Pharmacy Practice News - July 2019 by McMahon Group

The Best-Read Pharmacist’s News Source

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CLINICAL

ASHP opposed to removal plan

The case for marijuana Rx in PTSD and anxiety ....................... 17 Tailoring nutrition to challenging patient populations ...

POLICY

Ensuring access to medications remains a moving target ...........

The push for reimbursement transparency ..................

OPERATIONS & MGMT

Care transition project cuts hospital readmissions ..................

TECHNOLOGY

Cybersecurity a big problem even for small pharmacies ........

Safe Harbor For Rebates Not So Safe?

Volume 46 • Number 7 • July 2019

Patient Safety Gaps Still At ‘Unacceptable’ Levels

San Diego—A proposed rule published by the Department of Health and Human Services Office of Inspector General (OIG) earlier this year that would eliminate discount safe harbor protection for drug manufacturer rebates offered to Medicare Part D and Medicaid managed care plans has plenty in the pharmacy industry up in arms. Some 25,000 comments poured in to the OIG through early April from multiple stakeholders, including pharmacy benefit managers (PBMs), health plans, drug manufacturers, pharmacies and professional associations. “This is probably the biggest change to the drug supply chain since the creation of Part D, and it arguably may be one of the biggest changes to how actual drug transactions happen at

Boston—Patient safety is a public health issue that needs a total systems approach, and leaders must establish and maintain a culture of safety, according to a presentation at the 2019 ASHP Summer Meetings & Exhibition. Years after the Institute of Medicine released its landmark report “To Err is Human,” on medical errors in 1999, there has been no great epidemiological study that proves our health care system is safer now than it has been, said Tejal Gandhi, MD, MPH, the chief clinical and safety officer for the Institute for Healthcare Improvement (IHI). While we tend to focus on physical harm from errors, they also result in emotional, psychological and financial harms, Dr. Gandhi said.

Continued on page 32

Continued on page 12

SPECIALTY PHARMACY

Atopic dermatitis: tips for managing patients and d payors ...

Site-of-care optimization also works for health systems .............................

New Guideline On UTI Testing Urges Caution

The Roles of the Anesthesiologist, Pharmacist, and Nurse in Detecting and Preventing Opioid Diversion and Misuse See insert after page 24.

creening and testing for urinary tract infections (UTIs) should be limited to patients who are at risk for developing complications of asymptomatic bacteriuria (ASB) to avoid overdiagnosis and unnecessary antibiotic treatment. That is the verdict of an updated clinical practice guideline for the management of ASB by the Infectious Diseases Society of America (Clin Infect Dis 2019 Mar 21. [Epub ahead of print]). Continued on page 26

Adolescent Cancer Survivors Face an Uphill Toxicity Fight Fort Worth, Tex.—Aggressive identification and treatment strategies have led to an overall cure rate for childhood malignancies of greater than 80%, but an increasing number of surviving patients are developing therapyrelated toxicities later in life. At the 2019 annual meeting of the Hematology/Oncology Pharmacy Association (HOPA), Joseph Sciasci, PharmD, and Mary Mably, RPh, reviewed strategies for reducing the impact of late and specific effects of treatment on young adult and adolescent survivors of cancer. According to Dr. Sciasci, a clinical pharmacy specialist with the Cancer Center and the

Blood and Marrow Transplant Program at Children’s Hospital of Philadelphia, children, adolescents and young adults with cancer have benefited from protocol-based chemotherapy plans. Protocols led by cooperative groups have helped to increase enrollment, identify high- and low-risk patients, and increase overall survival while decreasing treatment-related toxicities. However, survivors still have a reduced life expectancy. “These patients are dying earlier and have a higher incidence of chronic health conditions … earlier in life [than] their peers,” Dr. Sciasci said.

Focus on

Medication Safety Section begins on page 4.

Continued on page 20

Clinolipid

(LIPID INJECTABLE EMULSION), FOR INTRAVENOUS USE

Provide your PN patients with a lipid option to help meet their nutrition needs. Clinolipid has le ess soybean oil than oth her commerrcially available lipid emulsions and delivers more Ome ega-9 fatty acids a than other lipid injectable emulsions.

An 80% Olive, 20% Soybean oil lipid emulsion

Please see Brief Summary including boxed warning below

Brief Summary of Presscribing Information See Package Insert forr Full Prescribing Information HIGHLIGHTS OF PRESC CRIBING INFORMATION These highlights do nott include all the information needeed to use CLINOLIPID safely and effectively. See full prescribing information foor CLINOLIPID. CLINOLIPID (lipid injecctable emulsion), for intravenouss use Initial U.S. Approval: 1975 WAR RNING: DEATH IN PRETERM INFA ANTS • Deaths in preterm infaants after infusion of intravenous lipid emulsions have been reported in the medicaal literature. • Autopsy findings incluuded intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fattty acid plasma levels following lipid em mulsion infusion. INDICATIONS AND USA AGE CLINOLIPID is indicated inn adults for parenteral nutrition providinng a source of calories and essential fatty acids when oral or enteral nutrition is not posssible, insufficient, or contraindicated. Limitations of Use: • CLINOLIPID is not indiccated for use in pediatric patients becauuse there is insufficient data to demonstrate thatt CLINOLIPID provides sufficient amounnts of essential fatty acids in this population • The omega-3: omega-6 fatty acid ratio in CLINOLIPID has not been shown to improve clinical outcomes compared to other intravenous lipid emulsions DOSAGE AND ADMINIS STRATION • Use a 1.2 micron in-linee filter when administering to a patient • See full prescribing infoormation for administration and admixinng instructions • CLINOLIPID is intended for intravenous infusion. • The recommended dosee depends on energy expenditure, cliniccal status, body weight, tolerance, ability to metaabolize and consideration of additional energy given to patient. The usual daily lipid dossage in adults is 1 to 1.5 g/kg/day and should not exceed 2.5 g/kg/day.

Baxter and Clinolipid are trademarks of Baxter Internattional Inc., or its subsidiaries. USMP/CLN/19-0030b 6/2019

DOSAG GE FORM MS AND STRENGTHS CLINOLLIPID 20% % is a lipid injectable emulsion. The lipid content is 0.2 grams/mL i 100 m in mL, 250 mL, 500 mL, and 1000 mL. CONTR RAINDICA ATIONS • Know wn hyperseensitivity iti it to t egg andd soybean b proteins, t i the lipid eemulsion and/or excipients. • Severre hyperlippidemia or severe disorders of lipid mettabolism. WARNIINGS AND PRECAUTIONS • Preterrm infantss have poor clearance of intravenous lippid emulsion. • Monit M ittor for signs or symptoms of hypersensitivity reaactions. • Monittor for signs and symptoms of infection, fat overlload, hypeertriglyceridemia and refeedding compplications. • Frequuent clinicall andd laboratory l b t determinations d t i ti are neecessary. • The aaluminum contained in CLINOLIPID may reach tooxic levels with prolonged adminnistration in patients with impaired kidney functioon. • Parennteral Nutrrition Associated Liver Disease (PNALD D) has been reported in patients who receivve parenteeral nutrition for extended periods of tim me, especiaally preterm infants. ADVER RSE REAC CTIONS The mosst commonn (5%) adverse drug reactions from clinical trials were w nausea and vomiting, hyperlippidemia, hyperglycemia, hypoproteinemia and abbnormal livver function tests. To repoort SUSP PECTED ADVERSE REACTIONS, coontact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.ggov/medwatch DRUG INTERAC CTIONS The antiicoagulantt activity of coumarin derivatives, includding warfaarin, may be counteracted. USE IN N SPECIFIC POPULATIONS Hepatic Impaired:: Use with caution in patients with preexxisting liveer disease or liver insufﬁciiency. Pleasee visit ww ww.baxterpi.com for Full Prescribbing Inforrmation

Baxter Healthcare Corporation p One Baxter Parkway Deerﬁeld, IL 60015 www.baxter.com

Up Front

Pharmacy Practice News • July 2019

#ASHPSM19

ASHP Summer Meeting in Video Pharmacy Practice News had an opportunity to sit down with several presenters and experts at the summer meeting in Boston to talk about some of the issues facing hospital pharmacists today. Here are just a few of the videos you can find at www.pharmacypracticenews. com/Multimedia. What Does USP <797> Mean for You?

