutr. 1977;1:11-22.

In a poster she presented at the Oncology Nursing Society’s 38th Annual Congress (abstract 363), Ms. Luszcz noted that the American Society of Parenteral and Enteral Nutrition recommends screening cancer patients for nutritional status frequently and intervening early if necessary (JPEN ( 2009;33:472-500). Nutritional support is more beneficial to patients when they are undernourished, with only minor weight loss, than when they are severely malnourished after significant weight loss, she said (Clin Nutr 2009;28:445-454). “Every new patient admitted to Walgreens home infusion services ... undergoes a complete nutrition evaluation, which includes a review of the patient’s diet, appetite, [and] weight and a comprehensive gastrointestinal system review,” she told Pharmacy Practice News. If a patient is identi-

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Van Hassel T. Improving the safety of IV drug delivery. Pharmacy Practice News. 2009;36:6-7. Van der Linden P, Douchamps J, Schmitt C, Forget D. Ready-to-use injection preparations versus conventional reconstituted admixtures: economic evaluation in a real-life setting. Pharmacoeconomics. 2002;20(8):529-536. 3 Fanikos J. Premixed products improve safe medication practices. Pharmacy Practice News. 2011;38:56-57. 2

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10 Clinical

Pharmacy Practice News • October 2013

Hem/Onc Pharmacy

Quality Cancer Care: No Longer Just About Survival Washington—The definition of quality is shifting in today’s rapidly changing field of cancer care, and clinicians need to step it up when explaining treatment options to patients and helping them achieve their goals, a panel told community oncologists at the Association of Community Cancer Centers’ national meeting. Oncology used to have one measure of quality—survival, said moderator Cliff Goodman, PhD, a senior vice president and principal of The Lewin Group, a health care consulting firm. Now survival is only one of many things physicians are asked to measure. There are a few trends forcing a change in how quality is assessed. “Imperatives to spend wisely have really changed our definitions of quality to one of value,” said Randall Oyer, MD, the medical director of the cancer program at Lancaster General Hospital, in Pennsylvania. Additionally, today’s patients are more engaged and empowered, and have different expectations. Finally, the complexity of care requires the development of new methods of communication. Baby boomers are now 67 years old, the median age of cancer diagnosis, said Linda House, RN, BSN, the executive vice president of external affairs for the Cancer Support Community

At a Glance Three important factors affecting how oncologists’ care is judged: • The value of therapies, as opposed to solely survival • Patients’ increasing knowledge of practice standards and new research • Complexity of new treatment options demanding better communication

MALNUTRITION continued from page 9

clinicians on the benefits of adequate nutrition, including the lower mortality risk associated with the intervention ((J Parenter Enteral Nutr 2007;31:451455), according to Randy Fasnacht, RPh, the director of pharmacy at Advanced Infusion Services in Akron,

of Washington, D.C., a nonprofit organization providing support and education to people affected by cancer. Seventy-seven percent of cancers are diagnosed in people aged 55 and older, she said: “We’re seeing this swoon of very empowered people who either are or have been making health care decisions on the part of their parents and are now doing so for themselves. We have a real opportunity to engage these decision makers in a different way than we have in previous generations.” John Fox, MD, the associate vice president of medical affairs for Priority Health, a health plan in Michigan, said there are many measurable factors that affect patient outcomes. “There’s a tremendous amount of information on patients’ understanding of their cancer condition that impacts decisions, including end-of-life treatment,” he said. Despite these clear changes, defining quality isn’t easy in a field like oncology, which has many variables. “We’ve been accustomed for a long time to thinking about cancer as an acute illness, and now it’s chronic disease management, which none of us in oncology training really expected to happen,” Dr. Oyer said. Data management of quality measures also is critical, Dr. Fox said. And physicians and payors working in partnership need to make sure the right things are being rewarded. “If we want discussions around endof-life care and patient goals and priorities to occur, we have to recognize that’s an important determinant of outcome, and we should pay for that,” he said. “We have to recognize that it takes time not only to plan a chemo regimen but equally important, you have a conversation that educates a patient on that regimen and whether or not it’s curative.” Ms. House said she worries that physicians aren’t always transparent in the reasons why they make certain decisions within clinical pathways. More than half of the 3,600 patients in her organization’s patient experience registry reported a treatment decision being made during their first oncologist visit,

yet only 15% said they received information to support the choice. But pathways, on balance, are positive and help physicians know what choices are reasonable, according to Dr. Oyer. “I don’t think using pathways necessarily takes out the customization for patient preferences, or social/cultural background. In any industry, standardization improves safety and efficiency,” he said. Pathways were never meant to demand 100% compliance, Dr. Fox said. In his organization, individual oncology practices can determine their preferred regimens, but if they have a patient who needs to vary from that regimen for good reason, “that’s fine with us.” Panelists agreed that currently, the idea of including the patient voice as part of quality conversations is mostly lip service. “We still fall down on what defines quality and value from the patient perspective in oncology,” Ms. House said. Providers should do distress screening as part of a pathway, within so many days of cancer diagnosis or making a health care decision, she said. The main causes of patient distress are fatigue, sexual dysfunction, sleep issues, weight loss and worry about the future, she said: “These are things we don’t measure in traditional ways.” Payors are willing to pay for services

that support the “triple aim” of patient experience, health outcomes and total cost of care, Dr. Fox said, “but we have to find things that balance all three of those.” Ms. House said her organization has tools patients can use to have conversations with their health care teams about how pathway decisions are made, what the incentives are, how much it will cost patients and their insurance carriers, and what incentives favor one plan versus another. Patients know what they want as long as they’re asked, Dr. Fox said. “We don’t have the infrastructure in place to make sure we engage patients in those discussions and hear what’s most important to them, like being able to travel or spend time with family,” he said. Evidence suggests that patients get more care than they want, had they known what the options were, he said. Often, patients get treatments because they think that’s what their families want, and families want patients to get treatments because they think that’s what the patient wants. “The overall measure of quality from my frame of reference,” he said, “is that we’re providing the care that the patients wanted.” —Karen Blum

Ohio. “There are still those physicians who believe that if you feed the patient, you feed the tumor,” said Mr. Fasnacht, who was not involved in the abstract. Mr. Fasnacht added that even clinicians who know about the risks for malnutrition and use screening tools face administrative barriers to timely intervention. “Insurance companies and Medicare and Medicaid

are the thorn in everybody’s side,” he said. “You need to make sure you have reams and reams of documentation showing EN or PN are justified if you want to go ahead with it.” The need to overcome these educational and administrative barriers, as well as any others that prevent timely screening and nutritional intervention, is imperative, noted Mr. Fasnacht. “The

fact is we need to think about ensuring adequate nutrition from day one.”

Evolving treatments demand better communication from oncologists.

—David Wild Ms. Luszcz and Mr. Fasnacht reported no relevant ﬁnancial conﬂicts of interest. Mr. Fasnacht requested that his colleague, Talon Schroyer, a 2014 PharmD candidate, be cited as a contributor to the research that informed Mr. Fasnacht’s comments.

Clinical 11

Pharmacy Practice News • October 2013

Hem/Onc Pharmacy Virtual cancer centers:

A Panacea for the Rising Costs of Coordinated Care? Washington—In an era when W patients, providers and insurers are demanding increased coordination of cancer care services but the costs of establishing freestandingg cancer centers run in the multimiillion-dollar range, hospitals and health lth systems should consider forming “virtual” cancer centers as less capitalintensive alternatives, said presenters at the Association of Community Cancer Centers’ national meeting. For health systems spread out over multiple campuses or cities, “it may be physically impossible, or unrealistic, to centralize or consolidate all cancer care services,” said Matt Sturm, MBA, a senior manager with ECG Management Consultants’ office in Seattle. But, thinking outside the box, such systems can work to establish a virtual cancer center, in which services normally offered by a single cancer center are organized so that patients and providers can easily access them throughout the system, Mr. Sturm said.

Hawaii Pacific Goes Virtual A virtual center has been working well for Hawaii Pacific Health (HPH), a network of four hospitals and 44 outpatient clinics across six Hawaiian islands, said Kristen Chun, RN, MBA, the executive director of HPH’s oncology service line, in Honolulu. HPH offers adult oncology, pediatric oncology and women’s oncology, and, through partnerships with additional health providers, radiation oncology and clinical trials. Most services are based on Oahu, yet there is also a need to provide services to patients living on the neighboring islands. “It’s really important that our network reach out statewide,” Ms. Chun said. “It’s not uncommon to have patients on Kauai be diagnosed with a serious form of cancer that requires radiation therapy and simply opt out of treatment because they have no interest in traveling to Oahu for six-week periods of time. “What we’re interested in doing is letting patients know we have all the components of a one-site building, but we share them in the community and provide care where the patient is. That’s the model that is going to be the most successful for us.” Some patients do travel to other islands for care, and the local Blue Cross and Blue Shield will occasionally fly patients to the mainland United States for treatments not offered locally, such as bone marrow transplant. In 2010, HPH worked with Mr. Sturm’s group to evaluate what they could do to better serve patients. Reviews showed

A virtual approach to coordinated care helps sidestep the financial burden of building a single comprehensive cancer center. that although the individual clinical programs were very good, leaders needed to improve leveraging of programs across the system. Patients and some referring physicians were “very clueless” about the services offered by HPH, Ms. Chun said: “They would see one hospital, and one site of service, and think that’s what we had, not understanding that the four hospitals can provide pretty much any service you need.” Executives also discovered there were some redundancies in programs, there was no overriding physician leadership, and each hospital was focused on its own needs without an overarching direction. Over the past two and a half years, HPH executives have worked to improve organizational structure, operations, technology and marketing. They named a medical director and an executive director of oncology, who work with the hospital chief operating officers (COOs) and report to HPH leadership. These leaders work with the hospitals’ COOs, chief medical officers and oncology program

m managers to review program needs and share resources. All hospitals and clinics use the Epic electronic medical records (EMR) system, which allows for a seamless experience for patients and offers leaders easy access to volumes and outcomes data. They’re working to implement Epic in community physician offices; 150 joined them last year. They also are developing a comprehensive marketing tool to emphasize the scope and quality of services, Ms. Chun said. “We have the second largest market share in the state, so we’re not out there necessarily to battle for market share. We are out there to make sure that when our patients come to us, we provide them with quality, coordinated care,” she added. Organizations looking to establish virtual cancer centers first need a strategic plan outlining the intended geographic locations the center would serve, the scope of services to be provided, any need to increase alignment with oncologists, and how to improve focus on patients, Mr. Sturm said. Successful cancer programs have eight key elements, he said, the first three of which are crucial to a virtual cancer center: physician leadership and expertise; coordinated clinical care through efforts like patient navigation or tumor boards; consistent protocols based on National Comprehensive Cancer Network or other guidelines; investment in diagnostic and treatment technologies; patient support services; making clinical research available to patients; use of quality improvement tools; and screening, outreach and prevention services. Patient navigation, technology and

multidisciplinary care are the essential elements of clinical coordination in an oncology program, Mr. Sturm said. In virtual cancer programs, nurse navigators or trained lay personnel are critical to helping patients access clinical care and support services, and overcome logistical or financial barriers to care. The number and type of navigators should match the needs of the program. “Everyone in the program should know what services are offered throughout the organization, where to find those [services] and how to access them,” he said. A six- to eight-member leadership council of physicians and administrators with expertise from different tumor sites or specialties most often governs the centers. Each participating campus or location should be represented. Leaders need to provide strategic direction in research, technology, program development and quality. It is recommended that organizations have both an administrative and a physician leader, who dedicate time to the virtual center. EMRs also are key to keeping all providers up to date on patient care, and reducing the burden on patients of having to transport files from site to site. And, providers should work to offer multidisciplinary care, either through regular tumor conference meetings or teleconferences to review patient cases and devise treatment plans, or through multidisciplinary clinics where multiple specialists can see a patient in one visit. Finally, Mr. Sturm said, providers must develop and follow consistent clinical protocols so the same high-quality care is offered throughout the network. —Karen Blum

The Pharmacy Piece of the Virtual Puzzle

hen establishing any virtual health system, one has to consider pharmacy operations as an integral part of the clinical services mix. Pharmacists were part of a team working for two years to establish the Levine Cancer Institute, which opened last September as part of Carolinas HealthCare System. The system has more than 30 hospitals throughout North and South Carolina. Cancer patients are seen at 12 of those locations, including the main campus in Charlotte, N.C. The cancer institute aims to provide consistent high-quality patient care at all of its locations, according to Dragos Plesca, PharmD, PhD, a hematology/oncology clinical pharmacy specialist with the institute. “Communication and sharing of information is the most critical aspect,” Dr. Plesca said. “Being in contact with the other regional sites and providing them with all of the information necessary to establish the same practice as the main campus [is crucial].” To help streamline pharmacy operations, Dr. Plesca and colleagues developed standardized medication order sets that met the institute’s clinical pathway guidelines for all

malignancies, so that patients receive the same therapy whether at the main campus or a regional site. Because some locations differ in their mix of pharmacists and pharmacy technicians, the pharmacy team provides clear instructions for chemotherapy preparation to each site. The team also helps conduct site visits to ensure all protocols and procedures are followed. The pharmacy team also is exploring remote order verification and providing some of the satellite locations with pre-mixed chemotherapy and other agents. Meanwhile, pharmacists also worked to ensure consistent patient education. Andrea Bryant, PharmD, a clinical pharmacist with the cancer institute, helped develop information packets for each medication, including an explanation of what the drug is, its class, how it works, what to tell a physician before taking it, medication instructions, and information on proper storage and adverse side effects. Once an oncologist selects a medication regimen, all information automatically prints out for the patient. —K.B.

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

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

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DESCRIPTION

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NDC #

PACK FACTOR (cartons/case)

2G3451

150 mg/100 mL

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2G3450

360 mg/200 mL

1.8 mg/mL

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NEXTERONE (amiodarone HCl) Premixed Injection

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

111932 07/13

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

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

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

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

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

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

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

Thyroid: d thyroid nodules/thyroid cancer

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

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

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

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

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

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

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

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

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

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

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

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

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

111923 04/13

16 Operations & Management

Pharmacy Practice News • October 2013

Education

DOOMSDAY continued from page 1

according to Dr. Brown. However, the job market for pharmacists is not keep ping pace, and by his estimatte, will accommodate only about 10,,000 to 12,000 new pharmacists peer year. Hence, by 2018, 3,000 grraduates (20%) per year will not find employment in their field. “I don’tt believe there currently is a need for more pharmacists,” Dr. Brown told d Pharmacy Practice News. “I think th he pipeline we’ve already got is more than enough.” h

Projections Don’t Equal Outcomes In a commentary in the same issue of AJPE (2013;77:91; doi: 10.5688/ ajpe77591), Katherine Knapp, PhD, and Jon C. Schommer, PhD, responded to

‘I don’t believe there currently is a need for more pharmacists. I think the pipeline we’ve already got is more than enough.’ —Daniel L. Brown, PharmD ““looming joblessn ness” might not haappen, including rissing demand for all health care servicees as the economy imprroves, and increasing retirement in the llarge cohort of pharmacists trained in the 1970s. Dr. Knapp, who is the dean of the Touro University California College of Pharmacy, in Vallejo, said in an interview that Dr. Brown’s commentary “was helpful in bringing to a wide audience data about the pharmacy

‘I continue to think that jobs are available, and I see that continuing for the foreseeable future.’ —Steven J. Martin, PharmD, BCPS Dr. Brown’s argument, asserting that “projections, even when based on the most solid evidence available, are not inescapable outcomes.” They outlined six scenarios under which Dr. Brown’s

education enterprise and the job market. It was not helpful because it tends to cause panic among students that there’s a bleak future for them.” She also faulted Dr. Brown for an “inac-

curate portrayal of the ability of the current pharmacy schools or accrediting agencies to prevent new schools from opening or schools from expanding. That clearly would be considered restraint of trade, and they could be sued under the Sherman Anti-Trust Act of 1890.” Furthermore, Dr. Knapp argued that Dr. Brown ignored factors other than an increase in graduates, such as the Great Recession. “I don’t agree that a glut [of pharmacists] is inevitable,” she said. Lucinda L. Maine, PhD, RPh, the executive vice president and CEO of the American Association of Colleges of Pharmacy (AACP), in Alexandria, Va., said in an interview: “The question is ‘is there any threat of significant unemployment facing our almost 300,000 licensed pharmacists now?’ I think that Dan’s answer was too unidimensional and simplistic.” An important unknown, Dr. Maine said, is the rate of expansion of the pharmacists’ patient care activities. Pharmacists will be doing more patient care in the future, and more of those positions will open up, she indicated.

Steven J. Martin, PharmD, BCPS, FCCP, FCCM, a professor and chairman, Department of Pharmacy Practice at the University of Toledo, Ohio, said Dr. Brown’s commentary “brought up a clear problem that we recognize in the academic world and that we’re seeing across the profession: that we have an increased number of graduates and that the job situation for those graduates has become tighter over the last few years.” However, he said, increasing demand for patient care services would continue to fuel job growth. Residency training, certificate programs, and MBA or MPH degrees will continue to make pharmacists “better able to be employed,” he suggested. “I continue to think that jobs are available, and I see that continuing for the foreseeable future.” —George Ochoa Drs. Brown, Knapp and Martin reported no relevant ﬁnancial conﬂicts of interest. Dr. Maine reported that a portion of AACP’s annual revenue comes from member institutions.