The Pharmacist’s Role in Anticoagulation Stewardship

Patricia C. Kienle, RPh, MPA, FASHP, the director of Accreditation and Medication Safety at Cardinal Health Innovative Delivery Solutions, discussed the newly released United States Pharmacopeial Convention General Chapter <797> Pharmaceutical Compounding guidelines that will go into effect Dec. 1. She said that even if state boards of pharmacy are slow to enforce the new standards, the feds will begin enforcement on day 1.

Elizabeth Pogge, PharmD, MPH, BCPS-AQ Cardiology, sat down with us to talk about anticoagulation stewardship. Dr. Pogge is an associate professor, Midwestern University College of Pharmacy – Glendale and a clinical pharmacist at Cardiac Solutions in Peoria, both in Arizona. Anticoagulation therapy management can be very complex. She shared her thoughts about how the pharmacist can help improve medication management and the quality of life of these patients.

Also Check Out

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The Psychology of Pain

Macy England, PharmD candidate

Jeff Little, PharmD, MPH, BCPS, FASHP, FACHE

Tu Anh Ngo, PhD, MPH

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

Michele McMahon Velle, MAX Graphics/Creative Director

James A. Jorgenson, MS, RPh, St. Paul, MN

Volume 46 • Number 7 • July 2019 • pharmacypracticenews.com

Indu Lew, PharmD, Livingston, NJ

/ Director Frank Tagarello, Senior Art Director/Managing MAX Graphics James O’Neill, Senior Systems Manager

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL David S. Craig, PharmD, BCPS, Tampa, FL

NUTRITION Beverly Holcombe, PharmD, BCNSP, FASHP, FASPEN Chapel Hill, NC

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

Vanessa Kumpf, PharmD, BCNSP, Nashville, TN

CARDIOLOGY C. Michael White, PharmD, Storrs, s CT

ONCOLOGY Cindy O’Bryant, PharmD, Aurora, CO Ali McBride, PharmD, MS, BCPS, Phoenix, AZ

CNS/PSYCHIATRY Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE Cathy Rosenbaum, PharmD, Cincinnati, OH CRITICAL CARE Judi Jacobi, PharmD, FCCM, Indianapolis, IN INFECTIOUS DISEASES Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH David P. Nicolau, PharmD, Hartford, CT Jason Pogue, PharmD, Detroit, MI LEADERSHIP Ernest R. Anderson Jr., MS, RPh, Boston, MA

Sara S. Kim, PharmD, BCOP, New York, NY ORGAN TRANSPLANT PHARMACY Eric Tichy, PharmD, BCPS, New Haven, CT PEDIATRICS Gretchen Brummel, PharmD, BCPS, Hudson, OH

EDITORIAL STAFF

Marty Barbieri, Director of Production

David Bronstein, Editorial Director davidb@mcmahonmed.com

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McMAHON PUBLISHING

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PHARMACOGENOMICS Henry “Mark” Dunnenberger, PharmD, Evanston, IL

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NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

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4 Focus on Medication Safety

Pharmacy Practice News • July 2019

Michael R. Cohen, MS, RPh

Family members or patient advocates can play an important role in detecting untoward events in their loved ones by calling a rapidresponse team if they suspect something is not right.

Founder and President, President Institute for Safe Medication Practices Horsham, Pa.

ou likely heard about this incident in the news earlier this year: A woman died after receiving the paralyzing agent vecuronium instead of the sedative midazolam (Versed, discontinued brand) when the wrong medication was retrieved from an automated dispensing cabinet (ADC) (see sidebar). Starting in January 2019, the Institute for Safe Medication Practices (ISMP) published a series of articles about the event, extracting from the terrible tragedy lessons learned about the use of neuromuscular blocking agents, ADCs and a just culture of safety.1-4 The series of ISMP articles prompted significant dialogue and questions about the event to maximize its value for learning. One thought-provoking question stands out, however, and was recently asked not by a health care provider but by a friend of mine, Ilene Corina, the president and founder of Pulse, who is focused on improving patient outcomes and sharing patient safety information: “Is there anything that health care consumers themselves could have done to prevent or detect this event that might have improved the patient outcome?” My initial response to the question was “no,” as I couldn’t think of anything that a consumer could have done to prevent this terrible tragedy. But the consumer advocate clearly had been thinking about this event and delved a little deeper, asking: “What if the patient had been encouraged to have a relative or patient advocate go along with her to radiology to sit with her while waiting for the tracer to perfuse?” The idea gave me pause as I thought about the numerous events that had been reported to ISMP in which a family member or patient advocate had noticed something unusual about their loved one, brought it to the attention of health care providers, and thus avoided a potentially tragic outcome. What harm would it cause to allow, even encourage, a family member or consumer advocate to accompany a patient to a diagnostic area to wait with them prior to a test? In this case, the patient had been observed via a camera that was not sensitive enough to pick up that the patient’s chest was not rising and falling when she stopped breathing after receiving the neuromuscular blocking agent in error. But, no doubt, a family member or advocate likely would

have recognized that the patient had stopped breathing and alerted radiology staff to the emergency. I had to agree that the presence of a family member or patient advocate might have resulted in a more favorable outcome for this patient. Furthermore, studies have shown that family members can help detect harmful or potentially harmful critical events precipitated by health care professionals, particularly when they spend time with the patient observing their care.5,6 In these studies, respiratory distress was one of the most common types of safety problems detected by patient advocates, along with medication errors and tubes or drains that become disconnected.

Keeping Safety in the Family Patient advocacy begins by including the family in the patient’s care and keeping them well informed, so they know what to expect and can recognize whether something is not right. Then, family members and patient advocates should be encouraged to speak up about any concerns or worries. They know their family member better than anyone on the medical team, so communication of their observations is extremely important. When family members and patient advocates speak up, health care professionals should perceive and reflect their actions in a manner that fosters true collaboration and empowerment.

6 Steps to Tragedy:

The Vanderbilt Error Revisited 1. A woman was admitted to the hospital with a hematoma of the brain, possibly related to a mass. Several days later, she was transported from a step-down unit to radiology for a full body positron emission tomography (PET) scan.

2. While a radiology technician was explaining the PET scan to the patient, she requested medication to help ease anxiety due to claustrophobia. This led to an order for Versed (midazolam), and a nurse from the step-down unit was called to come to radiology to administer the drug to the patient.

3. To obtain Versed from the automated dispensing cabinet (ADC), the nurse typed just the first two letter characters of the drug name, V and E, into the search field but did not find the drug under that name, notably because the cabinet was set to retrieve drugs by the generic name— midazolam in this case.

4. The nurse then set the ADC to override, and again typed V and E into the search field, this time retrieving vecuronium instead of what she thought was Versed.

5. The nurse then traveled to the radiology department and prepared the drug as per instructions on the vial label. Not realizing she was administering a paralyzing agent to the patient instead of Versed, the nurse injected the vecuronium intravenously.

6. The unventilated patient was then left in a holding room while awaiting perfusion of a radioactive tracer that had been injected in preparation for the scan. Tragically, the patient stopped breathing, was unable to call for help and died.

In fact, some hospitals have recognized the important role that family members or patient advocates can play in detecting untoward events in their loved ones by allowing family members and advocates to call a rapid response team if they suspect something is not right. Certainly, the presence of family members and patient advocates during a loved one’s hospitalization is not possible in all circumstances. But perhaps more could be done to encourage family members and/or patient advocates to remain with patients and to accompany them to diagnostic areas or other clinical areas of the hospital where patients might await interaction with a health care professional. This is an idea worth exploring, not only for patients visiting radiology but throughout a hospital encounter. ■

References 1. ISMP. Safety enhancements every hospital must consider in wake of another tragic neuromuscular blocker event. ISMP Medication Safety Alert! 2019;24(1):1-6. www.ismp.org/resources/safety-enhancements-every-hospital-mustconsider-wake-another-tragic-neuromuscular. Accessed June 16, 2019. 2. ISMP. Another round of the blame game: a paralyzing criminal indictment that recklessly “overrides” just culture. ISMP Medication Safety Alert! 2019;24(3):1-5. www.ismp.org/ resources/another-round-blame-game-paralyzing-criminal-indictment-recklessly-overrides-just-culture. Accessed June 16, 2019. 3. ISMP. Sidebar 1: system vulnerabilities that contributed to the error. ISMP Medication Safety Alert! 2019;24(3):2. 4. ISMP. Don’t miss persuasive article by David Marx—reckless homicide at Vanderbilt? A just culture analysis. ISMP Medication Safety Alert! 2019;24(5):2-3. 5. Frey B, Ersch J, Bernet V, et al. Involvement of parents in critical incidents in a neonatalpaediatric intensive care unit. Qual Saf Health Care. 2009;18(6):446-449. 6. Hurst I. Vigilant watching over: mothers’ actions to safeguard their premature babies in the newborn intensive care unit. J Perinat Neonatal Nurs. 2001;15(3):39-57.

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6 Focus on Medication Safety

Boston—A “just” culture that allows for open communication of errors in a nonpunitive environment can and should be applied to critical evaluation of medication errors in hospitals and health systems, a patient safety expert said during the 2019 ASHP Summer Meetings & Exhibition. “We know things go wrong every day in all of our hospitals,” said Karen Fiumara, PharmD, the executive director of patient safety at Brigham and Women’s Hospital, in Boston. “Is there a way for us to build a system where we can all work in an environment where every time something goes wrong, we can say we analyzed the event, looked at the systems and contributors that led to that event, and remediated those, and in parallel took care of the patient and the family?” In that process, Dr. Fiumara added, “can [we be] completely, 100% supporting [of ] our employees?” A just culture of safety is an environment in which everyone is curious about why errors occur and where all employees feel a personal commitment to making care safer, Dr. Fiumara said. It also is one in which employees should be encouraged to be open about errors and the system vulnerabilities they see, as well as feel comfortable speaking up without fear of punishment. The challenge is that “we can only fix what we know [about],” Dr. Fiumara said. Like an iceberg, “we only see the errors that break the surface and result in harm, but we have to remember that there is a ton of risk that is lurking just below the surface.” Front-line staff often and almost always have the best insight into what works and what doesn’t, and can help identify problems to solve, she noted. Clinicians in varying positions often will tell Dr. Fiumara confidentially

about errors but feel afraid to share the information more publicly. Her colleagues aren aren’tt alone alone. In a 2016 survey by the Agency for Healthcare Research and Quality, about six of 10 respondents said they feared they would be punished if they made a mistake. Although it may be “really unpopular to talk about some of the major and fundamental problems in our hospitals,” she said, that presents a

Pharmacy Practice News • July 2019

Behaviors contributing to medication errors tend to fall into three main categories: human error, error an inadvertent act that could happen to anyone; at-risk behavior, a risk believed to be justified because other colleagues do the same thing; and reckless behavior, a conscious disregard of substantial, unjustified risk. Human error is not necessarily a cause of mistakes, Dr. Fiumara stressed; it is

Six of 10 Respondents to an AHRQ survey said they feared punishment if they made a mistake. Source: bit.ly/2Ks3on6

key vulnerability and safety risk. A just culture provides a framework to evaluate systems and behaviors to identify and fix vulnerabilities, Dr. Fiumara noted. Sometimes the risk lies in system practices; sometimes it results from individual behaviors; but most often it results from a combination of the two. A just culture should be viewed not about finding fault but in managing risk, she added. While we tend to judge the quality of an individual health care worker’s choice based on the outcome of the patient affected by an error, and base punishment on that outcome, we have to remain curious about why a mistake happened, Dr. Fiumara stressed. When investigating, “it’s important to keep calm to explore all contributing factors to an error,” she said. In such an approach, “it’s also important to evaluate the behavior, not the outcome. Start with asking if your expectation was clear—did the employee know what they should have done and how to do it?”

often attributable, at least in part, to other factors such as knowledge gaps, fatigue or environmental distractions. “Or did the person make an upstream choice that increased the risk an error might occur?” she asked. “Did an at-risk behavior result from a flawed system, or competing priorities?” In cases of human error or at-risk behavior, the organization may choose to support or coach employees to better practices, whereas reckless behavior calls for more serious corrective action or firing, she said. These cases are rare, however: In 10 years working in patient safety, Dr. Fiumara said, she has seen just two such instances. When an error does occur, Dr. Fiumara’s hospital follows a collaborative case review process to learn the facts of each error, asking these questions: What do we know happened? What do we believe happened? What does the policy/ procedure state? What is actually done in practice? This is considered a no-fault

‘Can [we be] completely, 100% supporting [of] our employees?’ —Karen Fiumara, PharmD finding exercise but helps identify areas of risk and vulnerability. Dr. Fiumara also recommends doing analyses within 24 to 48 hours of an event.

ASHP’s Take “Dr. Fiumara gave an excellent talk, and it’s consistent with what ASHP believes to be important,” commented program chair Anna Legreid Dopp, PharmD, the director of clinical guidelines and quality improvement with ASHP’s Center on Medication Safety and Quality. “A just culture embraces a safety support system both for patients and for health care providers. It’s what our members and our medication safety experts strive to do every day.” Adopting a curious mindset when looking for errors and system vulnerabilities is more of a growth mindset than a fixed mindset approach, which would be more punitive, Dr. Dopp said. “I thought she did a really good job at explaining that, and also emphasizing that we should not be biased toward outcomes. Regardless of the outcome, we should take steps toward a just culture very seriously.” ASHP has published three policies on just culture, Dr. Dopp noted, available at bit.ly/2IX8OmP. They are Just Culture (#1115), Just Culture and Reporting Medication Errors (#1021) and Support for Second Victims (#1524). —Karen Blum The sources reported no relevant ﬁnancial relationships.

In-House Bacteremia Monitoring System Found Cost-Effective Boston—The antimicrobial stewardship program (ASP) team at Massachusetts General Hospital augmented their electronic health record (EHR) system to provide real-time monitoring of positive blood cultures without incurring the cost of third-party surveillance software. Working with the hospital’s informatics team and the microbiology laboratory, the ASP team created a workflow to route real-time alerts of all positive blood cultures for admitted patients to a shared ASP in-basket in the EHR. “Inbasket alerts were automatically updated with any changes or additions to microbiology or susceptibility reports,” said Ronak Gandhi, PharmD, an attending clinical pharmacist of infectious diseases

at Massachusetts General Hospital, in Boston, and a lead author of a poster (65-M) presented at the ASHP 2019 Summer Meetings & Exhibition. The new monitoring system was initiated in the fall of 2017 and implemented in February 2018. During that time, a member of the ASP team reviewed all positive blood cultures on weekdays to assess whether the blood culture represented true bacteremia or contamination; ensured the patient was receiving the optimal antimicrobial at the best dose and duration; and recommended consideration for further testing or infectious disease (ID) consultation. All recommendations were discussed with the primary care provider, ID team (if

consulted) and the unit-specific clinical pharmacist, Dr. Gandhi said. Dr. Gandhi and his colleagues then reviewed the records of 1,767 patients with positive blood cultures between February 2018 and February 2019. Of those, 240 patients (13.6%) required an intervention by the ASP team, 81 of which (4.6%) were considered major interventions. Major interventions consisted of initiating antimicrobials in patients not on active treatment, notifying primary care providers of culture positivity if the patient had been discharged from the hospital, or escalating therapy based on culture and susceptibility data. The remaining 159 (9%) interventions consisted of treatment

or dosing optimization, de-escalation based on culture results, and discontinuation of therapy in the setting of likely contamination. The team found that the “real-time nature of the tool represents a major advantage for ASP teams to optimize workflow, communicate with covering providers in a timely manner, and potentially reduce time to optimal antimicrobial therapy including transition to effective outpatient treatments,” all without incurring the cost of a thirdparty surveillance system. —Nikki Kean The sources reported no relevant ﬁnancial relationships.

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Focus on Medication Safety 9

Pharmacy Practice News • July 2019

Anaheim, Calif.—Legislation to reduce errors in patient medication histories at hospital admission, admission a safer way to treat acetaminophen overdose, and better documentation of patient allergies were among the topics presented during the Safety and Quality Pearls session at the 2018 ASHP Midyear Clinical Meeting.