Web exclusive: Is the quality of pharmacy education another concern? See pharmacypracticenews.com for our continuing coverage.

Specialty Pharmacy

Getting—and Staying—In Limited Distribution Networks Las Vegas—Given the rapid growth of specialty pharmacy—by 2016, seven of the top 10 branded drugs in the United States are expected to be specialty pharmaceuticals, according to industry experts—it’s not surprising that healthsystems continue to seek a share of this growing, lucrative market. Just last month, UHC, an alliance of nonprofit academic medical centers, announced that it is launching a new national specialty pharmacy program for its members. This initiative follows the 2012 launch of Excelera, a network of hospitals that continues to seek specialty contracts and, according to a top-level executive of the consortium, is ready to make an announcement regarding its progress this fall. Part of the success of these efforts will hinge not only on how well health systems can gain access to limited distribution networks for specialty drugs, but also how well they can deliver on data aggregation, patient and provider registration and other complex requirements these network contracts often carry. In fact, the price for not delivering on those contract requirements can be ejection from a network, according to

William Roth, founding partner of the health care consulting company Blue Fin Group. At the 2013 Armada Summit, Mr. Roth described the experience of a specialty pharmacy provider who was too slow to respond to a particularly important contract stipulation—the filling of newly prescribed medications. “Every script matters,” Mr. Roth said. “Even time to therapy matters. I have a large manufacturing client about to pull its product from specialty pharmacies because it takes six weeks to get to firsttime-to-fill. Manufacturers are intolerant of service-level deficiencies.” Another key to success in gaining access to—and staying in—specialty pharmacy networks is to understand the criteria that manufacturers use to decide whether to partner with a pharmacy services provider. Pharmacy networks, Mr. Roth said, are designed to reach a balance between patient access and manufacturer control. If a manufacturer feels that just one specialty pharmacy can allow for necessary patient access, it will choose that single pharmacy, achieve control and cut others out, he noted. “Manufacturers are going to take control of the channels,” Mr. Roth said.

“Every large manufacturer that has a self-administered product has a hub. If the pharmacies don’t do well with these products, they’ll simply take them out of the pharmacy and sell directly to the physician or the patient.” One trend that bodes well for large integrated health systems is the fact that the size of the typical specialty pharmacy network is growing, said pharmaceutical economics expert Adam Fein, PhD, the founder and president of Pembroke Consulting, a management advisory and business research firm. “The number of pharmacies that have the capabilities to be in limited networks continues to [expand],” he said. “URAC has accredited or is in the process of accrediting 80 specialty pharmacies. Typically, there are anywhere from five to 20 pharmacies in a manufacturer’s network, and the networks for non-orphan drug indications are starting to get bigger. It’s not appropriate for most of these products to be in a network of 60,000 retail pharmacies, but I do think manufacturers are feeling some pressure to open up their networks.” Another determining factor in network design, Mr. Roth said, is the competitive landscape among manufacturers. “If a

competitor has an exclusive network, so can you. If the competitor is wide open, that may influence you.” Traceability also is becoming a big selling point in specialty pharmacy networks. Mr. Roth described one client who uses serial IDs on their product in a limited network of specialty pharmacies. “When the 100 network pharmacies adjudicate claims, they do it with a serial ID linked back to the manufacturer,” he said. “I can know that there’s no fraud or abuse, because you can’t reuse my package.” This level of personalization, on all fronts, is likely to become more and more characteristic of specialty pharmacy networks, he said. “I have another client where the CEO of the company knows every single patient who’s on their drug. He knows if they take it. He knows if they’re a week late getting their infusion. That’s the level of depth involved. Try that with any primary care product!” The competitive jockeying for position to participate in specialty pharmacy networks ultimately is good for patients, noted Dr. Fein. “Competition will only improve the services that specialty pharmacies are providing.” —Gina Shaw

SAMSCA AÂ® (tolvaptan) tablets for oral use Brief Summary of Prescribing Information. Please see Full Prescribing Information for complete product information. WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. 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Drug Interactions: Other Drugs Affecting Exposure to Tolvaptan: CYP 3A Inhibitors: 7ROYDSWDQ LV D VXEVWUDWH RI &<3 $ &<3 $ LQKLELWRUV FDQ OHDG WR D PDUNHG LQFUHDVH LQ WROYDSWDQ FRQFHQWUDWLRQV [see Dosage and Administration (2.3), Drug Interactions (7.1)]. 'R QRW XVH 6$06&$ ZLWK VWURQJ LQKLELWRUV RI &<3 $ [see Contraindications (4.4)] DQG DYRLG FRQFRPLWDQW XVH ZLWK PRGHUDWH &<3 $ LQKLELWRUV CYP 3A Inducers: $YRLG FR DGPLQLVWUDWLRQ RI &<3 $ LQGXFHUV H J ULIDPSLQ ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH 6W -RKQÂ¶V :RUW ZLWK 6$06&$ DV WKLV FDQ OHDG WR D UHGXFWLRQ LQ WKH SODVPD FRQFHQWUDWLRQ RI WROYDSWDQ DQG GHFUHDVHG HIIHFWLYHQHVV RI 6$06&$ WUHDWPHQW ,I FR DGPLQLVWHUHG ZLWK &<3 $ LQGXFHUV WKH GRVH RI 6$06&$ PD\ QHHG WR EH increased [see Dosage and Administration (2.3), Drug Interactions (7.1)]. 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P(T / DV ZHOO DV WKRVH ZKR DUH UHFHLYLQJ GUXJV NQRZQ WR LQFUHDVH VHUXP SRWDVVLXP OHYHOV ADVERSE REACTIONS: Clinical Trials Experience: %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÃ&#x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Â&#x2022; PRUH WKDQ SODFHER VHHQ LQ WZR GD\ GRXEOH EOLQG SODFHER FRQWUROOHG K\SRQDWUHPLD WULDOV LQ ZKLFK WROYDSWDQ ZDV DGPLQLVWHUHG LQ titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia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able 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term Gastrointestinal Disorders Dry mouth Constipation General Disorders and Administration Site Conditions 7KLUVWa Asthenia 3\UH[LD Metabolism and Nutrition Disorders Hyperglycemiab $QRUH[LDc Renal and Urinary Disorders Pollakiuria or polyuriad

Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%)

(N = 220) n (%)

Placebo

16 (7)

4 (2)

11 (5)

2 (1)

14 (6)

2 (1) 2 (1)

25 (11)

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SAMSCAÂ® (tolvaptan) JDVWURLQWHVWLQDO EOHHGLQJ ZDV UHSRUWHG LQ RXW RI WROYDSWDQ WUHDWHG SDWLHQWV DQG RXW RI SODFHER WUHDWHG SDWLHQWV 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLFF SDWLHQWV WUHDWHG ZLWK SAMSCA and at a rate greater than placebo LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV with hyponatremia (N = 111) and are not mentioned elsewhere in the label: Blood and Lymphatic System Disorders: Disseminated LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU Â¿EULOODWLRQ ,QYHVWLJDWLRQV 3URWKURPELQ WLPH prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis. Postmarketing Experience: 7KH IROORZLQJ DGYHUVH UHDFWLRQV KDYH EHHQ LGHQWLÂ¿HG GXULQJ SRVW DSSURYDO XVH RI 6$06&$ %HFDXVH WKHVH UHDFWLRQV DUH UHSRUWHG YROXQWDULO\ IURP D SRSXODWLRQ RI DQ XQNQRZQ VL]H LW LV QRW DOZD\V SRVVLEOH WR UHOLDEO\ HVWLPDWH WKHLU IUHTXHQF\ RU HVWDEOLVK D FDXVDO UHODWLRQVKLS WR GUXJ H[SRVXUH Neurologic: 2VPRWLF GHP\HOLQDWLRQ V\QGURPH Investigations: Hypernatremia 5HPRYDO RI H[FHVV IUHH ERG\ ZDWHU LQFUHDVHV VHUXP RVPRODOLW\ DQG VHUXP VRGLXP FRQFHQWUDWLRQV $OO SDWLHQWV WUHDWHG ZLWK WROYDSWDQ HVSHFLDOO\ WKRVH ZKRVH VHUXP VRGLXP OHYHOV EHFRPH QRUPDO VKRXOG FRQWLQXH WR EH PRQLWRUHG WR HQVXUH VHUXP VRGLXP UHPDLQV ZLWKLQ QRUPDO OLPLWV ,I K\SHUQDWUHPLD LV REVHUYHG PDQDJHPHQW PD\ LQFOXGH GRVH GHFUHDVHV RU LQWHUUXSWLRQ RI WROYDSWDQ WUHDWPHQW FRPELQHG ZLWK PRGLÂ¿FDWLRQ RI IUHH ZDWHU LQWDNH RU LQIXVLRQ 'XULQJ FOLQLFDO WULDOV RI K\SRQDWUHPLF SDWLHQWV K\SHUQDWUHPLD ZDV UHSRUWHG DV DQ DGYHUVH HYHQW LQ RI SDWLHQWV UHFHLYLQJ WROYDSWDQ YV RI SDWLHQWV UHFHLYLQJ SODFHER DQDO\VLV RI ODERUDWRU\ YDOXHV GHPRQVWUDWHG DQ LQFLGHQFH RI K\SHUQDWUHPLD RI LQ SDWLHQWV UHFHLYLQJ WROYDSWDQ YV LQ SDWLHQWV UHFH I LYLQJ placebo. DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHOÂ¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVWW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV should not be co-administered [see Dosage and Administration (2.3) and Contraindications (4.4)]. Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: Reduction in the dose of SAMSCA may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. Rifampin and Other CYP 3A Inducers: 5LIDPSLQ LV DQ LQGXFHU RI &<3 $ DQG 3 JS &R DGPLQLVWUDWLRQ RI ULIDPSLQ DQG 6$06&$ UHGXFHV H[SRVXUH WR WROYDSWDQ E\ I 7KHUHIRUH WKH H[SHFWHG FOLQLFDO HIIHFWV RI 6$06&$ LQ WKH SUHVHQFH RI ULIDPSLQ DQG RWKHU LQGXFHUV H J ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH DQG 6W -RKQÂ¶V :RUW PD\\ QRW EH REVHUYHG DW WKH XVXDO GRVH OHYHOV RI 6$06&$ 7KH GRVH RI 6$06&$ PD\ KDYH WR EH LQFUHDVHG [Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ GLJR[LQ IXURVHPLGH DQG K\GURFKORURWKLD]LGH ZLWK 6$06&$ KDV QR FOLQLFDOO\ UHOHYDQW LPSDFW RQ WKH H[SRVXUH WR WROYDSWDQ Effects of Tolvaptan on Other Drugs: Digoxin: 'LJR[LQ LV D 3 JS VXEVWUDWH &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK GLJR[LQ LQFUHDVHG GLJR[LQ $8& E\ DQG &PD[ E\ Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide: Co-administration RI WROYDSWDQ GRHV QRW DSSHDU WR DOWHU WKH SKDUPDFRNLQHWLFV RI ZDUIDULQ IXURVHPLGH K\GURFKORURWKLD]LGH RU DPLRGDURQH RU LWV DFWLYH PHWDEROLWH GHVHWK\ODPLRGDURQH WR D FOLQLFDOO\ VLJQLÂ¿FDQW GHJUHH Lovastatin: 6$06&$ LV D ZHDN LQKLELWRU RI &<3 $ &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ DQG 6$06&$ LQFUHDVHV WKH H[SRVXUH WR ORYDVWDWLQ DQG LWV DFWLYH PHWDEROLWH ORYDVWDWLQ È&#x2022; K\GUR[\DFLG E\ IDFWRUV RI DQG UHVSHFWLYHO\ 7KLV LV QRW D FOLQLFDOO\ UHOHYDQW FKDQJH Pharmacodynamic Interactions: 7ROYDSWDQ SURGXFHV D JUHDWHU KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDQ GRHV IXURVHPLGH RU K\GURFKORURWKLD]LGH &RQFRPLWDQW DGPLQLVWUDWLRQ RI WROYDSWDQ ZLWK IXURVHPLGH RU K\GURFKORURWKLD]LGH UHVXOWV LQ D KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDW LV VLPLODU WR WKH UDWH DIWHU WROYDSWDQ DGPLQLVWUDWLRQ DORQH $OWKRXJK VSHFLÂ¿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during concomitant drug therapy. As a V2 UHFHSWRU DQWDJRQLVW WROYDSWDQ PD\ LQWHUIHUH ZLWK WKH 92 DJRQLVW DFWLYLW\ RI GHVPRSUHVVLQ G'$93 ,Q D PDOH VXEMHFW ZLWK PLOG 9RQ :LOOHEUDQG Y: GLVHDVH LQWUDYHQRXV LQIXVLRQ RI G'$93 KRXUV DIWHU DGPLQLVWUDWLRQ RI RUDO WROYDSWDQ GLG QRW SURGXFH WKH H[SHFWHG LQFUHDVHV LQ Y: )DFWRU $QWLJHQ RU )DFWRU 9,,, DFWLYLW\ ,W LV QRW UHFRPPHQGHG WR administer SAMSCA with V2 agonist. USE IN SPECIFIC POPULATIONS: 7KHUH LV QR QHHG WR DGMXVW GRVH EDVHG RQ DJH JHQGHU UDFH RU FDUGLDF IXQFWLRQ [see Clinical Pharmacology (12.3)]. Pregnancy: Pregnancy Category C. 7KHUH DUH QR DGHTXDWH DQG ZHOO FRQWUROOHG VWXGLHV RI 6$06&$ XVH LQ SUHJQDQW ZRPHQ ,Q DQLPDO VWXGLHV FOHIW SDODWH EUDFK\PHOLD PLFURSKWKDOPLD VNHOHWDO PDOIRUPDWLRQV GHFUHDVHG IHWDO ZHLJKW GHOD\HG IHWDO RVVLÂ¿FDWLRQ DQG HPEU\R IHWDO GHDWK RFFXUUHG 6$06&$ VKRXOG EH XVHG GXULQJ SUHJQDQF\ RQO\ LI WKH SRWHQWLDO EHQHÂ¿W MXVWLÂ¿HV WKH SRWHQWLDO ULVN WR WKH IHWXV ,Q HPEU\R IHWDO GHYHORSPHQW VWXGLHV SUHJQDQW UDWV DQG UDEELWV UHFHLYHG RUDO WROYDSWDQ GXULQJ RUJDQRJHQHVLV 5DWV UHFHLYHG WR WLPHV WKH PD[LPXP UHFRPPHQGHG KXPDQ GRVH 05+' RI WROYDSWDQ RQ D ERG\ VXUIDFH DUHD EDVLV 5HGXFHG fetal weights and delayed fetal RVVLÂ¿FDWLRQ RFFXUUHG DW WLPHV WKH 05+' 6LJQV RI PDWHUQDO WR[LFLW\ UHGXFWLRQ LQ ERG\ Zeight JDLQ DQG IRRG FRQVXPSWLRQ RFFXUUHG DW DQG WLPHV WKH 05+' :KHQ SUHJQDQW UDEELWV UHFHLYHG RUDO WROYDSWDQ DW WR times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all GRVHV DQG LQFUHDVHG DERUWLRQV DW WKH PLG DQG KLJK GRVHV DERXW DQG WLPHV WKH 05+' $W WLPHV WKH 05+' WKHUH ZHUH increased rates of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations [see Nonclinical Toxicology (13.3)]. Labor and Delivery: 7KH HIIHFW RI 6$06&$ RQ ODERU DQG GHOLYHU\ LQ KXPDQV LV XQNQRZQ Nursing Mothers: ,W LV QRW NQRZQ ZKHWKHU 6$06&$ LV H[FUHWHG LQWR KXPDQ PLON 7ROYDSWDQ LV H[FUHWHG LQWR WKH PLON RI ODFWDWLQJ UDWV %HFDXVH PDQ\ GUXJV DUH H[FUHWHG LQWR KXPDQ PLON DQG EHFDXVH RI WKH SRWHQWLDO IRU VHULRXV DGYHUVH UHDFWLRQV LQ QXUVLQJ infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother. 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Use in Patients with Congestive Heart Failure: 7KH H[SRVXUH WR WROYDSWDQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH LV QRW FOLQLFDOO\ UHOHYDQWO\ LQFUHDVHG 1R GRVH DGMXVWPHQW LV QHFHVVDU\ OVERDOSAGE: 6LQJOH RUDO GRVHV XS WR PJ DQG PXOWLSOH GRVHV XS WR PJ RQFH GDLO\ IRU GD\V KDYH EHHQ ZHOO WROHUDWHG LQ VWXGLHV LQ KHDOWK\ VXEMHFWV 7KHUH LV QR VSHFLÂ¿F DQWLGRWH IRU WROYDSWDQ LQWR[LFDWLRQ 7KH VLJQV DQG V\PSWRPV RI DQ DFXWH RYHUGRVH FDQ EH DQWLFLSDWHG WR EH WKRVH RI H[FHVVLYH SKDUPDFRORJLF HIIHFW D ULVH LQ VHUXP VRGLXP FRQFHQWUDWLRQ SRO\XULD WKLUVW DQG GHK\GUDWLRQ K\SRYROHPLD 7KH RUDO /' RI WROYDSWDQ LQ UDWV DQG GRJV LV ! 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Concomitant Medication: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ DUH WDNLQJ RU SODQ WR WDNH DQ\ SUHVFULSWLRQ RU RYHU WKH U counter drugs since there is a potential for interactions.Strong and Moderate CYP 3A inhibitors and P-gp inhibitors: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ XVH VWURQJ H J NHWRFRQD]ROH LWUDFRQD]ROH FODULWKURP\FLQ WHOLWKURP\FLQ QHOÂ¿QDYLU VDTXLQDYLU LQGLQDYLU ULWRQDYLU RU PRGHUDWH &<3 $ LQKLELWRUV H J DSUHSLWDQW HU\WKURP\FLQ GLOWLD]HP YHUDSDPLO Ã&#x20AC;XFRQD]RO RU 3 JS LQKLELWRUV (e.g., cyclosporine) [see Dosage and Administration (2.3), Contraindications (4.4), Warnings and Precautions (5.5) and Drug Interactions (7.1)]. Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$MSCA >VHH 8VH ,Q 6SHFLÂ¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered g trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

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INDICATION and Important Limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

IMPORTANT SAFETY INFORMATION SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, and anuric patients. Warnings and Precautions: • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • SAMSCA can cause serious and potentially fatal liver injury. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired. Limit duration of therapy with SAMSCA to 30 days • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Co-administration with hypertonic saline is not recommended • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors • Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptan-treated patients vs 2% for placebo. Commonly Observed Adverse Reactions: (SAMSCA incidence ≥5% more than placebo, respectively): thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%).