Legislate It!

Delta Health Care District, in Visalia, Calif., agreed. Once a regulatory body says something must be done, done it encour encourages facilities to find the resources to make it happen, said Dr. Stephens, a member, with Dr. Shane, of the California Hospital Association Medication Safety Committee, which helped push the bill through the state legislature. At her facility, a nurse may take a high-risk patient’s initial history, but a pharmacist team member will check it for errors and interact with doctors and patients during the hospital stay. “It’s really good work. It needs to happen for everybody,” said Dr. Stephens, who moderated the pearls session.

A Better Way to Treat Acetaminophen n Overdose The medication histories pearl began with a bit of back story: at the ASHP Midyear meeting in 2017, a group of pharmacists discussed a major problem: Too many errors are introduced in patients’ medication histories when they are admitted to the hospital. This wasn’t just their own observations: According to the Agency for Healthcare Research and Quality, more than half of such histories contain at least one error at admission, some of which could cause moderate to severe harm if uncorrected (bit.ly/31tsQOq). Part of the problem, the group acknowledged, is no one takes ownership of the medication list. Some members of the group were based at Cedars-Sinai Health System in Los Angeles, where a study had shown that when pharmacy staff interview complex patients about their medication history, the odds of an error in histories and orders fall by more than 80% ((BMJ Qual Saff 2018;27[7]:512-520). Clearly, pharmacists are best suited to do the job, they said, since they’ll catch missing meds or dosing errors. But how could they encourage other facilities to follow their lead? One colleague knew California state senator Jeff Stone (R-Sacramento), who seemed open to the idea of drafting a bill that would require a hospital pharmacy staff member to obtain medication histories for high-risk patients (i.e., those taking many medications for chronic illnesses) at admission. So Rita Shane, PharmD, drafted text for the bill. After a series of conference calls, a letter-writing campaign, a change.org petition and multiple Senate hearings, the bill (S.B. 1254) was signed by the governor nine months after its creation. “I just think that we should do this nationally because everyone in this room knows that we’re the best at it,” Dr. Shane said at this year’s meeting. Sarah Stephens, PharmD, the medication safety coordinator for Kaweah

Acetaminophen is one off the oldest and most commonly used drugs for pain, but it’s also potentially dangerous. According to data from 2015 presented by Paul E. Milligan, PharmD, among the more than 2 million calls to the U.S. poison control centers, more than 100,000 (5%) came from an overdose of acetaminophen. One out of five people who take too much acetaminophen—many of whom are children who accidentally overdose—are treated with acetylcysteine, a modified amino acid, which has been used for decades. Although acetylcysteine saves lives, it carries its own risk; too much could result in acute renal failure and even death. Part of the risk of acetylcysteine, Dr. Milligan explained to ASHP meeting attendees, is that emergency care providers administering the antidote are using a three-bag protocol that hasn’t been updated since 1979, and which is rife with confusing instructions—for instance, using volume instead of mass units for preparation. “It’s a mess,” he said. Furthermore, when patients are transferred (as children often are following emergency treatment), providers may not be sure what stage of treatment they’re at. Not surprisingly, mistakes occur. Among 66 people who received acetylcysteine following an acetaminophen overdose, doses in 17 bags were off by more than 50% ((Br J Clin Pharmacoll 2001;52[5]:573-577). In his presentation, Dr. Milligan, who is a system medication safety pharmacist at BJC HealthCare in St. Louis, described a much simpler solution: Mix everything together in one bag, then program a smart pump to give a bolus dose (150 mg/kg per hour for one hour) and then the rest at a consistent rate

(12.5 mg/kg per hour) until it’s gone. “You program that all into the pump, and you set it and forget it, it ” he said. said A study of 70 patients who received the one-bag protocol showed a similar rate of administration errors as with the three-bag protocol ((Ann Pharmacother 2011;45[6]):713-720). According to Dr. Milligan, during the study, nurses were not able to program the maintenance dose to start automatically after the bolus—but that has since changed. He said he believes that if nurses could have automatically programmed the protocol, “virtually all timing errors would be eliminated.” Dr. Milligan said he and his colleagues have been contacted by providers all over the country about the one-bag solution, an nd hospitals throughout the St. Louis areea are adopting it. One limitation, he no oted, is that sometimes patients have to be treated for more than 24 hours, but if the single bag is prepared under nonsterile conditions in the emergency department, it is only usable for 24 hours. In response, some pharmacies are splitting the treatment into two bags so expiration time isn’t a problem.

Learning by Doing For pharmacy students learning how to understand what caused an error to occur, is reading about root cause analysis (RCA) enough? Probably not, according to Shantel Mullin, PharmD. Her program at the University of Utah Health in Salt Lake City, where she is the director of pharmacy quality, safety and training, includes readings and discussion during the medication safety rotation, “which is great at building knowledge, but not necessarily so great at that skill and attitude piece,” she said. Now, students and residents enrolled in the Utah Health program perform a socalled “mini-RCA,” in which they identify a small pharmacy error that occurred but didn’t necessarily cause harm. They complete a 12-step process, which includes interviewing staff members, looking for variation in the workflow, and facilitating discussion during a team meeting of staff who had hands on the process. According to Dr. Mullin, it has been a great way to teach pharmacists-in-training about discussing safety culture and how to approach someone who may have been involved in an error—not an easy task. “The learners have loved this process,” Dr. Mullin told her audience. “They feel like they’re part of a team and they’re really making meaningful change. But also, we’ve found some big issues with these small events and have been able to make those corrective actions.” This kind of program is “so great,” and

helps teach students about a topic that’s not covered well in the pharmacy school curriculum, Dr. Stephens told Pharmacy Practice News. “It’s a really great opportunity for students to start thinking of error from a systems perspective. It’s not about the people; it’s the process.”

Documenting Allergies When it comes to allergies, documentation is key. Failing to report that patients have serious reactions to some medications can put their lives at risk, but noting all reactions—even minor local ones—as an “allergy” may steer providers away from the most appropriate treatments. It’s a common problem in every institution. Concord Hospital, in New Hampshire, wanted to try to address it by tweaking its electronic health record (EHR) system. Elizabeth Wade, PharmD, Concord’s medication safety officer, and some colleagues reviewed information about voluntarily reported errors and what might have caused them. Some trouble spots, they noted, included a lack of documentation about patients’ reactions to the substance in question, and the fact that allergy lists often were “overloaded” with irrelevant information.

Now the hospital’s EHR has been modified to create one central record system, which asks providers to indicate whether a reaction to a substance is an allergy, contraindication, intolerance or side effect— of which only the first two will prompt an alert. Anyone adding an allergy to a patient’s EHR must also include information about the reaction. “If we don’t know the reaction, then obviously no one has enough info to act on it,” Dr. Wade said. Only pharmacists can add free text. “If you encounter some of these issues in your organization,” she said, “you may want to consider all of the design options you have available to you in your EHR to help reduce that risk.” —Alison McCook The sources reported no relevant ﬁnancial relationships.

10 Focus on Medication Safety

hen it comes to vaccine errors, the needle has yet to move, and hundreds of related move Table 1. Most Frequent Types and harmful errors occur every Of Vaccine Errors year. Nevertheless, the Institute for Safe Medication Practices Wrong vaccine (23%) (ISMP) continues its push for changes to how vaccines are Wrong dose (19%) manufactured and improveExpired vaccines or contamination/ ments in clinical and operationdeterioration (19%) al practice, hoping to increase vaccine safety. Wrong age (17%) “We can all do a much betWrong time or interval (8%) ter job in ensuring the safety of vaccine use,” Michael R. Vaccine/component omission, such as Cohen, MS, RPh, the president diluent or a single component of a twoof Horsham, Pa.–based ISMP, component vaccine (4%) told Pharmacy Practice News. Wrong route of administration (2%) One of ISMP’s most important efforts in addressing Wrong patient (1%) vaccine safety has been the Source: Acute Care ISMP Medication Safety Alert! establishment of its Nation2018;23(12):1 4. 2018;23(12):1-4. al Vaccine Errors Reporting Program (ISMP VERP; www. ismp.org/report-error/verp) in 2012. “We’ve received many thousands of The recommendations address a number vaccine error reports since 2012, and of vulnerable points along the vaccine use we keep seeing the same kinds of things process, including suggestions for protooccur again and again,” said Mr. Cohen, cols and other measures to ensure vacnoting that all reports received through cines are stored and administered propthe ISMP VERP are shared directly with erly, and that staff are properly trained. the FDA and CDC, so “reporting to us Mr. Cohen encouraged institutions to assures the information will get to both follow such recommendations, noting that federal agencies through their shared while none of the vaccine errors reported Vaccine Adverse Event Reporting Sys- in 2017 caused immediate patient harm, tem (VAERS)” (https://vaers.hhs.gov). previously reported mistakes have. “Some Gathering these data has yielded of the most serious errors have been miximportant insights into trends in vac- ups where other medications have been cine errors, Mr. Cohen said. For exam- mistaken for the diluent,” he noted. For ple, ISMP analyzed 575 vaccine-related example, 15 children died in Syria after events submitted to its VERP in 2017— being given a vaccine mixed with atrawhich is 100 cases more than were curium instead of the look-alike ampules reported in 2012, an increase that Mr. of diluent ((Acute Care ISMP Medication Cohen attributed to greater awareness Safety Alert! 2014;19[19]:1-3). of the ISMP reporting system—and Closer to home, there have been a identified important features of errors number of cases where paralytics have (Tables 1 and 2; Acute Care ISMP Medi- been administered instead of influencation Safety Alert! 2018;23[12]:1-4). za, measles and hepatitis B vaccines, They found that 85% of errors occurred including at an emergency department in physicians’ offices or public health in the United States where several clinics, but 3% of reported vaccine errors patients received pancuronium instead took place in the inpatient setting, 6% of influenza vaccine and survived, occurred in the hospital ambulatory set- according to ISMP, which detailed the ting, and 2% took place in community and error in the same Safety Alert! issue retail pharmacies. The latter number may that described the atracurium mix-up. be underrepresentative, as some pharmaApart from the harm vaccine adminiscies only report errors to company head- tration errors can cause patients, these quarters, Mr. Cohen noted. “I hope more can also compromise herd immunity, pharmacists will report to ISMP VERP risking disease outbreaks and propaso more can be learned about problems gating epidemics, Mr. Cohen said. “All common to community pharmacies.” it takes is contact between one person Based on its 2017 analysis of reports to with measles who is nearby and coughthe ISMP VERP, the organization devel- ing and those who are not vaccinated oped a set of recommendations to help properly for an outbreak to emerge.” providers prepare for immunization iniMr. Cohen said ISMP has been encourtiatives in the hospital and ambulatory aging manufacturers to make changes clinic settings ((Acute Care ISMP Medi- that might reduce the likelihood of cation Safety Alert! 2018;23[13]:1-4, 6-8). mix-ups. “For example, we would love

Pharmacy Practice News • July 2019

Table 2. Most Common Vaccines Administered With Error HepA (hepatitis A vaccine; inactivated) DTaP-IPV (diphtheria and tetanus toxoids and acellular pertussis absorbed and inactivated poliovirus) Trivalent influenza virus (types A and B)

to see diluents and vaccines either packaged together or as two-component vials,” he said. Despite ISMP’s efforts, to date, he noted, manufacturers have failed to act on these requests, citing high costs of making such changes or noting that other companies make the diluents. “Many of the involved vaccines cost hundreds of dollars per dose, so adding a dollar or so to overall cost is not going to be a big deal if it will protect patients,” Mr. Cohen asserted.

Latest Research

Tdap (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis) Quadrivalent influenza virus (recombinant) HepB (hepatitis B vaccine; recombinant) MMRV (measles, mumps, rubella and varicella virus; live) 9vHPV (HPV 9-valent vaccine; recombinant) DTaP (diphtheria and tetanus toxoids and acellular pertussis adsorbed) DTaP-IPV/Hib (diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus and Haemophilus influenzae b conjugate; tetanus toxoid conjugate)

ISMP continues to study vaccine errors reported to VERP. At Source: Acute Care ISMP Medication Safety Alert! the 2019 ASHP Summer Meet2018;23(12):1-4. 0 8; 3( ) ings & Exhibitions, the group presented a poster (35-T) which found that from Jan. 1, 2017 through Dec. or bone-marrow transplantation also 31, 2018, 1,143 vaccine errors were report- require special vaccines to protect themed. Of those, 1,008 (87.8%) reached the selves, so vaccine safety is an important patient. Most of the reports were submit- component of overall medication safety ted by a practitioner working in the out- in health systems.” patient setting, including medical clinASHP has developed guidelines detailics (36.6%), physician practices (24.4%), ing safe vaccine management (bit.ly/ ambulatory areas of hospitals (13.7%) 2ZK0hdz). The guidelines state that and public health immunization clinics even pharmacists not administering (12.5%). The error types reported most vaccines can help to ensure safe vacoften included wrong vaccine (25.1%, n cine use, for example when document= 287), wrong patient age (17.4%, n = 199) ing patient records, making formulary and extra dose (10.7%, n = 122). management decisions, taking patient Michael Ganio, PharmD, director of histories and providing counseling. Dr. Ganio added that pharmacists’s pharmacy practice and quality at ASHP, said that although most vaccines are efforts at immunization advocacy “is administered in the primary care set- increasingly critical as measles cases rise.” ting, vaccine safety is not something —David Wild health systems should take lightly. “Not all patients have a primary care provider, The sources reported no relevant ﬁnancial relationships. and patients undergoing splenectomy

12 Focus on Medication Safety

Pharmacy Practice News • July 2019

continued from page 1

The good news, she stressed, is most patients have positive interactions in health care. But despite progress in some areas, such as medication safety, preventable harm remains “unacceptably frequent,” she said. “Patient safety is a public health issue that has significant mortality and morbidity, quality of life implications, and it really adversely affects patients in every care setting from

inpatient and ambulatory to home.” A 2015 report from the National Patient Safety Foundation (NPSF), “Free From Harm” (bit.ly/2RGikNF), called for a total systems approach to a culture of safety and action by government, regulators and health professionals to place a higher priority on patient safety science and implementation. Dr. Gandhi, who served as the NPSF’s president and CEO

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before it merged with IHI, discussed the report s eight recommendations to accel report’s accelerate progress. Ensure leaders establish and sustain a safety culture. Improving safety requires an organizational culture that enables and prioritizes safety, Dr. Gandhi said. Care providers should be held accountable for unprofessional conduct but not punished for mistakes.

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Errors should be identiified and mitigated proactively, and strong feedback loops sh hould be implemented to enab ble learning from errors to preevent recurrences. recurrences Hospitals have made some progress in this area by instituting programs such as executive walking rounds, morbidity and mortality conferencess, just culture algorithms, an nd huddles, she noted. The IHI HI produced a blueprint report on how to lead a culture of safety (bit.ly/ 2XHHpeI) that features six domains: 1) Set a vision for zero harm; 2) promote trust, respect and inclusion; 3) engage your board; 4) develop leadership; 5) establish a just culture; and 6) have clear behavioral expectations. Create a centralized and coordinated approach to patient safety. The Institute of Medicine’s report called for patient safety coordination on a national level, but that hasn’t happened, Dr. Gandhi said. Many organizations work on patient safety but there should be a more coordinated strategy to avoid unnecessary duplication of efforts and ensure sharing of best practices and lessons learned. In 2018, IHI convened a National Steering Committee on Patient Safety (bit.ly/2s1YHFD), co-chaired by Dr. Gandhi and featuring representatives from more than 26 health care organizations—including ASHP, the FDA and the Joint Commission—to create a National Action Plan for the Prevention of Health Care Harm. Subcommittees have been delving into culture, leadership and governance; learning systems; patient and family engagement; and workforce safety. The group aims to release the action plan in early 2020. Create a common set of safety metrics. Measuring safety is difficult, and any study that comes out spurs debate about the metrics used, Dr. Gandhi noted. “The vast majority are hospital metrics, so we’re not even measuring safety in other settings where patients receive care,” she said. Additionally, measures tend to be reactive, studying harm months after it occurs. There is a need to establish standard metrics that span the care continuum and create ways to proactively identify and measure risks and hazards in real time, ideally so errors can be prevented, she noted. Increase funding for research. Safety science is still in early development, and there is a lot more research needed to understand how to improve and implement what has been learned to make substantial advances, Dr. Gandhi said. This will require sustained financial resources from governmental and nongovernmental sources.