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on previous page. For more information, visit SAMSCA.com or call 1-877-726-7220. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

May 2013

0713A-7891G

Operations & Management 19

Pharmacy Practice News • October 2013

Leadership in Action

Is It Time To Change Your Thinking? W

e often learn our most valuable lessons from children, so here’s an instructive tale of a grade school that made an unexpected discovery about the nature of boundaries and the effect they have on our behavior. The school had a large playground surrounded by a chain-link fence. The children enjoyed playing on nearly every corner of that enclosure, using almost— but not quite—all of the available space for their activities. Still, someone was concerned that the fence was too enclosing and would undermine the children’s social development, so they convinced the school to remove the fence. Lo and behold, rather than encourage even more freedom and social engagement, the children no longer played to the perimeter of the playground area but tended to congregate more toward the middle of the field of play. The boundary of the fence was in fact security for the children. Without it, they tended to huddle, maybe not in fear but with a degree of insecurity that held them back from realizing their full potential. We too need boundaries as adult professionals in order to perform to our maximum potential.

thinking at higher levels of brain function to solve our current problems in health care. I continue to be amazed the more I learn about neuroplasticity and the ability to expand our thinking. When people are engaged at high levels of problem solving and thinking, powerful results are possible. Creating this type of culture in an organization is liberating and exciting. This type of culture allows people to grow professionally. There is continual learning and constant adaptation to a changing environment. In health care today, we are learning to think differently in a risk-sharing environment that measures quality outcomes versus the feefor-service mentality that drives an overuse of resources without attention to quality of care. I constantly think about the role of pharmacy in these new environments. We are the professionals who need to think these pharmacy roles through and sell them to the health community at large. Others are not going to think the way pharmacists think! We need to remember that our perspective of health care is unique. Do others sense the power of our thinking as pharmacists?

The Nature of Boundaries

Creating the Right Emotional Climate

In last month’s column, we began to explore the manager’s responsibility for setting clear boundaries within his or her department. As Henry Cloud said in his book “Boundaries for Leaders” (HarperCollins, 2013), “Boundaries are made up of two essential things; what you create and what you allow.” Giving employees boundaries sets expectations and actually frees people to be creatively empowered. We must ensure that the energy of the department is focused on what is important to drive results, while limiting distractions, intrusions and toxic interactions. Clarity leads to attention and attention leads to results.

The Higher Orders of Thinking For this strategy to work, the manager needs to create a climate that challenges people to “figure things out in the best way possible,” rather than dictating to them with a “top-down” approach. During this process, the manager also notes what is not important and steers people back on track if they get distracted. But it’s also crucial to give employees the space they need to work through the challenges they are given. In fact, studies have shown that when people are given the space to create their own pathways to success—with guidance, of course—they create new neural pathways that lead to higher levels of thinking. Why is this process so important? Because we need transformational

Is it your experience, as it is mine, that people have trouble moving forward and achieving their professional goals when they are distracted by personal feelings and emotions at work? People think best when they are not stressed, afraid or depressed. Therefore, it is incumbent on us as leaders to create a positive emotional climate within our depart-

ments. I have worked in an atmosphere of fear as people and/or their jobs were being eliminated all around me, until it eventually included me. Stress or fear also can come from public humiliation. In my case, I have seen that exemplified by a senior executive at a health care organization who was a screamer. I bore the brunt of that outburst once and witnessed it in public meetings often. If you have been on the receiving end, you understand how fear creates inaction; you become afraid to move forward for fear of being yelled at or being asked, “who gave you the authority to make that decision?” Now some of these may be extreme examples that you may not have experienced. However, as leaders we need to consider the more subtle ways in which we can negatively influence others. Perhaps our tone of voice has been overly critical. When others perceive aggressive, angry or harsh tones that are overly critical, it can cause a shift in brain function. This is often called an “Amygdala Hijack.” This moves our thinking to the emotional center of our brain and away from the prefrontal cortex where higher thinking takes place. As we were taught in school, this is the flight-or-fight response. Stress and fear cause people to shift to the limbic system and move away from the higher cortical areas that are responsible for logic, problem solving, analysis, planning, prioritization, working memory and so on—in short, the area in which we want our people to be functioning. As Henry Cloud said, “when the options for ‘fight-or-flight’ aren’t available, it’s as if a giant ‘freeze button’ gets hit. We

‘When people are given the space to create their own pathways to success ... they create new neural pathways that lead to higher levels of thinking.’

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at anderson489@ comcast.net.

Ernest R. Anderson Jr., MS, RPh

shut down entirely. We get paralyzed.” How do people respond in this mode of thinking? They usually are defensive or angry or they avoid conflict by avoiding the instigator. Often this negative type of atmosphere is palpable in a department, hospital or even health system.

Be Positive! Building positive relationships with co-workers or subordinates encourages people to use their prefrontal cortex, enabling them to maximize problem solving and to be open to new ideas. In nearly all cases I’ve seen, this type of workplace environment, given enough time, improves efficiency and productivity. Remember, positive attitudes are contagious; people flourish under a positive leader who is fostering a climate conducive to using and expanding the intellectual capacity and abilities of everyone. Does that mean we allow people to fly off into tangential areas because we do not want to rein them in? Absolutely not! Our job is to create the boundaries in which to operate. We need to combine a goal-oriented, yet relational, approach. We care about the people and have a work ethic that requires drive, expectations and discipline. Structure is important. Lack of structure creates its own type of stress. If leaders are too aggressively pursuing results with no focus on their emotional tone to the employees, employees can have a brain freeze and shut down. So we must give direction, structure, accountability and expectations that drive toward the goals in a way that does not create stress. This is where our tone is so important, where remaining calm and showing empathy (when appropriate) can make a huge difference in helping us build and maintain positive relationships. Another way I often teach the approach is to “be hard on the issue but soft on the people.” In other words, never belittle or attack the person, but address the issue. The time you take to take a deep breath, show restraint and strike the right balance between firmness and support will pay off in dedicated workers who enjoy being in your department and reaching common goals set forth under your leadership. Good luck! ■

20 Policy

Pharmacy Practice News • October 2013

Reimbursement

IPPS RULE continued from page 1

likely be expanded to include readmissions for other medical conditions. CMS also included a safe harbor in its readmissions payment policy by adding 15 new discharge status codes for planned readmissions that do not incur any federal pay cuts. But that cushion should not detract hospital pharmacies from acting now to shore up efforts to stay under the CMS readmissions ceiling, according to Ernie Anderson

Jr., MS, RPh, a Brockton, Mass.–based health care consultant. “Pharmacy can play a key role here, because roughly half of all readmissions are medicationrelated,” Mr. Anderson said. “Most hospitals have already organized or are forming multidisciplinary readmission committees. Pharmacists should have a seat at the table.”

Improving Transition of Care Pharmacists need to focus more on the patient discharge process and transition of care issues to improve medi-

‘Academic medical centers and community hospitals may not have the staff available to devote to discharge. But they can still improve.’ —Ali McBride, PharmD cation adherence and reconciliation, Mr. Anderson said. “You hear horror stories all the time about patients who got readmitted because they didn’t take their medications properly.” Discharge counseling, when pharmacists make sure patients and their care-

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givers understand how to manage their medications, and post-discharge followup calls to patients in their homes are two proven ways to improve medication adherence, he noted. If it’s not possible for a pharmacist to contact all discharged patients, he suggested using an algorithm to determine which patients are most likely to be readmitted. The pharmacist can then call those patients at home. Yet another component to preventing readmissions due to medication mishaps would be to better use retail pharmacies in the community. “Pharmacies like CVS and Walgreens could conduct brown-bag reviews of the patients who spend the most on medications,” Mr. Anderson said. “Their local pharmacists may pick up on problems that otherwise wouldn’t come to light.” He acknowledged, however, that “no good consistentt mechanism exists to bridge the gap between the health system and the retail pharmacy.” Still, “professionals from these two traditional silos have started to have some dialogue to determine how this can be remedied.” For 340B hospitals, there may be a built-in solution for bolstering patient care and reducing hospital readmissions. These facilities can work with retail pharmacies to be their “contract pharmacy” under the federal drug discount program, Mr. Anderson noted. “This relationship can help these entities bridge care gaps and manage patients’ medications collaboratively,” he said.

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Although some hospital pharmacies already are deeply involved with the discharge process, other institutions will have a tougher time making changes. “Larger hospitals are where you may see more discharge-based interventions,” said Ali McBride, PharmD, MS, BCPS, the clinical coordinator of Hematology and Oncology at the University of Arizona Cancer Center, in Tucson. “Academic medical centers and community hospitals may not have the staff available to devote to discharge. But they can still improve. For example, they may be able to partner with social workers to help make sure patients have their medications from the local retail pharmacy already waiting for them when they return home.” However, pharmacists should be careful with relying too heavily on nurses or social workers during the discharge process, Mr. Anderson said. “They just don’t have the same knowledge base as pharmacists. Often, they only know about the products on the hospital formulary.

Policy 21

Pharmacy Practice News • October 2013

Reimbursement

Hospital-Acquired Conditions Among Other IPPS Pains

lthough hospital readmission reduction is a central goal under the updated Inpatient Prospective Payment System (IPPS), other components need to be heeded in order to dampen the fiscal pain that may result from the payment changes. These include a clarification of how a patient’s admission status affects reimbursement, the process for implementing the new hospital-acquired conditions (HAC) reduction program, and a refinement of the hospital valuebased purchasing (VBP) incentive program. Here’s a look at some of the changes: Hospital–acquired conditions: The Affordable Care Act (ACA) requires the Centers for Medicare & Medicaid Services (CMS) to establish a program to improve patient safety by imposing financial penalties on hospitals that perform poorly with regard to HACs. The conditions cited in the updated policy include everything from pressure ulcers, and foreign objects left in the body, to central line–associated bloodstream infection and catheter-associated urinary tract infection. Under the program, hospitals that rank in the lowest-performing quartile of HAC will be paid 99% of what they otherwise would have been paid under IPPS, beginning in fiscal year 2015. “The spread of infection in hospitals is well-documented,” said Ernie Anderson, MS, RPh, a Brockton, Mass.-based independent healthcare consultant. “But now the government is saying to hospitals: ‘Hey,

So when a patient says to them, ‘I have ramipril in my medicine chest at home, and they sent me home with lisinopril,’ a non-pharmacist might not know that they’re both ACE [angiotensin-converting enzyme] inhibitors, and it would be dangerous to take them together.”

Change Now or Falter Experts advise pharmacists to begin now to shift some of their focus from inpatient care to transition of care—or risk suffering financially. “My perception is the pharmacy clinician thinks it’s someone else’s responsibility to follow up on medications,” said Bonnie Kirschenbaum, MS, FASHP, a Boulder, Colo.-based, independent health care consultant specializing in reimbursement issues. “But if penalties shrink the hospital’s budgets, that means the pharmacy’s budget shrinks too.” Ms. Kirschenbaum said many pharmacists are resistant to adopting a more basic, proactive stance when it comes to interacting with patients. “Pharmacists like being an antibiotic or infectious disease specialist; they don’t like sitting with Grandma Smith going over her diabetic

•

see IPPS RULE, page 26

if you caused this infection, we’re going to dock you, because you’re responsible for it.’ ” Observation status: The final rule distinguishes inpatient admission from observation status—for which hospitals receive lower rates of Medicare reimbursement because it’s considered as an outpatient stay. Pharmacists can help their facilities navigate this tricky area of IPPS policy, according to Bonnie Kirschenbaum, MS, FASHP, a

Boulder, Colo.-based independent consultant. “The key is to make sure your facility is billing based on the admission status of the patient, rather than their physical location,” she stressed. “I would strongly urge that pharmacists take ownership of this important area of payment policy.” (For tips on how to make sure your hospital’s billing department is actually billing correctly, based on the admission status of patients, see this month’s

“Reimbursement Matters” column by Ms. Kirschenbaum on page 22.) Hospital VBP: The update for this program measures the quality of care patients report they received in the hospital. “It gives providers an incentive to make sure [that] we’re doing a good job educating patients, listening to what they say, and that we display a good bedside manner,” Mr. Anderson said. “Things you think would be fundamental, but sometimes don’t happen in hospitals.” —D.S.

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t who have intolerance to oral iron or have had unsatisfactory response to oral iron

INDICATIONS Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.

IMPORTANT SAFETY INFORMATION Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration. In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).

t who have non-dialysis dependent chronic kidney disease Up to 750 mg can be delivered in a single dose*1

t Give 2 doses separated by at least 7 days for a total cumulative dose of 1500 mg

t Administer intravenously by

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– Infusion over at least 15 minutes – Slow push injection at the rate of approximately 100 mg (2 mL) per minute over at least 7.5 minutes * For patients weighing 50 kg (110 lb) or more, give each dose as 750 mg. For patients weighing less than 50 kg (110 lb), give each dose as 15 mg/kg body weight. †

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

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

The following serious adverse reactions have been most commonly reported from the postmarketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

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22 Policy

Pharmacy Practice News â&#x20AC;˘ October 2013

Reimbursement Matters

Donâ&#x20AC;&#x2122;t Let Distractions Lead to Revenue Loss T

hereâ&#x20AC;&#x2122;s no question that the pharmacy management team has an overflowing basket of tasks and important issues to tackle and myriad infrastructure problems to solve. But letâ&#x20AC;&#x2122;s not forget that ensuring a healthy revenue stream should be a priority. This monthâ&#x20AC;&#x2122;s column will focus on some of the reimbursement areas that may have been overlooked or pushed aside. Once again, Medicare will be the model dis-

Brief Summary of Full Prescribing Information

INJECTAFERÂŽ (ferric carboxymaltose injection)

cussed as third-party payors and Medicaid often follow its lead.

A Quick Review The Centers for Medicare & Medicaid Services (CMS) uses two primary reimbursement models for hospital payments. The first, known as the Inpatient Prospective Payment System (IPPS), is based on the Diagnostic-Related Group (DRG) model and, with few exceptions,

Rx Only

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

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

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

has no provision for separate reimbursement for drugs, biologics or immunologic agents. In fact, itâ&#x20AC;&#x2122;s the quintessential model of bundled payment, where a fixed amount is paid to the facility and that amount is based on an aggregate of all of the detailed information regarding a patientâ&#x20AC;&#x2122;s care that is provided to Medicare. However, the facility is still required to line-item bill because CMS uses data from those payment claims, in

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

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

)SS

â&#x20AC;&#x153;Reimbursement Mattersâ&#x20AC;? is a tool for maintaining your health systemâ&#x20AC;&#x2122;s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

part, to set nationwide reimbursement rates. Thus, failure of the hospital to provide accurate data is interpreted by CMS as a product not ever being used, and subsequent reimbursement for all facilities gets artificially compressed. The second payment model used by CMS is known as the Outpatient Prospective Payment System (OPPS), which in some cases does allow for separate reimbursement for medications, biologics or immunologic agents. OPPS also has a model of bundled or packaged payment for drugs under $80 per day in 2013, where a fixed amount is paid to the facility and, like IPPS, that amount is based on an aggregate of all of the detailed information provided to Medicare. Additionally, if the facility is 340B-eligible, then all medications purchased for eligible outpatients are done so at 340B pricing, which yields considerable savings to the facility.