Focus on Medication Safety 13

Pharmacy Practice News • July 2019

1 in 10 patients develops a health care–acquired condition such as an infection, pressure ulcer, fall, adverse drug event during hospitalization. Source: National Patient Safety Foundation.

Address safety across the entire care continuum. Much work in patient safety has focused on inpatient settings but most care is provided outside of hospitals, Dr. Gandhi said. “There has been less research on ambulatory settings so we don’t know all the risks, and each setting has its own unique safety issues.” Principles used in inpatient settings need to be applied to all outpatient settings. Medication safety, transitions of care, and missed and delayed diagnoses are common areas for errors in ambulatory care. “We need to develop more robust systems around these areas and strategies to ensure that every test result or referral ordered gets followed up. Patient engagement also is critical to prevent delays in diagnosis.” Support the health care workforce. If health care professionals are to achieve their highest potential as healers, attention needs to be paid to the physical and emotional harm they are experiencing and make sure they have the skills and capabilities to work safely in their jobs, Dr. Gandhi noted. “They went into health care to help people and that should be bringing them joy, not bringing them burnout,” she said. Unless caregivers are provided the protection, respect and support they need, they are more likely to make errors or fail to follow safe practices. Too many workers today suffer from emotional or physical harm, stress and lack of respect. The IHI produced a white paper in 2017, on a framework for improving joy in work (bit.ly/2zHs16F). Partner with patients and families for the safest care. Patients and families should be actively engaged at all levels of health care and always should be treated with respect, Dr. Gandhi said. Patient engagement has been linked to better satisfaction and health outcomes, safer care and improved work experience for caregivers. The NPSF published a report on consumer engagement (bit.ly/ 2ILc2dc). Patients should be engaged in patient/family advisory councils, can provide input on educational materials and brochures produced by medical centers, and be part of medical rounds making decisions. They also should have

access to their health record through programs like OpenNotes. Physicians should move from asking patients, “What’s the matter?” to “What matters to you?” Ensure technology is safe and optimized to improve patient safety safety. Technology has proven potential to bolster patient safety but only if risks can be minimized, Dr. Gandhi noted. Technologies such as computerized provider order entry (or CPOE) and barcoding have helped reduce errors, but some technologies have led to alert fatigue, and the current state of

electronic health record system technology dissatisfies health care workers. What is needed, she stressed, is to optimize technologies and improve interoperability among devices and systems systems.

A Message That Needs To Be Heard

“While we know there is much to be done to quantify and qualify our safety efforts, Dr. Gandhi offered a multidisciplinary-based path we can all take. Pharmacists are perfectly positioned as part of the health care team to focus on the steps outlined in the ‘Free From Harm’ report to improve safety, both for our patients and ourselves.”

“Dr. Gandhi’s talk was one I wish all pharmacists had the opportunity to hear,” said program chair Natasha Nicol, PharmD, the director of global patient safety affairs for Cardinal Health.

—Karen Blum Drs. Gandhi and Nicol reported no relevant ﬁnancial relationships.

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IMPORTANT SAFETY INFORMATION OMIDRIA must be added to irrigating solution prior to intraocular use. OMIDRIA is contraindicated in patients with a known hypersensitivity to any of its ingredients. Systemic exposure of phenylephrine may cause elevations in blood pressure. Use OMIDRIA with caution in individuals who have previously exhibited sensitivities to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory drugs (NSAIDs), or have a past medical history of asthma. The most commonly reported adverse reactions at ≥2% are eye irritation, posterior capsule opacification, increased intraocular pressure, and anterior chamber inflammation. Please see the Full Prescribing Information for OMIDRIA at www.omidria.com/prescribinginformation. You are encouraged to report Suspected Adverse Reactions to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. References: 1. Omeros survey data on file. 2. Silverstein SM, Rana V, Stephens R, Segars L, Pankratz J, Shivani R, et al. Effect of phenylephrine 1.0%-ketorolac 0.3% injection on tamsulosin-associated intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2018;44(9):1103-1108. 3. Rosenberg ED, Nattis AS, Alevi D, et al. Visual outcomes, efficacy, and surgical complications associated with intracameral phenylephrine 1.0%/ketorolac 0.3% administered during cataract surgery. Clin Ophthalmol. 2018;12:21-28. 4. Bucci FA Jr, Michalek B, Fluet AT. Comparison of the frequency of use of a pupil expansion device with and without an intracameral phenylephrine and ketorolac injection 1%/0.3% at the time of routine cataract surgery. Clin Ophthalmol. 2017;11:1039-1043. 5. Visco D. Effect of phenylephrine/ketorolac on iris fixation ring use and surgical times in patients at risk of intraoperative miosis. Clin Ophthalmol. 2018;12:301-305. 6. Walter K, Delwadia N. Miosis prevention in femtosecond cataract surgery using a continuous infusion of phenylephrine and ketorolac. Presented at: 2018 American Society of Cataract and Refractive Surgery (ASCRS) and American Society of Ophthalmic Administrators (ASOA) Annual Meeting; April 13-17, 2018; Washington, DC. 7. Matossian C. Clinical outcomes of phenylephrine/ketorolac vs. epinephrine in cataract surgery in a real-world setting. Presented at: American Society of Cataract and Refractive Surgery (ASCRS) and American Society of Ophthalmic Administrators (ASOA) Annual Meeting; April 13-17, 2018; Washington, DC. 8. Al-Hashimi S, Donaldson K, Davidson R, et al. Medical and surgical management of the small pupil during cataract surgery. J Cataract Refract Surg. 2018;44:1032-1041. 9. Gayton JL. E-poster presented at: 15th International Congress on Vision Science and Eye; 2017 Aug 10-11; London, UK. 10. Katsev DA, Katsev CC, Pinnow J, Lockhart CM. Intracameral ketorolac concentration at the beginning and end of cataract surgery following preoperative topical ketorolac administration. Clin Ophthalmol. 2017;11:1897-1901. 11. Waterbury LD. Alternative drug delivery for patients undergoing cataract surgery as demonstrated in a canine model. J Ocul Pharmacol Ther. 2018;34:154-160. 12. Visco D. et al. Study to evaluate patient outcomes following cataract surgery when using OMIDRIA with postoperative topical NSAID administration versus a standard regimen of postoperative topical NSAIDs and steroids. Presented at: 28th Annual Meeting of the American College of Eye Surgeons (ACES), the American Board of Eye Surgery (ABES), and the Society for Excellence in Eyecare (SEE), Caribbean Eye Meeting; February 1-5, 2019; Cancún, Mexico. 13. OMIDRIA [package insert]. Seattle, WA: Omeros Corporation; 2017. OMIDRIA® and the OMIDRIA logo® are registered trademarks of Omeros Corporation. © Omeros Corporation 2019, all rights reserved. 2019-004

14 Focus on Medication Safety

Pharmacy Practice News • July 2019

‘[Cannabis] … takes up everything in the soil, such as pesticides and heavy metals. So soil conditions are very important. Are the growers using proper extraction techniques to make sure [CBD] product is not contaminated?’

How should you advise your patients?

ometimes what happens in comometimes, com munity pharmacies doesn’t always stay in community pharmacies. That may well be the case with a decision by the nation’s two biggest drugstore chains, CVS and Walgreens, to soon be selling products made with cannabidiol— commonly called CBD—in some of their locations. With so many patients taking CBD products for relief from cancer and other chronic diseases, health-system pharmacists will likely have to factor in potential drug–drug interactions and other potential issues that could arise when managing these patients in the hospital or ambulatory settings. CVS pharmacies will sell CBD products in eight states: Alabama, California, Colorado, Illinois, Indiana, Kentucky, Maryland and Tennessee. Walgreens will sell them in nine states: Colorado, Illinois, Indiana, Kentucky, New Mexico, Oregon, South Carolina, Tennessee and Vermont. Both companies have said they will not sell CBD in pill form or other edible products, only topical preparations such as oils and creams. However, plenty of the oral products— along with every other type of preparation—can already be found on Amazon, in nutritional stores, and from other artisanal vendors both online and in brick-and-mortar locations.

Epidiolex an Island of Data Most of what is known about the effectiveness, side effects and drug–drug interactions of CBD products comes from clinical trials of the only cannabinoid prescription medication approved by the FDA: cannabidiol oral solution (Epidiolex, GW Pharmaceuticals). The agent was approved in June 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients 2 years of age and older. However, most people who will be using these over-the-counter CBD products won’t be using them to treat epilepsy or other seizure disorders, but for a range of other conditions for which there is less high-level evidence, such as anxiety, depression and pain conditions. Even without clinical trials, a varying number of states have approved CBD products for use in conditions ranging from Alzheimer’s disease and amyotrophic lateral sclerosis to multiple sclerosis, Parkinson’s disease and posttraumatic stress disorder. “The fact is we simply don’t know enough about the pharmacokinetic or pharmacodynamic interactions of these new products,” said Barry Gidal, PharmD, a professor of pharmacy and the chair

of the Pharmacy Practice Division at the University of Wisconsin-Madison, whose research interest is adult epilepsy. “What we do know came from the Epidiolex studies, and those involved a much higher dosage of cannabidiol than will be in these over-the-counter products. In terms of drug–drug interactions, those trials also only looked at a few specific drugs that related to their clinical development program.” Cytochrome P450 enzymes may be either inhibited or enhanced by CBD, which could reduce or intensify the activity of any CYP-metabolized drugs on the market. In the clinical trials that led to Epidiolex’s approval, there were potentially dangerous interactions with the antiepileptic drug clobazam (Onfi, Lundbeck and Sympazan oral film, Aquestive), necessitating a dosage adjustment for clobazam. Coadministration of CBD and valproate also increased the incidence of liver enzyme elevation. “These trials also showed us that use with strong CYP3A4 or CYP2C19 inducers may decrease cannabidiol plasma concentration,” said Jacci Bainbridge, PharmD, a professor in the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora. “Because of potential enzyme activity inhibition, patients taking Epidiolex should also have their doses adjusted for certain CYP substrates.” (See Table.) “Warfarin is a particularly relevant example,” said Tim Welty, PharmD, a professor and the chair of clinical science in the College of Pharmacy and Health Sciences at Drake University, in Des Moines, Iowa. “CBD could inhibit the breakdown of warfarin, increasing the INR [international normalized ratio] of that drug and thus elevating the risk of bleeding. Another example where cannabidiol interactions could play a potential role is in a patient who is taking clopidogrel for stroke or heart attack prevention. Clopidogrel is a prodrug and has to be metabolized through 2C19 for its active form, so if you are blocking that conversion, the clopidogrel may not work as well and put the patient at risk for a recurrent stroke or heart attack.” There are also potential food–drug interactions with CBD. For example, “taking cannabidiol with a high-fat meal can greatly increase its bioavailability and absorption,” Dr. Gidal said. Of course, the concentration of CBD in Epidiolex is much higher than will be found in any of the over-the-counter (OTC) products sold in CVS, Walgreens or anywhere else. But exactly how much

—Barry Gidal, PharmD

Table. DDI Substrates: What to Look For Enzyme

Drug Affected

UGT1A9

Propofol, fenofibrate and diflunisal

UGT2B7

Emfibrozil, lamotrigine, morphine and lorazepam

CYP2C8 and CYP2C9

Phenytoin, warfarin

CYP1A2

Theophylline, caffeine

CYP2B6

Bupropion, efavirenz

CYP34A

Erythromycin, verapamil and ritonavir

CYP2C19

Clopidogrel, diazepam

DDI, drug drug-drug drug interactions. Source: Jacci Bainbridge, PharmD

patients will be getting with OTC products is a bit of an unknown, given that they are not regulated by the FDA. “And we don’t really know at what concentrations of CBD do we really begin to see the inhibition or the induction effects,” Dr. Gidal said. “If people are using topical products, such as creams, it’s a localized effect that shouldn’t really have any interactions,” Dr. Bainbridge said. “But products taken orally can. There are also patch technologies that are specifically made to drive through the dermis and would have more of a systemic effect, as would oral agents.”

Confusing Labels Still another challenge, particularly with the oral agents, is that dosage labeling can be confusing if not downright misleading. “I have seen bottles that say ‘contains 1,500 mg of CBD.’ That’s the entire 30-mL bottle, not 1,500 per capsule. The average consumer has to be willing to do the arithmetic.” Quality assurance and oversight is also lacking. “While I have no doubt that there are some reliable growers and people doing the extractions, labeling and bottling, the problem is that there is now a plethora of all these preparations out there,” Dr. Gidal said. “We simply don’t know where these over-the-counter

agents are being grown and in what conditions.” He added that the cannabis plant “takes up everything in the soil, such as pesticides and heavy metals. So soil conditions are very important. Are the growers using proper extraction techniques to make sure the product is not contaminated?” Some states, including Illinois and Iowa, have state-run pilot programs assessing medical CBD in specific conditions. “In those cases, there typically is some more quality assurance and quality control,” Dr. Welty said. “But overall, we need to know a lot more about what is in these products.” “For the time being, the bottom line for pharmacists is that we should be talking to our patients about whether they’re using these agents,” Dr. Bainbridge said, “and if so, how they are using them. Then we should monitor and follow patients’ serum concentrations and adjust dosages of other drugs based on what we find.” —Gina Shaw Dr. Bainbridge reported financial relationships with the Colorado Department of Public Health and Environment, Corbus Pharmaceuticals, GW Pharmaceuticals and Zynerba Pharmaceuticals. Dr. Gidal reported a financial relationship with Greenwich. Dr. Welty reported no relevant financial relationships.

Simplist prefilled syringes were associated with a 4x lower error rate compared to traditional practice. 1

Manufacturer prepared 24 month shelf life Low dose preparation Single unit dose A prospective, multisite, observational study of IV push medication preparation and administration compared the error rates between ready-to-administer (RTA) products and traditional practice, including a cartridge-based syringe system (Carpuject ) and vial and syringe. ®

• Simplist was the only RTA delivery system used in the study. • Study limitations include only a select number of sites (3) and steps observed

Ready-to-administer prefilled syringes

1. Hertig JB, Degnan DD, Scott CR, Lenz JR, Li X, Anderson CM. A comparison of error rates between intravenous push methods: a prospective, multisite, observational study [published online ahead of print September 8, 2017]. J Patient Saf. doi:10.1097/PTS.0000000000000419. www.fresenius-kabi.com/us | 1.888.386.1300 ©2019 Fresenius Kabi USA, LLC. All Rights Reserved. 0004-SIM-05-01/19 Carpuject is a registered trademark of Hospira, Inc. ®

INDICATIONS AND USAGE DILAUDID INJECTION is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate.

DILAUDID INJECTION is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, known hypersensitivity to hydromorphone, hydromorphone salts, sulfite-containing medications, or any other components of the product.

Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve DILAUDID INJECTION for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: have not been tolerated, are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia

Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients: Monitor closely, particularly during initiation and titration.

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • DILAUDID INJECTION exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions. • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. • Prolonged use of DILAUDID INJECTION during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. Severe hypotension: Monitor during dosage initiation and titration. Avoid use in patients with circulatory shock. Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness: Monitor for sedation and respiratory depression. Avoid use patients with impaired consciousness or coma. DILAUDID INJECTION contains sodium metabisulfite. There is a risk of anaphylactic symptoms and lifethreatening asthmatic episodes in susceptible people. Additional serious adverse reactions: Apnea, circulatory depression, respiratory arrest, shock, cardiac arrest, seizures, withdrawal, anaphylaxis. Most common adverse reactions: Lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Overdosage: Acute overdose can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, miosis (or mydriasis when hypoxia is present), and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. This Important Safety Information does not include all the information needed to use DILAUDID safely and effectively. Please see full prescribing information, including BOXED WARNING, for DILAUDID INJECTION available at www.simplist-us.com. Please see Brief Summary of Prescribing Information including full boxed warning on the following page(s).