Does Site of Care Matter? Iâ&#x20AC;&#x2122;m often asked, â&#x20AC;&#x153;whoâ&#x20AC;&#x2122;s an inpatient or outpatient?â&#x20AC;? As noted above, thatâ&#x20AC;&#x2122;s a key question, because it will determine, among other things, whether bundled pricing applies. The simple answer is that anyone not admitted to the hospital as an inpatient is an outpatient. This includes patients who are being held for observation. So as you can see, it really has nothing to do with where in the hospital facility the patients are located or are being treated; instead, it is their admission status and how this real-time information is being made available to all members of the treatment team (including pharmacy) that drives reimbursement. Patients who are treated in a facilityâ&#x20AC;&#x2122;s outpatient clinic or infusion center are easily identified, and in such cases, lineitem billing, which is based on units (not dose) administered, is relatively straightforward. As a general rule, ambulatory surgery patients, patients with end-stage renal disease who are on dialysis and the majority of radiology patients are covered by bundled payments. Separate payment is available in a very few exceptions that are clearly outlined in the rules that cover those treatment domains. The missed opportunity usually lies with outpatients who are in observation status but who may be in a bed on

Policy 23

Pharmacy Practice News • October 2013

Reimbursement Matters Pharmacist Skills For Improving Revenue Stream Have a solid ongoing working relationship with the C-suite that allows frank discussions of areas for immediate improvement. Be committed to improving the revenue stream and understanding that billing is everyone’s responsibility, even though this is a skill set that needs to be learned.

you really afford to lose those precious dollars while you struggle to balance your pharmacy budget? This is particularly important starting next month, when hospitals that fail to hit certain performance targets—such as staying under CMS’ ceiling for 30-day readmission rates—will again have their Medicare payment rates reduced. So, where to start? First, don’t make the mistake of overcomplicating process improvement. From a reimbursement perspective, start with a relatively simple task: identifying high-cost

items as a target. For example, how are you handling adenosine or bivalirudin? The CMS quarterly average sales price (ASP) tables are a good entry point for figuring this out; they’ll give you payment rates and payment status. The next step is to identify which patients are 340B-eligible and use 340B acquisition models for all of their outpatient drugs. For more information, go to go.cms.gov/1es1w7R; go.cms.gov/16LuwS1; and go.cms. gov/161X6eF. To make all of this work, you really

need to do a critical evaluation of your pharmacy payment systems, procedures and staffing. That takes time, and it often requires additional resources— especially if major fixes are required. That means being able to approach administrators in your hospital, not only in the pharmacy department but also in the C-suite (box). This can be a challenging process, so if you encounter any problems along the way, email me about them; perhaps we can provide solutions in a future column! ■

Be able to identify admission status (inpatient vs. outpatient) on a real-time basis, and be able to track and identify this status for billing purposes and for audit after-the-fact. Have a working knowledge of services that are covered by bundled payment models and the products that are included in these bundles. Be part of the multidisciplinary team that makes the decisions that affect drug distribution in ancillary areas or in the everimportant milieu of observation patients. Help build a robust infrastructure that can identify which products, patients and care settings are eligible for 340B pricing.

an inpatient unit; those who are being treated in ancillary areas that also have inpatients—for example, the cath lab, interventional cardiology areas or interventional radiology; and patients who are being seen in the emergency room. Unfortunately, the distinction between an inpatient and observation stay isn’t always clear. CMS issued final regulations Aug. 2 intended to address the problem. The regulation, known as the Two-Midnight Rule, would assume that patients who stay two nights or longer in the hospital are inpatients (go.cms. gov/194Be2o). Those who have shorter stays would receive observation care, which is deemed an outpatient service. An observation patient can be treated in the emergency room or on an inpatient unit in the hospital. CMS does not require hospitals to tell patients they are receiving observation services, which can include some of the same procedures provided to admitted patients.

Yes, It’s Hard.... Several facilities cite staffing and/ or infrastructure pressures as justification for not addressing and correcting the issues of lost revenue. But the dollars being left on the table through missed reimbursement or overpayment for your purchases via such neglect—for example, by not using 340B pricing for eligible patients—are staggering! Can

AN APPROVED PATH TO A SAFE RECOVERY INDICATIONS AND USAGE BLOXIVERZ, a cholinesterase inhibitor, is indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery in adults and pediatric patients of all ages.

Important Safety Information

Choose Bloxiverz,™ the first and only FDA-Approved Neostigmine Methylsulfate Injection, USP. Now there is a clear choice among Neostigmine Methylsulfate Injection products offering proven efficacy • ACCUR ATE LABELING/DOSAGE • PROVEN SAFE AND EFFECTIVE

For more information please visit our website at www.bloxiverz.com.

CONTRAINDICATIONS BLOXIVERZ is contraindicated in patients with known hypersensitivity to neostigmine. It is also contraindicated in patients with peritonitis or mechanical obstruction of the intestinal or urinary tract. WARNINGS AND PRECAUTIONS Atropine or glycopyrrolate should be administered prior to BLOXIVERZ to minimize risk of bradycardia.

BLOXIVERZ should be used with caution in patients with the following coexisting conditions as serious reactions may occur: coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. Neuromuscular dysfunction can occur if large doses of BLOXIVERZ are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. ADVERSE REACTIONS The most common adverse reactions during treatment are bradycardia, nausea and vomiting.

To report SUSPECTED ADVERSE REACTIONS, contact Éclat Pharmaceuticals at 1-877-622-2320 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see the accompanying full prescribing information for complete safety information, and dosage and administration instructions.

www.eclatpharma.com

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BLOXIVERZ safely and effectively. See full prescribing information for BLOXIVERZ. BLOXIVERZ™ (Neostigmine Methylsulfate Injection), for intravenous use Initial U.S. Approval: 1939 INDICATIONS AND USAGE BLOXIVERZ, a cholinesterase inhibitor, is indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery (1). DOSAGE AND ADMINISTRATION • Should be administered by trained healthcare providers (2.1) • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when BLOXIVERZ should be initiated and if additional doses are needed (2.2) − For reversal of NMBAs with shorter half-lives, when first twitch response is substantially greater than 10% of baseline, or when a second twitch is present: 0.03 mg/kg by FULL PRESCRIBING INFORMATION: CONTENTS* 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1. Important Dosage Information 2.2. Dosage in Adults 2.3. Dosage in Pediatric Patients, including Neonates 2.4. Anticholinergic (Atropine or Glycopyrrolate) Administration 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1. Bradycardia 5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions 5.3. Hypersensitivity FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. 2. DOSAGE AND ADMINISTRATION 2.1. Important Dosage Information BLOXIVERZ should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses of BLOXIVERZ should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of BLOXIVERZ and should be used to determine the need for additional doses. BLOXIVERZ is for intravenous use only and should be injected slowly over a period of at least 1 minute. The BLOXIVERZ dosage is weight-based [see Dosage and Administration (2.2)]. Prior to BLOXIVERZ administration and until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Satisfactory recovery should be judged by adequacy of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ [see Dosage and Administration (2.4)]. 2.2. Dosage in Adults a. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ. b. There must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level, i.e., the response prior to NMBA administration, prior to the administration of BLOXIVERZ. c. Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration. d. BLOXIVERZ should be injected slowly by intravenous route over a period of at least 1 minute. e. A 0.03 mg/kg to 0.07 mg/kg dose of BLOXIVERZ will generally achieve a TOF twitch ratio of 90% (TOF0.9 ) within 10 to 20 minutes of administration. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the NMBA being reversed, and whether there is a need to rapidly reverse the NMBA. • The 0.03 mg/kg dose is recommended for: i. Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or ii. When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present. • The 0.07 mg/kg dose is recommended for: i. NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or ii. When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline, or iii. There is need for more rapid recovery. f. TOF monitoring should continue to be used to evaluate the extent of recovery of neuromuscular function and the possible need for an additional dose of BLOXIVERZ. g. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to adequately ventilate and maintain a patent airway following tracheal extubation. h. Patients should continue to be monitored for adequacy of reversal from NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used. i. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less. 2.3. Dosage in Pediatric Patients, including Neonates Adult guidelines should be followed when BLOXIVERZ is administered to pediatric patients. Pediatric patients require BLOXIVERZ doses similar to those for adult patients. 2.4. Anticholinergic (Atropine or Glycopyrrolate) Administration An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ. The anticholinergic agent should be administered intravenously using a separate syringe. In the presence of bradycardia, it is recommended that the anticholinergic agent be administered prior to BLOXIVERZ. 3. DOSAGE FORMS AND STRENGTHS BLOXIVERZ is available as: • Injection: 0.5 mg/mL, 5 mg of neostigmine methylsulfate in 10 mL, multiple-dose vials • Injection: 1 mg/mL, 10 mg of neostigmine methylsulfate in 10 mL, multiple-dose vials 4. CONTRAINDICATIONS BLOXIVERZ is contraindicated in patients with: • known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis). • with peritonitis or mechanical obstruction of the intestinal or urinary tract. 5. WARNINGS AND PRECAUTIONS 5.1. Bradycardia Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to BLOXIVERZ to lessen the risk of bradycardia [see Dosage and Administration (2.4)]. 5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions BLOXIVERZ should be used with caution in patients with coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. Because of the known pharmacology of neostigmine methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such as bradycardia, hypotension or dysrhythmia would be anticipated. In patients with certain cardiovascular conditions such as coronary artery disease, cardiac arrhythmias or recent acute coronary syndrome, the risk of blood pressure and heart rate complications may be increased. Risk of these complications may also be increased in patients with myasthenia gravis. Standard antagonism with anticholinergics (e.g., atropine) is generally successful to mitigate the risk of cardiovascular complications. 5.3. Hypersensitivity Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 5.4. Neuromuscular Dysfunction Large doses of BLOXIVERZ administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction.The dose of BLOXIVERZ should be reduced if recovery from neuromuscular blockade is nearly complete. 5.5. Cholinergic Crisis It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of BLOXIVERZ. Both conditions result in extreme muscle weakness but require radically different treatment. [see Overdosage (10)]. 6. ADVERSE REACTIONS 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

intravenous routee (2.2) − For reversal of NMBAs with longer half-lives or when ﬁrst twitch response is close to 10% of baseline: 0.07 mg/kg by intravenous routee (2.2) • Maximum total dosage is 0.07 mg/kg or up to a total of 5 mg (whichever is less) (2.2) • An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ (2.4) DOSAGE FORMS AND STRENGTHS Injection: 0.5 mg/mL and 1 mg/mL in 10 mL multiple-dose vials (3) CONTRAINDICATIONS • Hypersensitivity to neostigmine (4) • Peritonitis or mechanical obstruction of the intestinal or urinary tract (4) WARNINGS AND PRECAUTIONS • Bradycardia: Atropine or glycopyrrolate should be administered prior to BLOXIVERZ to lessen risk of bradycardia. (5.1)

• Serious Reactions with Coexisting Conditions: Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. (5.2) • Neuromuscular Dysfunction: Can occur if large doses of BLOXIVERZ are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. (5.4) ADVERSE REACTIONS Most common adverse reactions duringg treatment: bradycardia, y , nausea and vomiting. g (6) To report SUSPECTED ADVERSE REACTIONS, contact Éclat Pharmaceuticals at 1-877-622-2320 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS • Pregnancy: No human or animal data. Use only if clearly needed.

5.4. Neuromuscular Dysfunction 5.5. Cholinergic Crisis 6. ADVERSE REACTIONS 6.1. Clinical Trials Experience 6.2. Post Marketing Experience 7. DRUG INTERACTIONS

8.7. Hepatic Impairment 10. OVERDOSAGE 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action 12.2. Pharmacodynamics 12.3. Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility 14. CLINICAL STUDIES 16. HOW SUPPLIED/STORAGE AND HANDLING

8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy 8.2. Labor and Delivery 8.3. Nursing Mothers 8.4. Pediatric Use 8.5. Geriatric Use 8.6. Renal Impairment Adverse reactions to neostigmine methylsulfate are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The use of an anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, may prevent or mitigate these reactions. Quantitative adverse event data are available from trials of neostigmine methylsulfate in which 200 adult patients were exposed to the product. The following table lists the adverse reactions that occurred with an overall frequency of 1% or greater. SYSTEM ORGAN CLASS

ADVERSE REACTION

Cardiovascular Disorders

bradycardia, hypotension, tachycardia/heart rate increase dry mouth, nausea, post-procedural nausea, vomiting incision site complication, pharyngolaryngeal pain, procedural complication, procedural pain dizziness, headache, postoperative shivering, prolonged neuromuscular blockade insomnia

Gastrointestinal Disorders General Disorders and Administration Site Conditions Nervous System Disorders Psychiatric Disorders Respiratory, Thoracic and Mediastinal Disorders Skin and Subcutaneous Tissue Disorders

dyspnea, oxygen desaturation <90% pruritus

6.2. Post Marketing Experience The following adverse reactions have been identiﬁed during parenteral use of neostigmine methylsulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. SYSTEM ORGAN CLASS

ADVERSE REACTION

Allergic Disorders

allergic reactions, anaphylaxis convulsions, drowsiness, dysarthria, fasciculation, loss of consciousness, miosis, visual changes cardiac arrest, cardiac arrhythmia (A-V block, nodal rhythm), hypotension, nonspeciﬁc EKG changes, syncope bronchospasm; increased oral, pharyngeal and bronchial secretions; respiratory arrest; respiratory depression

Nervous System Disorders Cardiovascular Disorders Respiratory, Thoracic and Mediastinal Disorders Skin and Sub-cutaneous Tissue Disorders Gastrointestinal Disorders Renal and Urinary Disorders Musculoskeletal and Connective Tissue Disorders Miscellaneous

rash, urticaria bowel cramps, diarrhea, ﬂatulence, increased peristalsis urinary frequency arthralgia, muscle cramps, spasms, weakness diaphoresis, ﬂushing

7. DRUG INTERACTIONS The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Use with caution when using BLOXIVERZ with other drugs which may alter the activity of metabolizing enzymes or transporters. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Teratogenic Effects:: Pregnancy Category C. It is not known whether neostigmine methylsulfate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. BLOXIVERZ should be given to a pregnant woman only if clearly needed. Animal reproduction studies have not been conducted with neostigmine methylsulfate. 8.2. Labor and Delivery The effect of BLOXIVERZ on the mother and fetus with regard to labor, delivery, the need for forceps delivery or other intervention or resuscitation of the newborn, is not known. Cholinesterase inhibitor drugs may induce premature labor when given intravenously to pregnant women near term. 8.3. Nursing Mothers It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when BLOXIVERZ is administered to a nursing woman. 8.4. Pediatric Use BLOXIVERZ is approved for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery in pediatric patients of all ages. Recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children than in adults. However, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. The risks associated with incomplete reversal outweigh any risk from giving higher doses of BLOXIVERZ (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less). The dose of BLOXIVERZ required to reverse neuromuscular blockade in children varies between 0.03 mg - 0.07 mg/kg, the same dose range shown to be effective in adults, and should be selected using the same criteria as used for adult patients. [see Clinical Pharmacology (12.3)]. Since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (e.g., atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension. 8.5. Geriatric Use Because elderly patients are more likely to have decreased renal function, BLOXIVERZ should be used with caution and monitored for a longer period in elderly patients. The duration of action of neostigmine methylsulfate is prolonged in the elderly; however, elderly patients also experience slower spontaneous recovery from neuromuscular blocking agents. Therefore, dosage adjustments are not generally needed in geriatric patients; however, they should be monitored for longer periods than younger adults to assure additional doses of BLOXIVERZ are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient. [see Dosage and Administration (2.3)]. 8.6. Renal Impairment Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects. Although no adjustments to BLOXIVERZ dosing appear to be warranted in patients with impaired renal function, they should be closely monitored to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of BLOXIVERZ. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended. 8.7. Hepatic Impairment The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have

Revised: May 2013

*Sections or subsections omitted from the full prescribing information are not listed.

not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of BLOXIVERZ appear to be warranted in patients with hepatic insufficiency. However, patients should be carefully monitored if hepatically cleared neuromuscular blocking agents were used during their surgical procedure as their duration of action may be prolonged by hepatic insufficiency whereas BLOXIVERZ, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of BLOXIVERZ. This same situation may arise if the neuromuscular blocking agent has active metabolites. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended. 10. OVERDOSAGE Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of BLOXIVERZ (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored. Overdosage of BLOXIVERZ can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from r cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of BLOXIVERZ or other drugs in this class, in the presence of cholinergic crisis or of a refractory or “insensitive” state, could have grave consequences. The two types of crises may be differentiated by the use of edrophonium chloride as well as by clinical judgment. Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive antich linesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. Atropine may also be used to lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis. 11. DESCRIPTION Neostigmine methylsulfate, a cholinesterase inhibitor, is ((m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is: Neostigmine methylsulfate is a white crystalline powder and is very soluble in water and soluble in alcohol. BLOXIVERZ is a sterile, nonpyrogenic solution intended for intravenous use. Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, phenol 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to a value of 5.5. Each mL of the 1 mg/mL strength contains neostigmine methylsulfate 1 mg, phenol 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5. 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as nondepolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade. 12.2. Pharmacodynamics Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with nondepolarizing neuromuscular locking agents to reverse neuromuscular blockade. Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system. 12.3. Pharmacokinetics Distribution: Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%. Metabolism: Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Elimination: Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes. Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg. Renal impairment:: Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively. Hepatic impairment: The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment has not been studied. Pediatrics: Elimination half-life of neostigmine methylsulfate in infants (2-10 months), children (1-6 years) and adults (29-48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed neostigmine methylsulfate clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively. Drug Interaction Studies:: The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis:: Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine. Mutagenesis:: Neostigmine methylsulfate was not mutagenic in an in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility:: Studies on the effect of neostigmine methylsulfate on fertility have not been performed. 14. CLINICAL STUDIES The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with neostigmine methylsulfate treatment compared to spontaneous recovery. 16. HOW SUPPLIED/STORAGE AND HANDLING BLOXIVERZ (Neostigmine Methylsulfate Injection, USP) is available in the following: NDC NO.

STRENGTH

VIAL SIZE

76014-002-33 76014-003-33

0.5 mg/mL 1 mg/mL

10 mL multiple-dose vials supplied in packages of 10 10 mL multiple-dose vials supplied in packages of 10

The vial stopper is not made with natural rubber latex. BLOXIVERZ should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Protect from light. Store in carton until time of use.

Manufactured for: Éclat Pharmaceuticals Chesterﬁeld, MO 63005 USA

Policy 25

Pharmacy Practice News • October 2013

Medication Safety

FDA Updates Opioid Labeling Moderate pain no longer a treatment option; REMS revisions next

he FDA has modified the safety labeling for extended-release (ER) and long-acting (LA) opioid analgesics, as well as required further postmarketing studies to be conducted by the manufacturers of the agents. Although many of the changes reflect requests made in a petition from a physicians’ group looking to limit the prescribing and use of opioids for safety reasons, many of the group’s recommendations were not adopted by the FDA. The drug labeling sections that are affected include Dosage and Adminis-

tration, Warnings and Precautions, Drug Interactions, Use in Specific Populations and Patient Counseling Information, as well as the Medication Guide. “The labeling changes demonstrate the FDA’s resolve to reduce the serious risks of long-acting and extended-release opioids while still seeking to preserve appropriate access for those patients who rely on these medications to manage their pain,” FDA Commissioner Margaret A. Hamburg, MD, said in a statement. According to Douglas Throckmorton, MD, deputy director for regula-

As Opioid Scrutiny Grows, Will Risks Posed by NSAIDs Be Overlooked?

n the wake of FDA changes to labels for extended-release/long-acting opioid pain relievers, clinicians and patients may be looking elsewhere for ways to manage moderate pain. Non-steroidal anti-inflammatory drugs (NSAIDs) offer a potential alternative, but some clinicians are urging that a possible increase in NSAID consumption should be met with caution. “We hope the impact will not be great,” said Daniel Brzusek, DO, vice chair of the Alliance for Rational Use of NSAIDs. “But we think that not only physicians but the lay public will rely on NSAIDs.” According to Michael Carome, MD, director of Public Citizen’s Health Research Group, it’s “hard to say” if the new FDA labeling will influence NSAID use. He cited the variety of pain relief options that could be used in lieu of opioids or NSAIDs. “Non-NSAIDs, like Tylenol, may be reasonable for some patients,” said Dr. Carome. “And frequently, these are underutilized.” Both Dr. Carome and Dr. Brzusek mentioned there are ways to relieve pain that do not rely on pharmaceuticals, such as exercise and behavioral therapy. Dr. Brzusek also cited acupuncture as “a safer, zero-risk alternative” to NSAIDs. In the United States, an estimated 23 million people use NSAIDs for daily pain relief. Though considered safe when used properly, these drugs may result in adverse effects such as cardiovascular events and gastrointestinal (GI) bleeding. A recent meta-analysis of the adverse effects of NSAIDs found that, compared to placebo, for every 1,000 patients per year receiving a coxib or diclofenac, there would be three additional vascular events, of which one would be fatal. The meta-analysis also reported an increase in upper GI complications compared to placebo—most frequently, bleeding—at rate ratios of 1.81 for coxibs (P=0.0070), 1.89 for diclofenac (P=0.0106), 3.97 for ibuprofen (P<0.0001) and 4.22 for naproxen (P<0.0001) (Lancett 2013;382:769–779). Patients who use NSAIDs should take the “least dose possible for the shortest period of time,” Dr. Brzusek said. “That’s a maximum of 10 days.” Dr. Brzusek begins with a minimal dose—for example, 200 mg ibuprofen three times daily, 75 mg diclofenac daily or 250 mg naproxen twice daily—and titrates up the dosage every three days until there is no additional positive response. How big a problem NSAIDs pose is a matter of debate. In September, Lynn Webster, MD, president of the American Academy of Pain Medicine, told Pain Medicine News, a sister publication to Pharmacy Practice News, that “deaths from GI bleeding linked to NSAIDs rival deaths from opioids, according to some estimates.” This statement provoked a strong response from Andrew Kolodny, MD, president of Physicians for Responsible Opioid Prescribing, who wrote on Twitter that Webster’s remark was “false” and should be corrected. Estimates of deaths due to GI bleeding range from a high of 16,500 (J Rheumatol Suppl 1999;56:18-24) to a more conservative 2008 report from the Centers for Disease Control and Prevention, which cited 3,400 deaths. In contrast, the CDC recorded 14,800 deaths from opioids in 2008. When asked about the number of deaths from NSAIDs compared with the number of opioid-related deaths, Dr. Brzusek said he doesn’t believe deaths from NSAIDs are quite so high. “There are definitely a lot of deaths from bleeding,” he said, “but hospitalizations are more common.” According to the Alliance for the Rational Use of NSAIDs, NSAIDs contribute to at least 100,000 hospitalizations per year. Dr. Carome emphasized that he is not opposed to the reasonable administration of NSAIDs. “All drugs have problems,” he said. “Patients need to be made aware of that.” —Ben Guarino

tory programs in the FDA’s Center for Drug Evaluation and Research, the new labels “describe more clearly the risks and safety concerns associated with ER/LA opioids and will encourage better, more appropriate prescribing, monitoring and patient counseling practices involving these drugs.”

“We [PROP] were pleased, but we feel that FDA should have gone much further,” he said. “Their decision to exclude IR opioids is baffling, because all the risks are the same. We’re [also] disappointed that they didn’t add a suggested maximum duration of use of 90 days and a maximum dosage of 100 mg

‘[The FDA’s] decision to exclude IR opioids is baffling, because all the risks are the same [as ER and LA formulations].’ —Andrew Kolodny, MD Chief among the Physicians for Responsible Opioid Prescribing’s (PROP) requests that were included in the new labeling is language stating that opioids should not be prescribed for moderate pain. The updated labeling states that ER/LA opioids are indicated “for the management of pain severe enough to require daily, around-the-clock, longterm opioid treatment and for which alternative treatment options are inadequate.” Another major addition to the labeling is the inclusion of a boxed warning on the risk for neonatal opioid withdrawal syndrome associated with chronic use during pregnancy. In a press statement on its website, the FDA stressed the need for individualized treatment for chronic pain patients, and that the new labeling is designed to help health care professionals reach these goals with each of their patients. “The updated indication further clarifies that, because of the risks of addiction, abuse and misuse, even at recommended doses, and because of the greater risks of overdose and death, these drugs should be reserved for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated or would be otherwise inadequate to provide sufficient management of pain; ER/ LA opioid analgesics are not indicated for as-needed pain relief,” wrote the FDA in the statement. Lynn Webster, MD, president of the American Academy of Pain Medicine, said he was in favor of the new labeling that reserves opioid use for patients in severe pain who require long-term treatment. The change, he explained, “will take into account factors other than a pain scale score that should be considered when prescribing opioids.”

PROP Requests Left on Table Andrew Kolodny, MD, president of PROP, tempered his happiness about the labeling changes with frustration regarding changes that were not made.

morphine equivalents. We wanted use beyond these parameters to remain an option for physicians and patients, but we wanted it to be off-label because risks of long-term and high-dose use are likely to outweigh benefits for most chronic pain patients.” Dr. Webster said the labeling changes marked “a good day for people in pain who find opioids helpful. The FDA did a careful and thoughtful review of the petition presented by Physicians for Responsible Opioid Prescribing and decided there was not enough evidence to support most of the arguments made in the petition.”

More Research, Changes To REMS In addition to the labeling changes, the FDA announced new postmarketing clinical study requirements focusing on “the known serious risks of misuse, abuse, increased sensitivity to pain (hyperalgesia), addiction, overdose, and death.” Dr. Webster described the FDA’s requirement for manufacturers of opioids to conduct long-term safety and efficacy studies as “long overdue.” After final labeling is in place, the FDA intends to revisit the ER/LA opioid analgesics’ Risk Evaluation and Mitigation Strategies (REMS) program that was approved in 2012, “to reflect the updated information.” The current REMS mandates that the manufacturers of ER and LA opioid analgesics provide training for health care professionals who prescribe these agents, as well as educational materials for the health care professionals and for their patients that explain how to safely use the medications. —Donald M. Pizzi Web exclusive: Jeffrey Fudin, PharmD, FCCP, chairman of Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT), offers his views on the new opioid labeling. See pharmacypracticenews.com.

26 Policy

Pharmacy Practice News • October 2013

Medication Safety

FDA Flags Fluoroquinolones for Peripheral Neuropathy Risk

he FDA wants clinicians to pay more attention to the possibility that peripheral neuropathy (PN) may occur in people who have been prescribed oral or injectable fluoroquinolones. Although the FDA has required that PN be added to the warnings and precautions sections of all labels for systemic fluoroquinolone since 2004, under new requirements put in place on Aug. 15, 2013, the labels and medication guides for these medications also must indicate that fluoroquinoloneassociated PN may have a very rapid onset and be irreversible. “It’s important to note that the FDA’s decision to update information about peripheral neuropathy in the systemic fluoroquinolone drug labels is not based on the number of adverse event reports, but on the fact that this adverse event can be permanent,” Stephen King, a member of the agency’s Center for Drug Evaluation and Research Trade Press team, noted in an email. “Results of the FDA’s benefit–risk assessment do not warrant the

withdrawal of fluoroquinolones from the market. … We have revised the systemic fluoroquinolone drug labels and Medication Guides to clearly describe their benefits and risks.” Mr. King disclosed that a recent review of the FDA’s Adverse Event Reporting System (AERS) database identified 83 cases of fluoroquinolone-related PN with an outcome of disability, reported between Jan. 1, 2003 and Aug. 1, 2012. A Drug Safety Communication issued by the FDA on Aug. 15, discussed the 83 cases reported through AERS (http:// www.fda.gov/downloads/Drugs/DrugSafety/UCM365078.pdf ). “The onset of peripheral neuropathy after starting fluoroquinolone therapy was rapid, often within a few days,” according to the communication. “In some patients, the symptoms had been ongoing for more than a year despite discontinuation of the fluoroquinolone. Several patients were continued on the fluoroquinolone drug despite the occurrence of neuropathic symptoms. FDA has not identified any specific risk fac-

tors for the development of peripheral neuropathy. Peripheral neuropathy appeared to be unrelated to the duration of therapy or the age of the patient.” Additionally, FDA MedWatch, on Aug. 15, stated that physicians should give patients the medication guide with every oral- or injectable-fluoroquinolone prescription, and tell patients to contact their physician if they develop PN symptoms. MedWatch also instructed that the fluoroquinolone should be stopped immediately if PN symptoms occur, and the patient should be switched to a nonfluoroquinolone antibiotic—unless the benefits of continued treatment with a fluoroquinolone outweigh the risks. The FDA is encouraging physicians and patients to report adverse events and side effects related to oral and injectable fluoroquinolones by completing and submitting the form available at www.fda. gov/MedWatch/report.htm. Commenting on these developments, pain specialist Ezra B. Riber, MD, said, “A large percentage of patients with complaints that are consistent with

PN are termed idiopathic; they are not diabetic, [and have] no history of thyroid dysfunction, vitamin deficiency, environmental exposure, etc. These new findings may explain a significant proportion of these cases,” added Dr. Riber, the director of Palmetto Pain Management, in Columbia, S.C. “I would have never thought before to ask someone with PN symptoms if they have been prescribed fluoroquinolones, but this changes things dramatically. We’ve got to ask people with PN whether they have ever been on these medications.” Available fluoroquinolone products include levofloxacin (Levaquin, OrthoMcNeil; and generic versions), ciprofloxacin (Cipro, Bayer), moxifloxacin (Avelox, Bayer), norfloxacin (Noroxin, Merck), ofloxacin and gemifloxacin (Factive, LG Life Sciences). Fluoroquinolone topical formulations are not known to increase PN risk. —Rosemary Frei, MSc Dr. Riber did not report any relevant ﬁnancial conﬂicts of interest.

n August, the FDA issued an alert to the public that a European patient with multiple sclerosis (MS) developed progressive multifocal leukoencephalopathy (PML) after taking fingolimod (Gilenya, Novartis). This is the first case of PML reported following the administration of fingolimod to a patient who had not previously received natalizumab (Tysabri, Biogen Idec), an MS drug that also is indicated for the treatment of moderately to severely active Crohn’s disease and is associated with a higher risk for PML. PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that damages the myelin of the brain and usually causes death or severe disability. Fingolimod is used to treat relapsing

forms of MS, and Novartis reported that approximately 71,000 patients worldwide have been treated with the drug. The FDA recommended that patients should not stop taking fingolimod without first consulting with their health care providers. The FDA issued the alert while continuing to investigate the reported PML case and is working with Novartis to obtain and review all available information about this occurrence. The FDA will communicate its final conclusions and recommendations after its evaluation is complete. Additionally, the FDA is continuing to evaluate the risk for PML associated with natalizumab, which has been approved for the treatment of relapsing forms of MS since November 2004 and for the treatment of Crohn’s disease since

IPPS RULE

January 2008. In a 2012 FDA Drug Safety Communication, the agency stated that 201 cases of PML had been reported among approximately 96,582 patients treated with natalizumab worldwide through Jan. 4, 2012. The FDA has reported three risk factors associated with an elevated risk for PML in patients taking natalizumab: • the presence of anti–JC virus antibodies; • longer duration of treatment with natalizumab, especially beyond two years; and • prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil). Patients and health care professionals

Photo courtesy of Novartis

Fingolimod Tied to Elevated Risk for Leukoencephalopathy

Fi Fingolimod li d (Gilenya, (Gil Novartis) N i ) was recently l associated with a case of PML.

are encouraged to report adverse events or side effects related to the use of fingolimod or natalizumab to the FDA’s MedWatch Safety Information and Adverse Events Reporting Program at www. accessdata.fda.gov/scripts/medwatch. —Based on a press release from the FDA

FDA Approves New Dosage of Butrans Transdermal

continued from page 21

medications again and again because she doesn’t speak English well or is passive about her care.” Ms. Kirschenbaum said she thinks the new rule will improve the overall quality of patient care. “But when you’re in the middle of a significant shift in how you do things, it can be a struggle to see the end point,” she noted. “I’m hoping that eventually we’ll get there.” To access the final IPPS, visit go.cms.gov/194Be2o. —Dana Hawkins-Simons None of the sources had any relevant ﬁnancial conﬂicts of interest to disclose.

urdue Pharma announced that the FDA has approved a new 15 mcg per hour dosage strength of Butrans (buprenorphine) Transdermal System CIII. Four strengths of Butrans are now available: 5, 10, 15 and 20 mcg per hour. Butrans is indicated for the management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. Butrans is not for use as an as-needed analgesic; for pain that is mild or not expected to persist for an extended period of time; for acute pain; or for postoperative pain unless the patient is already receiving chronic opioid therapy

prior to surgery, or if the postoperative pain is expected to be moderate to severe and to persist for an extended period of time. Buprenorphine, a partial agonist at the μ-opioid receptor, is a Schedule III controlled substance by the Drug Enforcement Administration. The Full Prescribing Information for Butrans, including the Medication Guide and Boxed Warning, is available at www.purduepharma.com/butranspi and at www.butrans.com. Information on the shared opioid Risk Evaluation and Mitigation Strategies is available at www.ER-LA-opioidREMS.com. —Staff

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The burden of hyponatremia1,3 Hyponatremia occurs in up to 15% to 30% of hospitalized patients.4-6 Most cases are asymptomatic, and even when symptoms are present, they often overlap with other chronic comorbid conditions, making accurate assessment a challenge.3-6 Hyponatremia is known to complicate care, put patients with comorbid conditions at increased risk of mortality, and increase healthcare costs.1,3-5,7-9

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

Increased risk for hospitals and patients11

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

What you don’t know can cost you

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RECOGNIZE THE RISKS.

Realize the consequences. Visit HNupdates.com/hm

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

August 2013

0713A-8921C

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Pharmacy Practice News • October 2013

Implementation

NEW SYSTEM continued from page 1

attendees of the Hematology/Oncology Pharmacy Association’s (HOPA) fall conference in Chicago. To ensure successful implementation, he reiterated that the system has to be clean from the beginning (Table 1). “You can’t be importing databases from an old system and try to make it work,” he said. “We imported a database from another hospital and tried to modify it to save time, and when we launched in February, we found that we just didn’t get to everything we needed to [address]. There was a lot of disconnect between the systems. “So in June, with the second implementation, we started with a clean slate and went through each drug line-byline to make sure everything was accurate, and that launch went perfectly,” as opposed to the first, which “definitely hit some road bumps,” Dr. Soefje said. There were, he noted, “tens of thousands of lines that had to be edited. There were two people who spent the better part of two months doing it. But it was worth it. We are still cleaning up databases from our first launch. In contrast, the database from the June implementation is pretty much clean right now.”

Keep It Simple Also critical is the need to standardize and simplify. “This is particularly important with chemotherapy treatment plans. You can’t have multiple treatment [regimens] individualized for each doctor. It makes your system messy and difficult to manage. It’s not worth it.” For both implementations, the YNHH team sat down with doctors, grouped by their treatment specialties into teams, and worked together to agree “on what should and shouldn’t be in the standardized treatment plans,” Dr. Soefje said. “We got to the point where we realized that as we simplified, things got easier and easier to work with, and we believe it will ultimately save money.” YNHH also discovered, he said, that the EMR system “will pull from the drug database into the treatment plan, but it only does it one time. So if the drug database changes, the treatment plan has to be relinked to the drug again to make the plan work.” A related lesson learned: YNHH had to test all its interface systems to ensure that each drug routed correctly to all its systems, including Pyxis, billing etc., Dr. Soefje added. The first implementation showed that despite pre-study expectations to the contrary, workflow was significantly affected, in part because differences in how care is delivered in varying hospital areas were not fully appreciated.

Table 1. Start With a Clean EMR System Databases Drive EMR • Duplicate, mislabeled, misnamed drugs create chaos • Interfaces rely on the database message • Many subsystems rely on the drug database Standardize and Simplify • Especially important with chemotherapy treatment plans • Question everything • Don’t accept “that’s the way we have always done it” • Push for a standard way of approaching everything • Don’t have two when one will work • Demand consistency Testing, Testing, Testing • EMR is a technology tool that requires the proper infrastructure • Make sure the pieces fit together • Test interface systems • Test dispensing systems • Test chemotherapy plans • Test it again • Follow a drug order from start to finish • Test it all again Leadership Drives Change • Three components of change: people, process, technology • This change will take longer and cost more than you expect • Change is more than the EMR; focus on patient-centered care • Change is hard; expect resistance • Embrace the change; leaders must be the champion EMR, electronic medical record Source: Scott Soefje, PharmD, MBA, BCOP

‘We got to the point where we realized that as we simplified, things got easier and easier to work with, and we believe it will ultimately save money.’ —Scott Soefje, PharmD, MBA, BCOP

Table 2. Tips for EMR System Implementation The Build-up At Start-up

Ongoing Maintenance

Regimen eligibility

• Common regimens (adult vs. pediatric)

• New standards of care • New drugs • Salvage regimens • Rare diseases • Drug shortage management

Specialty regimens

• Bone marrow transplants • Intraperitoneal drugs • Research protocols

• Transarterial • Non-oncology antineoplastics and chemotherapy in the OR • ED methotrexate • Desensitization protocols

Supportive care

• Antiemetics • Hydration • Integrated labs and levels

• Leucovorin rescue • Standard of care changes • Formulary changes • Bar coding/NDC support

Special practices

• Dose rounding • Regimen validation • Inpatient/outpatient differences

• Pharmacy-managed supportive care • Oncology clinics • Specialty regimens

ED, emergency department; OR, operating room Sou ce Josep Source: Joseph Bubalo, uba o, PharmD, a , BCOP CO

For example, “you have to make sure that the EMR system provider understands that inpatient and outpatient treatments are different. They function differently, the workflow is different and so you have to walk the EMR provider through the system so they understand that,” Dr. Soefje stressed. Change management, he added, is also critical. “It requires leadership all the way from the top down through the department heads to drive the change. We kept reminding our people that these changes were being done to improve patient care. As we kept pushing that, even though change was hard, people more willingly began to accept it.” Dr. Soefje added another point worth stressing: “This process never stops. There is continued implementation and a continuing need for change management even after the system is up and running successfully.”

Even at Start-up, Keep Maintenance Top-of-Mind In another presentation, Joseph Bubalo, PharmD, BCPS, BCOP, an oncology clinical pharmacy specialist at the Oregon Health & Science University (OHSU), in Portland, described how OHSU included an ongoing maintenance program in the start-up building process for its EMR system, which went live in 2009 (Table 2). To ensure that maintenance would be successful, he said, OHSU employed two fulltime equivalent (FTE) technicians to support the module in OHSU’s EMR system dedicated to oncology when it went live. Today, OHSU still has one FTE on staff for support. “There is always going to be maintenance in these systems,” Dr. Bubalo noted, “so you have to have dedicated people to maintain the system. It won’t maintain itself.” The implementation team also decided

•

see NEW SYSTEM, page 30

30 Technology

Pharmacy Practice News • October 2013

Implementation

NEW SYSTEM

‘You have to have dedicated people to maintain the system. It won’t maintain itself.’

continued from page 29

during the build process to standardize supportive care such as fluids and hydration, lab data, safety parameters and hypersensitivity management. “At the onset, you get the system going and you’re taking care of patients,” he said. “But once you’re taking care of patients, things happen. The standard of care changes. New drugs are approved. Chemo regimens that you weren’t expecting to use become important. You have

—Joseph Bubalo, PharmD, BCPS, BCOP a rare disease to treat. [There are] drug shortages. We tried to build the system at start-up in a way that would make maintaining it easier.” To manage changes in supportive treatments, OHSU created “order groups” that helped streamline the start-up of their new EMR system. “Any

time a specific chemo drug is used and there is a special supportive care treatment like calcium and magnesium infusions, those are automatically added to the order set as a group,” Dr. Bubalo said. “So if the time comes to modify them, we can just change the group (add to it or delete it) and it automatically

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changes the chemo drug order. “The maintenance team can run a report to see which order records are going to be affected by a drug shortage or a change to a new product. That gives us a list of the regimens that need to be changed. And once you have that list, it’s just a matter of making sure you have adequate staff to make those changes.” The OHSU team uses a similar process for swapping drugs in or out of the system as generic drugs come on and off the market, when a branded drug becomes generic and when a drug shortage occurs. As part of maintenance, OHSU developed an electronic alert that tells physicians a drug is in short supply and directs them to approved alternative regimens. “That was not something we anticipated we would have to do when we went live,” Dr. Bubalo said, adding that when the drug comes off shortage, the system directs physicians back to the original regimen. OHSU has dedicated personnel to make sure bar codes and National Drug Code numbers are updated daily. “Every time there is a new generic drug, we have to make sure that the codes are updated. Otherwise the system will not recognize the code. We also update our in-house coding system for compounds that we create.” For busy times, OHSU uses flexible times or quiet times on regular shifts to add more help as needed to make changes in care plans. To optimize the system, Dr. Bubalo said that after the EMR system had been live for about a year, the maintenance team went back and started finding and identifying “exceptions,” such as other uses for cancer drugs that hadn’t been anticipated at start-up, and putting them into the EMR. “We ended up making a set of orders for the most common uses of cancer drugs in noncancer situations,” he said. The oncology pharmacists, he noted, became the “consultants to make sure that the noncancer uses of cancer drugs were safe for the patients.” Dr. Bubalo ended by reemphasizing that changes in the EMR system will affect workflow. “You have to realize that’s going to happen and plan for it.” —Liz Parks

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Technology 31

Pharmacy Practice News â&#x20AC;˘ October 2013

Compliance

Medication Adherence in the Palm of Your Hand â&#x20AC;&#x153;The smartphone will see you now.â&#x20AC;?

hat, declared noted cardiologist and technology guru Eric Topol, MD, might well be the motto for the next generation of health care. In a wide-ranging keynote address at the Armada Specialty Pharmacy Summit, Dr. Topol, the chief of innovative medicine at Scripps Research Institute, La Jolla, Calif., described an array of new remote monitoring and diagnostic options that are either already available or coming soon to a smartphone, tablet or computer near you, including apps that measure and track lung function, blood sugar, heart rate and blood pressure, and can even perform an electrocardiogram. Such personalized digital intervention (PDI) tools enable health care providers to tailor care more specifically for individual patients, noted Al Babbington, CEO of PrescribeWellness, a company that provides cloud-based providerto-patient communications. Such PDI â&#x20AC;&#x153;technologies must be more effectively leveraged to provide patients the support necessary to improve outcomes,â&#x20AC;? Mr. Babbington said during the Centers for Disease Control and Preventionâ&#x20AC;&#x2122;s recent Conference on Health Communication, Marketing and Media. Remote monitoring via smartphone and other technology tools is likely to transform the practice of pharmacy within the next few years, and holds particular promise for solvingâ&#x20AC;&#x201D;or at least mitigatingâ&#x20AC;&#x201D;a challenge that has long confounded pharmacists: patient nonadherence. dh

One example: eMedonline, a â&#x20AC;&#x153;medication adherence telehealth platformâ&#x20AC;? that already has secured multiple rounds of National Institutes of Health funding. It works on multiple devicesâ&#x20AC;&#x201D;smartphones, BlackBerry, and for patients with no such devices, a basic Internet appliance from the company. This tool gives â&#x20AC;&#x153;the patient a reminder on their phone or their device when itâ&#x20AC;&#x2122;s time to take a specific dose of medication,â&#x20AC;? said Kevin Clauson, PharmD, an associate professor of pharmacy practice at Nova Southeastern University, in Fort Lauderdale, Fla. â&#x20AC;&#x153;Then, they have to use the camera on their phone or a scanning app to scan the specific bottle or pill that theyâ&#x20AC;&#x2122;re taking. The program then confirms that theyâ&#x20AC;&#x2122;re getting the right drug, at the right dose, at the right time.â&#x20AC;? In some cases, the patient is then prompted to answer a few questions about the medication via text, such as â&#x20AC;&#x153;how do you feel this drug is working for you?â&#x20AC;? and â&#x20AC;&#x153;what side effects have you noticed?â&#x20AC;? The data can be used to do predictive modeling, Dr. Clauson told Pharmacy Practice News. â&#x20AC;&#x153;For example, if the data shows that your patient is usually taking all of their doses correctly, but on Tuesday afternoons they often miss a dose, you can pinpoint what might be happening then. The patient might realize, â&#x20AC;&#x2DC;Oh, thatâ&#x20AC;&#x2122;s when I take Ella to soccer, and thereâ&#x20AC;&#x2122;s so much going on that I forget.â&#x20AC;&#x2122; So, you can develop nonpharmacologic interventions to help the pharmacologic piece.â&#x20AC;? AdhereTechâ&#x20AC;&#x2122;s patented â&#x20AC;&#x153;smart â&#x20AC;&#x153; bottlesâ&#x20AC;? approach compliance from another direction. Som mewhat akin to scales at the groceryy store selfcheckout lane that notiice if youâ&#x20AC;&#x2122;ve pulled that two-ouncee magazine back out of your bagg, these vials measure the exactt amount of pills or liquid in a bottle

â&#x20AC;&#x2DC;With a biosensor, you know where and when the patient takes the drug. ... Thatâ&#x20AC;&#x2122;s not a proxy, thatâ&#x20AC;&#x2122;s [evidence of] actual adherence.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Kevin Clauson, PharmD in real time and wirelessly send the information to a system that reminds patients to take their medication via automated phone calls or text messages. â&#x20AC;&#x153;If you donâ&#x20AC;&#x2122;t take the medication after that, the prompts become more insistent. Theyâ&#x20AC;&#x2122;ll text, then theyâ&#x20AC;&#x2122;ll call, then maybe theyâ&#x20AC;&#x2122;ll call your mom,â&#x20AC;? joked Dr. Clauson. â&#x20AC;&#x153;You can control how much you want that to escalate.â&#x20AC;? AdhereTech recently got funding through Pilot Health NYC, a project of the New York City Economic Development Corporation and Health 2.0, for a trial at Weill Cornell Medical Center, where it will be used to assess patient adherence to an HIV drug regimen over a 12-week period and compare it with the usual standard of care. Maybe the most promising and the most controversial drug adherence technology is Helius, the long-await-

ed ingestible biosensor from Proteus Digital Health, which got the green light from the FDA last year after four years of wrangling over exactly how the agency would oversee it. (It was ultimately approved as a de novo medical device because there is no comparable technology on the market.) An â&#x20AC;&#x153;ingestible event monitorâ&#x20AC;? is embedded within a pill a patient takes; that monitor then communicates with a patch worn on the patientâ&#x20AC;&#x2122;s stomach. â&#x20AC;&#x153;The other devices are proxiesâ&#x20AC;&#x201D; strong proxies, but still proxies,â&#x20AC;? said Dr. Clauson. â&#x20AC;&#x153;But with a biosensor, you know where and when the patient takes the drug; it also transmits basic physiologic data as well as drug disposition information. Thatâ&#x20AC;&#x2122;s not a proxy, thatâ&#x20AC;&#x2122;s [evidence of ] actual adherence.â&#x20AC;? Dr. Clauson noted that when the

â&#x20AC;˘

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32 Technology

Pharmacy Practice News • October 2013

Compliance

ADHERENCE continued from page 31

sensor was rolled out in the United Kingdom, it wasn’t piloted through clinics or hospitals. “They partnered with Lloyds, a pharmacy chain, to introduce Helius.” Some pharmacies are working to develop their own remote monitoring tools. Diplomat Specialty Pharmacy, the largest privately owned specialty pharmacy in the United States, is developing an interactive texting tool that uses decision-tree technology to

allow automated two-way conversations based on the patient’s responses. Describing how the texting tool works, Gary Rice, RPh, Diplomat’s vice president of clinical services, said, “If you want to validate that a patient took their medication today, you can send them a text asking if they took it. If they did [take it], then you’re done, and the system records that the patient has acknowledged taking their medication. If they say no, they’ll get another text message asking which of five reasons describes why they haven’t taken it.”

If, for example, the patient selects “side effects,” the system will ask, “Which of the following side effects are you experiencing?” At some point, the patient can ask to be transferred to a live pharmacist for education on managing that particular side effect; or if the side effects described are severe enough, they may be transferred directly to their physician’s office. Mr. Rice told Pharmacy Practice News that Diplomat plans to implement this program over the next year “to enhance [their] patient care man-

Read Pharmacy Practice News Anywhere, Anytime!

agement program.” The transition of the health care system from a fee-for-service to a “feefor-outcomes” model, the participatory medicine movement and quantum-leap style advances in technology are converging to jump-start remote monitoring, said Dr. Clauson. “It’s not a wave of the future. It’s quickly becoming a wave of the present.” —Gina Shaw None of the sources reported any relevant ﬁnancial conﬂicts of interest.

Biometrics Coming To a Pharmacy macy Near You

elios Biometriccs and ScriptPro o announced they have entered into a multi-year licensingg agreement wherebyy Xelios will supplyy biometric authentication technology to be used in ScriptPro’s pharmacy automation and management systems. “We believe biometric authentication is the simplest and most powerful way to implement controls over pharmacy processes,” said Mike Coughlin, CEO and president of ScriptPro, which is based in Mission, Kan. “We have tested a number of technologies in this area and feel that Xelios has taken this method to a new level of speed and accuracy.” Biometric identifiers, such as fingerprints, are distinctive, measurable characteristics that can be used to identify individuals, and, according to a press release issued by the two companies, biometric identifiers are more reliable in verifying identity than ID cards or PIN codes. ScriptPro said it will use Xelios Biometrics during the prescription dispensing process to identify authorized pharmacy staff and track and store information about who handles a prescription. The goal is to provide ScriptPro customers with a biometric alternative to replace ID cards and PIN codes currently in use, the company noted. Xelios Biometrics is a leading developer and supplier of biometric identity solutions based on technologies originally developed by Safran for police and military applications. The company said its products are used worldwide for identity authentication, fraud prevention and securing access to facilities and information networks. ScriptPro “develops, provides and supports state-of-the-art, roboticsbased management, workflows, and telepharmacy systems for pharmacies,”

Technology 33

Pharmacy Practice News • October 2013

Bytes the company noted, adding that the products help pharmacies “lower operating costs, reduce medication errors and maximize customer satisfaction.” ScriptPro provides automation “to thousands of pharmacies worldwide.”

Florida Pharmacists’ App Wins Microsoft Challenge

ealth eConnect, a prototype smartphone app created by research fellow Zaher Hajar, PharmD, and a team of colleagues at Nova Southeastern University’s College of Pharmacy’s Center for Consumer Health Informatics Research (CCHIR), has won an international contest seeking the most innovative apps to manage health. Sponsored by Microsoft, the contest, which called on innovators to design a next-generation health management app, awards a $10,000 first prize as well as what many smartphone app designers might regard as an even better bounty: inclusion as one of the Windows 8 “preferred partners” for 2013-2014, and a waiver of the standard $20,000 “go-live” fee when the app is submitted to the Windows store. Dr. Hajar and his team, including CCHIR’s director, Kevin Clauson, PharmD, designed Health eConnect to leverage the individual health data that are

stored on Microsoft’s HealthVault platform. The app uses a wireless interface to connect with devices such as blood pressure cuffs, glucometers and activity trackers, and then gives patients a user-friendly, visually appealing assessment of their health status, along with reminders about what they need to do to actively manage their health. “The pharmacist is the most accessible health care provider nowadays, and we know what the patient needs in terms of engagement,” Dr. Hajar told Pharmacy Practice News. “We wanted to

design an app that would really help individuals with their day-to-day health management.” Because the Microsoft challenge was only one month long, Dr. Hajar and his team chose one piece of the app—the blood pressure section—to complete as a prototype. With the award secure, they now plan to design the medication section in a way that will sync with major pharmacy chains that are compatible with Microsoft HealthVault. “Then we can

use this information to provide specific tips and cues that may educate patients and help them better adhere to their medication regimens.” With a planned submission of Health eConnect to the Windows store by December 2013 to meet Microsoft’s “preferred partner” deadline, Dr. Hajar said the team is “excited to test the app in the real world and conduct clinical studies about the beneficial use of the app by consumers.” —Gina Shaw

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34 Final Word

Pharmacy Practice News • October 2013

Opinion

Sounding Off on AMA Resolution We’ve received a steady stream of reader responses to the article, “Pharmacists Feeling Pain Over AMA Resolution” (Pharmacy Practice News August 2013;40:1,16), which detailed attempts by the American Medical Association (AMA) to put limits on the ability of “big-box” pharmacies, such as Walgreens, to question physicians’ prescriptions for opioids and other abuse- and misuse-prone controlled substances. Here is a selection of comments on both sides of the debate over just what role— if any—pharmacists should play in the vetting of these prescriptions.

Walgreens Doing Too Much …

It’s Our Right To Question Opioid Prescriptions

I have seen how Walgreens’ interference with patients’ prescriptions has resulted in our patients not receiving their necessary prescriptions and going without pain control unnecessarily, sometimes for days. Furthermore, some patients have been made to feel so bad, being treated by Walgreens staff like some drug-abusing criminal, that they will no longer take the medication that could significantly impact their quality of life. Collaboration between pharmacists and medical staff is critical, but should not be at the unnecessary badgering of the physician and especially not at the suffering of the patient. —“nbumg” Via website Sept. 13, 2013

Physicians who complain about pharmacists questioning opioid prescriptions are overreacting to the situation; they should instead take an honest, critical look at their own prescribing habits when it comes to opioids. Hopefully, electronic prescribing will resolve this issue, as there are certain requirements that will force the physician to write prescriptions in the proper manner and for the appropriate indications. As for the criticisms that Walgreens pharmacists were being too aggressive in their review of opioid prescriptions, if there is a problem with certain chain pharmacies then it should be addressed with them. AMA has no right to say pharmacists are “intrusive.” Since pharmacists are taking care of the patient, they too should know enough about the patient so they can safely dispense these prescriptions. It is their right. Physicians, on the other hand, should not feel second-guessed or their time wasted when speaking to the pharmacist. There needs to be an interdisciplinary communication for resolving these issues, but AMA’s involvement in this manner so far does not improve the communication between the two professions.

… Or Too Little? Kermit Crawford [president of the Pharmacy, Health and Wellness division of Walgreens] is not telling the truth [about the chain’s commitment to prevent drug abuse]. When I worked for Walgreens in Florida, we were threatened with disciplinary action if we refused to fill narcotic prescriptions. Management told us that it is unethical for us to question a patient [seeking to fill a prescription for] narcotics, even if they drove a car with Tennessee plates and carried a North Carolina driver’s license. Oh, did I mention these patients all paid cash, and their prescriptions were all written in even hundreds and the patients wanted them left in the original bottles? I had a woman in a new Thunderbird convertible drive up to the window one evening and pay $1,000 in cash for her prescriptions. Of course, I did the ethical thing by Walgreens standards and sold them to her. I felt like taking a shower afterward, but at least I still had my job. By the way, I have no respect for the AMA. It is a political organization, and I could [not] care less what they think. —“rchar” Via website Sept. 16, 2013

—“Karen” Via website Sept. 2, 2013

MD: We Should Welcome Collaboration We docs can’t run the show by ourselves. Medical care is a team sport. We are all taking care of patients and can’t do it right if our egos get in the way. —“drmfr” Via website Aug. 8, 2013

Physicians, Heal Thyself Really? Drug abuse and fraudulent use of controlled substances is not a new subject, and pharmacists have been on the front lines fighting this problem for many years. I am sorry if there are some

physicians who may feel that their toes are being stepped on by our actions. Do these physicians think pharmacists have nothing better to do than fill out the paperwork and fax physicians? If the physician is getting these faxes, then there are red flags on these individuals for a good reason. Thank you, AMA, for neglecting your portion of the problem and trying to cover it up by sweeping it under the carpet! It should also be remembered here that pharmacists are NOT the ones prescribing and writing the prescriptions. AMA, just what are you doing to regulate your portion of the problem? —“kathe” Via website Aug. 7, 2013

Are We Forgetting HIPAA Violations? What is forgotten in this debate is this: The physician CANNOT legally provide the patient and prescription information being requested by Walgreens and others. Verbal transmission to an unverified third party of a patient’s personal health information is a punishable HIPAA violation. Thus as a physician, I could not provide detailed information to a calling putative pharmacist even if I wanted to—and so I don’t. In fact, until or unless pharmacists perform comprehensive patient evaluations (never will happen), most of the information Walgreens is requesting is legitimately off-limits. As Dr. Hopkins noted [in the sidebar, “A Pain Physician’s Perspective”], communication about prescription opioid problems is welcomed. Requesting information to which the pharmacy is not entitled is an unwelcome intrusion and a waste of time. —“dr.no” Via website Aug. 7, 2013

Who Am I To Question A Prescriber? As a pharmacist, I agree with the AMA position and appreciate where it’s coming from. But the AMA doesn’t understand the level of scrutiny that phar-

macies and pharmacists are currently dealing with when it comes to government regulators, such as the Drug Enforcement Administration (DEA). The DEA states in its handbook for pharmacists that pharmacists have a “corresponding responsibility” along with the prescriber when it comes to filling a controlled substance prescription. In addition, the agency continues, “a prescription issued not in the usual course of professional treatment or in legitimate and authorized research is an invalid prescription within the meaning and intent of the Controlled Substances Act (CSA).” What? Who am I to question physicians? Doesn’t their license to practice imply they have the appropriate level of knowledge and skill to write that prescription? I’m not saying we should bury our heads in the sand and blindly fill every script; rather, use common sense. I run a closed-door pain specialty pharmacy and deal with these issues every day. I’ve heard this same complaint from the physicians whom we deal with, but then I proceed to explain why we ask or do what we do. They get it after an explanation. In fact, the problem isn’t the pharmacists or the physicians; it’s the DEA and its ignorance. We can’t grow our business because of all this crap. Our wholesaler has allocation limits on the controlled substances that we order. So we never know when we hit our limit until after it’s too late. I don’t fault the wholesaler either; they’re getting pressured from the DEA as well. What really bothers me is the vast majority of these patients are legitimate people who need these medications and can’t access them because of this regulatory mess. I had a woman call me just yesterday, crying because every pharmacy she contacts states they don’t stock OxyContin. She’s been wheelchair-bound for 20 years and suffers with chronic pain secondary to multiple sclerosis. I told her we could fill her prescription, and also told her to call her congressman/woman after explaining what’s going on as it relates to this problem. I could go on, but to sum up, this all comes down to ignorance, a poorly informed media and a knee-jerk government response, along with poor communication. We can do better. —“john” Via website Aug. 7, 2013

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Contemporary Management of

Hyponatremia JOAN M. STA TACHNIK AC ACHNIK K, PH HARM ARMD, AR D, B BC BCPS CPS PS Clinical Associate iate e Professor Pro ofess of sso sso o orr Department off P Pharmacy Practice harm macy Pra mac ma P rac ac a cttic tiic ice College of Pharmacy arm macy y University of Illinois att C Chicago llin nois a hi ag hic hi ago go g o Chicago, Illinois is

yponatremia, a common electrolyte imbalance, generally is defined as a serum sodium concentration of less than 135 mEq/L.1 Patients with acute or moderate to severe

hyponatremia may present with neurologic signs and symptoms, and may be at risk for long-term complications. However, even patients with mild, chronic forms of the disorder may be at risk for significant morbidity, making recognition and appropriate treatment essential.2-4

Classification and Epidemiology Hyponatremia can be classified by rate of onset, as either acute (ie, rapid-onset) or chronic, and by the degree of sodium deficitâ&#x20AC;&#x201D;mild (125-130 mEq/L), moderate (115-125 mEq/L), or severe (110-115 mEq/L). Estimates of the prevalence of hyponatremia vary, ranging from less than 1% to 45%, depending on the setting and the population studied. High rates of hyponatremia have been reported in hospitalized patients, with about 40% having low sodium levels either at hospital admission or during a hospital stay.5,6 In a retrospective study, Wald et al reviewed the discharge records of 53,236 hospital admissions for which serum sodium was recorded, along with information on mortality, length

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of stay, and patient disposition at time of hospital discharge.6 At the time of admission, low serum sodium levels (referred to as community-acquired hyponatremia) were present in 37.9% of hospitalizations. Hyponatremia worsened during the hospital stay for 5.7% of these hospitalizations. Hospital-acquired hyponatremia (in which serum sodium levels were within normal range at the time of admission) occurred in 38.2% of hospitalizations. In a similar analysis, using data from the American College of Surgeons National Surgical Quality Improvement Program, Leung et al identified 75,423 patients with hyponatremia out of a cohort of 964,263 adults undergoing major surgery, for a prevalence of about 8%.7

P H A R M AC Y P R AC T I C E N E WS â&#x20AC;˘ O C TO B E R 2 0 1 3

The prevalence of hyponatremia also has been assessed in specific patient populations, including patients with heart failure, cancer, and cirrhosis. In an analysis of data from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Patients with Heart Failure) registry, Gheorghiade et al reported that 9,368 of 47,647 patients with heart failure (19.7%) had hyponatremia at study entry.8 Klein et al reported a somewhat higher prevalence of hyponatremiaâ&#x20AC;&#x201D;256 of 943 patients with heart failure (27%)â&#x20AC;&#x201D;in the OPTIMECHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) study.9 More recently, Shchekochikhin et al conducted a retrospective analysis of 5,347 patients with heart failure who were admitted to a single institution over a 7-year period.10 The authors identified community-acquired hyponatremia in 19.4% of the admitted patients; another 30.2% of the patients who had normal sodium levels at admission developed hyponatremia during their hospital stay. Among patients with cancer, Doshi et al reported hyponatremia in 1,596 of 3,357 patients (47%) admitted to a single institution over a 3-month period.5 Among patients with cirrhosis, higher rates of hyponatremia have been reported. In a prospective study evaluating 997 patients with cirrhosis from 28 hospitals and clinics, 49.5% of those patients had hyponatremia. When only hospitalized patients were considered, 57.4% had hyponatremia. For outpatients, the prevalence was 40.2%.11

The Clinical Burden Hyponatremia has been associated with significant morbidity and mortality, regardless of severity. A study reported that the lower the hospital admission serum sodium level, the greater the risk for poorer outcomes, including in-hospital mortality, need for discharge to short- or long-term care facilities, and longer hospital stays.6 Compared with patients admitted with a serum sodium of 138 to 142 mEq/L, those with a serum sodium less than 138 mEq/L had an adjusted odds ratio (OR) for in-hospital mortality of 1.52 (95% confidence interval [CI], 1.36-1.69). As serum sodium levels decreased, the risks for all 3 outcomes increased, and all differed significantly from risks of patients with normal-range sodium levels. Among 3,075 patients admitted to the hospital with a serum sodium of 128 to 132 mEq/L, there were 151 in-hospital deaths, for an OR of 1.99 (95% CI, 1.65-2.40) relative to patients with normal levels. This risk for in-hospital death increased to 2.46 (95% CI, 1.38 to 4.90) for those with sodium levels 122 mEq/L or lower. Similar results were seen for hospital length of stay, with an OR of 1.09 (95% CI, 1.05-1.14) for hyponatremic patients. For patients who acquired hyponatremia during their hospital stay, the OR for in-hospital mortality was 1.66 (95% CI, 1.39-1.98) compared with patients

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without hyponatremia. The rate of discharge to a care facility and the need for a longer hospital stay also were both significantly increased among patients with hospital-acquired hyponatremia. The effects of hyponatremia on surgical outcomes also have been investigated. A large cohort trial included 964,263 patients undergoing major surgery over a 5-year period and compared outcomes between patients with preoperative hyponatremia (75,423 patients) and those with normal-range serum sodium (888,840 patients).7 The primary outcome of the study was 30-day mortality. The types of surgery varied, with most procedures (about 70%) described as general surgery. A total of 15,630 deaths occurred within 30 days of surgery. The risk for death was highest among patients with moderate to severe hyponatremia (sodium <130 mEq/L), with an OR of 1.72 (95% CI, 1.58-1.88) compared with those with normal-range sodium levels. The risk also was significantly increased among patients with mild preoperative hyponatremia (sodium 130-134 mEq/L) (OR, 1.38; 95% CI, 1.32-1.45). Secondary outcomes, such as major coronary events, wound infection, and pneumonia, also were significantly increased among patients with preoperative hyponatremia. Crestanello and colleagues investigated the effects of hyponatremia in a cardiac surgery population. Among 4,850 patients who underwent cardiac surgery, hyponatremia was seen in 59% during hospitalization after surgery.12 Both 1-year and 5-year mortalities were increased in the presence of postoperative hyponatremiaâ&#x20AC;&#x201D;15.6% and 39.4%, versus 7.9% and 25.0% in patients with normal-range sodium levels, respectively (P<0.001). In addition, hospital length of stay was prolonged significantly (10.7 vs 7.0 days), with significantly higher rates of operative, infectious, pulmonary, and renal complications (P<0.001 for all comparisons). Poorer outcomes also have been reported among hyponatremic hospitalized patients with heart failure, liver disease, and cancer.5,10,13 In-hospital mortality, length of stay, in-hospital worsening of kidney function, and need for discharge to a short- or longterm care facility were significantly increased in the presence of hyponatremia, whether present at hospital admission or acquired during the hospital stay. The risk for death among patients with liver disease also may be increased in the presence of hyponatremia.13 In a study of nearly 14,000 patients who had severe liver disease and were awaiting liver transplantation, the risk for death increased by 5% for every unit decrease in serum sodium when levels were between 125 and 140 mEq/L. Increases in mortality and hospital length of stay also have been reported in cancer patients with hyponatremia, whether the hyponatremia was mild, moderate, or severe, compared with patients with normal sodium levels.5

Mild hyponatremia also may increase the risk for falls and fractures, especially in elderly individuals. In a series of patients admitted for hip fractures secondary to a fall, Kengne et al reported that 13% (67 of 513 patients) had mild asymptomatic hyponatremia (mean serum sodium level 131 mEq/L), compared with 3.9% (20 of 513) of a similar group of patients without a fracture.14 Although the exact mechanism of the relationship of hyponatremia to falls is unclear, low sodium levels have been suggested to cause impairment of both gait (balance and posture) and attention compared with normal sodium levels. Beyond hyponatremia’s effects on general health, this disorder has a significant economic impact.15 Treatment for hyponatremia in the United States, in either inpatient or outpatient settings, has been estimated to cost between $1.6 billion and $3.6 billion annually. In a retrospective analysis, Amin estimated significantly higher health care costs for hospitalized patients with hyponatremia than for non-hyponatremic patients—$15,281 versus $13,439 (P<0.001).16 This cost difference was seen for several subgroups based on reasons for admission, including community-acquired pneumonia, heart failure, and chronic obstructive pulmonary disease.

Mechanisms of Water–Sodium Balance The balance of both water and sodium is important for the regulation of plasma osmolality and blood volume.1 Water in the body is divided between the extracellular (approximately 33%) and intracellular (approximately 67%) compartments.17 Sodium (and its associated anions) is the major determinant of the osmotic pressure and volume of extracellular fluids (ECFs); therefore, any changes in total body content of sodium can result in changes in ECF osmolality. Similarly, intracellular osmotic pressure primarily is determined by potassium. Normally, the osmolality of the intracellular fluid (ICF) and ECF is the same, maintained by the free exchange of water between the 2 compartments and a balance of the solutes sodium and potassium (referred to as effective osmoles).1,18 However, changes in the osmolality of the ECF will influence this free-water exchange between the 2 compartments. Hypertonicity of the ECFs (as with excessive sodium) will result in a decrease in ICF volume (ie, a shift in free water to the extracellular compartment). Hypotonicity (as with low sodium) will cause an increase in ICF volume (ie, a shift in free water to the intracellular compartment). This increase in ICF volume is especially important in cerebral tissues, where an increase in cell volume can result in significant cellular damage. Other mechanisms also can affect the water–sodium balance. Water retention or metabolism is controlled primarily by arginine vasopressin (AVP or antidiuretic hormone), a peptide produced by the pituitary gland in

response to osmotic and non-osmotic changes.19-21 An increase in plasma osmolality results in stimulation of AVP secretion by osmo-receptors in the anterior hypothalamus, causing antidiuresis and reabsorption of water into the circulation. This, along with stimulation of thirst, results in a decrease in water excretion and an increase in water intake.1,19,21 When plasma osmolality is below a biologically preset threshold (approximately 280 mOsm/kg), AVP levels usually are undetectable, allowing for excretion of free water and normalization of osmolality.20,21 Secretion of AVP also is stimulated via a more potent non-osmotic mechanism—arterial stretch baroreceptors—in response to a reduction in blood pressure or blood volume of approximately 8% to 10%. Although osmotic mechanisms generally control AVP secretion over non-osmotic mechanisms, under certain pathophysiologic conditions, such as cardiac failure or liver cirrhosis, pressure and volume responses for AVP secretion predominate and allow for elevated AVP levels despite low plasma osmolality, resulting in hyponatremia.

Causes of Hyponatremia Hyponatremia usually results when there is a loss of balance between intake and excretion of water, or from renal or extra-renal sodium loss.22 Initial evaluation of a patient with hyponatremia generally includes plasma or serum osmolality and volume status to determine the type of hyponatremia and to identify possible causes (Tables 1 and 2).18,23 Plasma osmolality, which is normally between 280 and 295 mOsm/kg with normal hydration, can determine whether the hyponatremia is isotonic, hypertonic, or hypotonic.

Hypotonic Hyponatremia Hypotonic hyponatremia is the most common type and also is associated with critical illnesses.24 It can be further classified based on ECF status (including urine osmolality and sodium) as hypovolemic, euvolemic, or hypervolemic.23 Hypovolemic hyponatremia results in reductions in both total body water (decreased ECF) and, to a certain extent, total body sodium.18,23 Urine osmolality is elevated (>450 mOsm/kg). Urine sodium measures can indicate the cause of water and sodium loss. Urine sodium of less than 20 mEq/L suggests extra-renal loss, such as diarrhea, vomiting, excessive sweating, or blood loss.1,24 High urine sodium levels (>20 mEq/L) indicate renal loss of sodium and water as a cause, such as diuretic use, adrenal insufficiency, or certain nephropathies. Euvolemic hyponatremia presents with clinically normal ECF volume and is the most common of the hypotonic hyponatremias.18,24 Although total body water is increased, it is not enough to cause edema, making the patient appear clinically euvolemic.1 Euvolemic

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Table 1. Types of Hyponatremia by Plasma Osmolality Isotonic

Hypertonic

Hypotonic

• Pseudohyponatremia due to an artifactual reduction in sodium that is caused by elevation of the nonaqueous, non-sodium portion of plasma by proteins and lipids relative to the aqueous portion, with no true reduction in total sodium

• Elevation in plasma osmolality due to presence of effective osmoles (eg, glucose, mannitol, sorbitol) and movement of water from intracellular to extracellular spaces

• Excess water relative to effective osmoles (solute) in extracellular space that is caused by either a decrease in total body solute (depletion) or an increase in total body water (dilution)

• No movement of water between extracellular and intracellular spaces

• Plasma osmolality: >295 mOsm/kg

• Result is a reduction in serum sodium with elevated osmolality

• Plasma osmolality: <280 mOsm/kg

• Plasma osmolality: normal range

Based on references 18, 23, and 24.

hyponatremia is most commonly the result of the syndrome of inappropriate antidiuretic hormone (SIADH), in which water intake exceeds excretion by the kidney. Urine osmolality generally is higher than 100 mOsm/ kg and urine sodium levels are high (>20 mEq/L). Euvolemic hyponatremia also can result from primary polydipsia (water intake >20 L/d) or very low-solute diets. In this case, urine osmolality is less than 100 mOsm/L and the urine sodium level is low (<20 mEq/L). Hypervolemic hyponatremia is associated with excess total body sodium, along with a greater expansion of total body water, resulting in hyponatremia with clinically evident edema.18,24 The increase in total body water results from a reduction in water excretion by the kidneys—a response to a decrease in effective circulating blood volume.1,18 Conditions associated with hypervolemic hyponatremia include heart failure, cirrhosis, and nephrotic syndrome.18 Urine osmolality is higher than 100 mOsm/kg, with a urine sodium concentration of less than 20 mEq/L.1

Clinical Presentation Symptoms of hyponatremia vary greatly, depending on the type and degree of hyponatremia and the rate of onset.1,2,25 Hypovolemic hyponatremia typically causes signs of dehydration, such as dry mucous membranes, tachycardia, and hypotension.25 Hypervolemic hyponatremia can cause peripheral or pulmonary edema; these are not present with euvolemic hyponatremia. Symptoms of hyponatremia also differ depending on the degree of sodium loss. Individuals with mild (>125-130 mEq/L) and chronic hyponatremia generally are asymptomatic. However, it has been suggested that symptoms of mild hyponatremia may be too subtle to notice, yet result in significant morbidity among certain patient groups, such as the elderly.2 Moderate to severe hyponatremia or rapid-onset (≤48 h) hyponatremia may present with neurologic symptoms ranging from confusion,

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agitation, or impaired mental function to seizures and coma if sodium levels fall to less than 115 mEq/L.25,26 The rate of change in sodium levels may be especially important because a rapid drop in sodium does not allow the cells of the brain time to adapt to the change in osmolality, resulting in cerebral edema as water moves intracellularly.18 Although solutes such as sodium and potassium move from the brain cells to the extracellular space quickly, other solutes (organic solutes such as taurine, creatine, and glutamine) are slower, requiring up to 48 hours to completely compensate for the fluid shift.1,25,26 Onset of hyponatremia over several days, even if severe, allows time for this adaptation process and reduces the risk for cerebral edema.

Treatment of Hyponatremia Treatment of hypertonic or isotonic hyponatremia generally consists of addressing the underlying cause of the sodium decrease.18,24,25 For example, hypertonic hyponatremia secondary to hyperglycemia may resolve with a reduction in blood glucose.25 For isotonic hyponatremia (an artifactual decrease in serum sodium concentrations), appropriate laboratory assessment is needed to determine the true serum sodium concentration.24,25 The following section relates primarily to the treatment of hypotonic hyponatremia.

SODIUM CHLORIDE INFUSIONS Because of the risk for cerebral edema and death, acute symptomatic, severe hyponatremia is considered a medical emergency.27 Although prompt treatment is needed, too rapid a correction of serum sodium levels should be avoided because of the risk for osmotic demyelination or central pontine demyelination, a potentially severe neurologic complication.23,25,26,28 However, cerebral edema and severe neurologic symptoms generally can be reduced or stopped with only a small increase in serum sodium—about a 5% increase for cerebral edema

Table 2. Common Etiologies for Hyponatremia Hypotonic Isotonic

Hypertonic

Hypovolemic (Depletional)

Euvolemic (Dilutional)

Hypervolemic (Dilutional)

• Marked hyperlipidemia

• Hyperglycemia

• Diuretics

• SIADH

• Heart failure

• Mannitol administration

• Mineralocorticoid deficiency

• Glucocorticoid deficiency

• Cirrhosis

• Vomiting/diarrhea

• Hypothyroidism

• Nephrotic syndrome

• Excessive sweating

• Polydipsia

• Renal failure

• Marked hyperproteinemia

• Burns SIADH, syndrome of inappropriate antidiuretic hormone Based on references 17, 18, and 23.

and a 3 to 7 mEq/L increase for seizures.26 Therefore, an initial rate of correction of 1 to 2 mEq/L per hour for several hours has been recommended for patients with severe symptoms. This rate can be reduced once symptoms begin to subside or a serum sodium level of 125 to 130 mEq/L (or lower if starting level is ≤100 mEq/L) is achieved. Other researchers have recommended slowing the infusion rate when a sodium level of 118 to 120 mEq/L has been reached and the patient is asymptomatic.23 Regardless, the sodium level should not be increased by more than 8 to 12 mEq/L in the first 24 hours, because correction rates higher than this are associated with an increased risk for osmotic demyelination.1,22,23,26 A more conservative limit of 6 mEq/L also has been advocated.29,30 Several methods for calculation of the infusion rate for sodium chloride are available. One method calculates the rate of infusion based on total body water, the change in sodium per liter of solution infused, the target sodium increase, and the desired rate of sodium correction (Table 3).1,22,23,26 (For general management strategies, see Table 4.1,26,30-33) There is some concern regarding the use of hypertonic sodium chloride infusions, such as 3% sodium chloride, for correction of hyponatremia.1 These infusions can rapidly correct serum sodium in emergent situations and may be needed when isotonic infusions are not appropriate, such as for SIADH. However, there is a risk for too rapid a correction with hypertonic solutions, with the potential for osmotic demyelination. One approach to avoid overcorrection in severe chronic hyponatremia that has been described in the literature is the use of desmopressin (2 to 4 mcg given every 8 hours) with 3% sodium chloride.29,34 Desmopressin, which prevents water diuresis that may occur in some patients with severe chronic hyponatremia, helps decrease the likelihood of overcorrection of sodium.35 However, this strategy has not been supported by some authors due to concerns that it might

worsen hyponatremia, rather than correcting the imbalance, and increase the risk for pulmonary edema from sodium and water retention.30 Overall, for the treatment of severe hyponatremia, the risks and benefits associated with any approach to sodium correction should be considered. In nonemergent situations when patients are asymptomatic or have mild to moderate symptoms, 0.9% sodium chloride may be used to slowly correct sodium levels as well as to replace deficits in ECF volume for those who are hypovolemic.

FLUID RESTRICTION For patients with nonemergent euvolemic or hypervolemic hypotonic hyponatremia, fluid restriction has been recommended, along with identification and correction of underlying causes.1,18,19,22 Fluid intake usually is restricted to no more than 1,200 mL per day, so that urine output and insensible losses exceed intake, resulting in a negative water balance. For example, in a patient with a urine output of 550 mL per day, with 200 mL of insensible losses, fluid should be restricted to less than 750 mL per day.19

DRUG THERAPY Conventional Therapies. For some patients with chronic forms of hyponatremia, such as hyponatremia secondary to SIADH, fluid restriction may be difficult to maintain, necessitating drug therapy.18,22 Demeclocycline is a tetracycline derivative that inhibits tubular AVP activity, leading to a decrease in plasma osmolality and an increase in serum sodium levels.1,18,22 When used for hyponatremia, the dose ranges from 600 to 1,200 mg daily in divided doses. Lithium carbonate also has been used and has an effect that is similar to that of demeclocyline, increasing water clearance and serum sodium levels. Doses have ranged from 900 to 1,200 mg per day. However, because of its adverseeffect profile and less consistent effects, the use of

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Table 3. Calculation for Rate of Sodium Chloride Infusion Formula for Sodium Chloride Infusions

Sodium Content of Infusions a

Total body water = weight (kg) x % body water

5% sodium chloride

855 mEq/L

Change in sodium per liter of infusion = (infusion sodium content – baseline serum sodium) / (total body water + 1)

3% sodium chloride

513 mEq/L

Infusion rate = (target serum sodium increase / change in sodium per liter of infusion) administered over desired time

0.9% sodium chloride

154 mEq/L

0.45% sodium chloride

77 mEq/L

Calculation example 68-year-old man, weighing 60 kg, presents with lethargy and extreme confusion and a serum sodium of 108 mEq/L. Assuming a 3% sodium chloride infusion is appropriate, what infusion rate is needed to increase serum sodium by 5 mEq/L over the next 12 h? Total body water = 60 x 0.6 = 36 L Change in sodium per liter of 3% sodium chloride = (513 – 108) ÷ (36 + 1) = 10.9 mEq/L Infusion rate = 5 ÷ 10.9 = 0.46 L over 12 h or 38 mL/h for 12 h a

0.6 for men, 0.5 for women, 0.5 for men >70 years, 0.45 for women >70 years.1,25

Based on references 1, 22, 26, and 27.

lithium is limited in this setting. Diuretics have been used in the treatment of hypervolemic hyponatremia in addition to fluid restriction to help reduce volume overload in patients with underlying causes such as heart failure.22,25 Although loop diuretics are more potent for producing diuresis, thiazide diuretics are more likely to cause hyponatremia, possibly secondary to impairment of renal diluting mechanisms.36 The risk for hyponatremia is lower with loop diuretics because these agents affect both renal concentrating and diluting mechanisms.37,38 Arginine Vasopressin Receptor Antagonists. The AVP receptor antagonists are a newer class of agents approved for the treatment of hypervolemic or euvolemic hypotonic hyponatremia.31,32 Two agents are available— conivaptan (Vaprisol, Astellas) and tolvaptan (Samsca, Otsuka America). These agents block one or both of the AVP receptors (V2 or V1a). Antagonism of the V2 receptors on the renal collecting tubules and vascular endothelium results in the stimulation of water excretion with no significant increase in solute excretion.18,33 The lack of solute (ie, sodium) excretion by these agents results in increases in serum sodium levels. This effect has been referred to as aquaresis rather than diuresis because there is only loss of free water. Blockade of the V1a receptors, located on vascular smooth muscle cells, may reverse the vasoconstriction mediated by these receptors.18 Tolvaptan is an orally administered AVP receptor antagonist of the V2 receptor that is indicated for

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treatment of euvolemic or hypervolemic hyponatremia in symptomatic patients who have failed fluid restriction.31 In the SALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) trials, tolvaptan resulted in greater increases in serum sodium compared with placebo within 8 hours of first treatment among patients with hyponatremia secondary to heart failure, cirrhosis, or SIADH.39 By day 4, significantly more patients had normalization of serum sodium levels with tolvaptan than with placebo. Conivaptan is a parenteral AVP receptor antagonist of the V2 and V1a receptors that also is indicated for the treatment of euvolemic or hypervolemic hyponatremia.32 In a study involving 84 patients with hypervolemic or euvolemic hyponatremia (serum sodium 115-130 mEq/L) given conivaptan 20 mg as an intravenous loading dose followed by a 40- or 80-mg continuous infusion per day for 4 days, conivaptan resulted in significantly greater increases in serum sodium concentrations compared with placebo.40 Increases of 4 mEq/L over baseline with conivaptan were seen within the first 24 hours; this effect did not occur with placebo. At 72 hours, increases with conivaptan were 6.9 and 8.8 mEq/L over baseline, whereas serum sodium was increased by 1.9 mEq/L with placebo. In this study and both SALT trials, patients with hypovolemic hyponatremia were excluded from participation.39,40 For both tolvaptan and conivaptan, close monitoring of serum sodium levels is necessary to avoid too

Table 4. General Management Strategies for Hypotonic Hyponatremia Treatment Sodium chloride infusion

Clinical Issues 3% or 0.9% solution Euvolemic and hypervolemic patients: may require hypertonic sodium chloride (3%) to avoid volume overload and worsening of hyponatremia

• Rate of correction depends on severity of symptoms but should not exceed 6-8 mEq/L in 24 h to lessen risk for osmotic demyelination

Hypovolemic patients: may require 0.9% sodium chloride to replace extracellular fluid Fluid restriction

1,200 mL/d or less (intake should be less than urine output and insensible losses combined)

• All fluids need to be restricted • Slow onset • Compliance difficult • Increase in serum sodium generally small (1-2 mEq/L per day) • May require addition of sodium chloride and/or loop diuretics

Demeclocycline

600-1,200 mg/d in divided doses

• Slow onset (3-6 d) • Expensive • Potential for nephrotoxicity, especially with concurrent liver disease

Lithium

900-1,200 mg/d

• Slow onset • Less predictable effects

Conivaptan

Tolvaptan

20 mg IV bolus followed by 20 mg as continuous infusion over 24 h for up to 4 d; up to 40 mg/d may be administereda

• Only indicated for euvolemic or hypervolemic hyponatremia

15 mg once daily titrated to a maximum of 60 mg once daily

• Only indicated for euvolemic or hypervolemic hyponatremia

• Avoid increases of serum sodium >12 mEq/L per 24 h • Potential for drug interactions via CYP3A4 isoenzymes

• Therapy should be initiated in the hospital to allow for close monitoring of serum sodium levels • Avoid increases of serum sodium >12 mEq/L per 24 h • Potential for drug interactions via CYP3A4 isoenzymes

Although higher doses have been used in clinical trials, the maximum dose per product labeling is 40 mg over 24 hours.

Based on references 1, 26, and 30-34.

rapid sodium correction.31,32 Although tolvaptan is an oral agent, therapy should be initiated in the hospital setting to allow for sodium monitoring. In addition, because of the potential for serious liver injury, use of tolvaptan should be limited to 30 days.

Summary Hyponatremia can result in significant morbidity a n d m o r t a l i t y, m a k i n g i t s r e c o g n i t i o n a n d

appropriate treatment essential. Prompt treatment of hyponatremia is critical if severe sodium deficits are present, or if the onset is rapid, to avoid cerebral edema and progressive neurologic effects. Sodium chloride infusion is the most commonly used treatment for acute hyponatremia. For more chronic hyponatremia, other therapies, such as fluid restriction or agents that inhibit the actions of AVP, can be used.

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