Simplist Dilaudid Injection (hydromorphone hydrochloride) CII, for intravenous, intramuscular, or subcutaneous use BRIEF SUMMARY OF PRESCRIBING INFORMATION This brief summary does not include all the information needed to use DILAUDID INJECTION safely and effectively. Please see full prescribing information for DILAUDID INJECTION, including BOXED WARNING, at www.fresenius-kabi.com/us. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISK FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse DILAUDID INJECTION exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing DILAUDID INJECTION and monitor all patients regularly for the development of these behaviors and conditions Life-Threateningg Respiratory p y Depression p Serious, life-threatening, or fatal respiratory depression may occur with use of DILAUDID INJECTION. Monitor for respiratory depression, especially during initiation of DILAUDID INJECTION or following a dose increase. Neonatal Opioid p Withdrawal Syndrome y Prolonged use of DILAUDID INJECTION during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risks From Concomitant Use With Benzodiazepines p Or Other CNS Depressants p Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. • Reserve concomitant prescribing of DILAUDID and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation. INDICATIONS AND USAGE DILAUDID INJECTION is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve DILAUDID INJECTION for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: • Have not been tolerated, or are not expected to be tolerated • Have not provided adequate analgesia, or are not expected to provide adequate analgesia

CONTRAINDICATIONS DILAUDID INJECTION is contraindicated in patients with: • Significant respiratory depression. • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. • Known or suspected gastrointestinal obstruction, including paralytic ileus. • Known hypersensitivity to hydromorphone, hydromorphone salts, sulfite-containing medications, or any other components of the product. WARNINGS AND PRECAUTIONS (also see BOXED WARNING) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely at initiation, dose titration. See Contraindications for use in patients with bronchial asthma. • Adrenal Insufficiency: If diagnosed, wean the patient off of the opioid and treat with physiologic replacement doses of corticosteroids. • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use in patients with circulatory shock. • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of DILAUDID INJECTION in patients with impaired consciousness or coma. • Risks of Use in Patients with Gastrointestinal Conditions: The hydromorphone in DILAUDID INJECTION may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. • Increased Risk of Seizures in Patients with Seizure Disorders: Monitor patients with a history of seizure disorders for worsened seizure control. • Withdrawal: When discontinuing DILAUDID INJECTION in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue therapy in physically-dependent patients. • Risks of Driving and Operating Machinery: DILAUDID INJECTION may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of DILAUDID INJECTION and know how they will react to the medication. • Sulfites: DILAUDID INJECTION contains sodium metabisulfite. See Contraindications. • Increased Risk of Hypotension and Respiratory Depression with Rapid Intravenous Administration: should be given very slowly. ADVERSE REACTIONS (see Boxed Warning and Warnings and Precautions) Serious adverse reactions: Addiction, abuse, and misuse, lifethreatening respiratory depression, neonatal opioid withdrawal syndrome, interactions with benzodiazepines and other CNS depressants, adrenal insufficiency, severe hypotension, gastrointestinal adverse reactions, seizures, withdrawal, respiratory depression and apnea, circulatory depression, respiratory arrest, shock, and cardiac arrest. Most common adverse reactions: Lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. Less frequently observed adverse reactions: tachycardia, bradycardia, palpitations, blurred vision, diplopia, miosis, visual impairment, constipation, ileus, diarrhea, abdominal pain, weakness, feeling abnormal, chills, injection site uticaria, fatigue, injection site reactions, peripheral edema, biliary colic,

anaphylactic reactions, hypersensitivity reactions, increase in hepatic enzymes, decreased appetite, muscle rigidity, headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence, agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams, urinary retention, urinary hesitation, antidiuretic effects, erectile dysfunction, bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling, injection site pain, urticaria, rash, hyperhidrosis, flushing, hypotension, hypertension, serotonin syndrome, and androgen deficiency. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA at 1-800-551-7176 option 5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm (see BOXED WARNING for neonatal opioid withdrawal syndrome). • Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Naloxone must be available for reversal. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. • Lactation: Low levels of opioid analgesics have been detected in human milk. Monitor infants for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydromorphone is stopped, or when breast-feeding is stopped. • Females and Males of Reproductive Potential: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. • Pediatric Use: The safety and effectiveness of DILAUDID INJECTION in pediatric patients has not been established. • Geriatric Use: Patients 65 years of age or older may have increased sensitivity to hydromorphone. Start at the low end of the dosing range, titrate the dosage slowly and monitor for signs of CNS and respiratory depression. • Hepatic and Renal Impairment: Start patients on one-fourth to one-half the usual starting dose depending on the degree of impairment and closely monitor during dose titration. DRUG INTERACTIONS Clinically significant drug interactions with DILAUDID INJECTION: benzodiazepines and other CNS depressants, serotonergic and anticholinergic drugs, monoamine oxidase inhibitors (MAOIs), mixed agonist/antagonist and partial agonist opioid analgesics, muscle relaxants, diuretics. OVERDOSAGE Acute overdose with DILAUDID INJECTION can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis, rather than miosis, may be seen with hypoxia in overdose situations. In case of overdose, reestablish patent and protected airway, institute assisted or controlled ventilation, manage circulatory shock, pulmonary edema, cardiac arrest or arrhythmias, as indicated. Administer opioid antagonists only for clinically significant respiratory or circulatory depression. Carefully monitor the patient until spontaneous respiration is reestablished. Administration of opioid antagonist in a physically dependent patient should be initiated with care and by titration with smaller than usual doses of the antagonist.

Clinical 17

Pharmacy Practice News • July 2019

Point/Counterpoint

Part 2: Weighing the data on PTSD and Anxiety

Fire It Up: Pros and Cons of Medical Marijuana As contentious as the political debate over state-by-state efforts to legalize marijuana has been, discussions about the clinical evidence for cannabis safety and efficacy are equally charged. To help shed more light and less heat on the topic, the American College of Clinical Pharmacy sponsored a debate between two pharmacists with expertise on the topic during its most recent Global Conference. Taking the pro side was Ann M. Philbrick, PharmD, an associate professor at the University of Minnesota College of Pharmacy, in Minneapolis. On Richard J. Silvia, Ann M. Philbrick, Kelly C. Lee, the con side was Kelly C. Lee, PharmD, a professor of clinical pharmacy PharmD, BCPP PharmD PharmD, BCPP at the University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, in La Jolla. Moderating the debate and finding some middle ground was Richard J. Silvia, PharmD, an associate professor of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences in Boston. Part 1 of this two-part series focused on seizure disorders and neuropathic pain (bit.ly/2IuQmTI). In this second installment, the experts explore post-traumatic stress disorder (PTSD)/anxiety.

PTSD and Anxiety

lthough previously considered an anxiety disorder, PTSD is now labeled by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as a trauma- and stressor-related disorder. Hallmarks of PTSD include reexperiencing (flashbacks), nightmares, disturbing dreams, hypervigilance (startle response), duck and cover, avoidance (avoid cues and triggers), and negative mood (anxiety, cognitive deficits).

PRO

Dr. Philbrick admitted that studies on the use of cannabis for PTSD are not great. “There is limited information and the designs are very flawed,” she said. “I would like to point out, though, that our current [standard] treatment options for PTSD are also very limited. In a recent VA [Veterans Affairs] study, for example, the effectiveness of prazosin, an alpha-1 adrenoreceptor antagonist that has been a mainstay for PTSD treatment, in alleviating distressing dreams and improving sleep in veterans with PTSD has been called into question” ((N Engl J Med 2018;378[6]:507-517). One positive study by Jetly et al (Psychoneuroendo( crinology 2015;51:585-588) included 19 Canadian men (aged 18-65 years; mean, 43.6 years) serving in the military. “Participants needed to have at least a twoyear history of PTSD; their trauma had to be of military origin; and they had to have a history of current distressing nightmares and difficulty falling asleep,” Dr. Philbrick said. Patients were excluded from the study if they had significant cognitive impairment, serious medical conditions, or screened positive for illicit substances, including THC. The study focused on the use of nabilone (Cesamet, Meda), a synthetic form of cannabis that mimics THC, the primary psychoactive compound found naturally occurring in cannabis. The FDA approved nabilone for chemotherapyinduced nausea and vomiting. Patients were randomly assigned to receive either nabilone (0.5 mg) or placebo, given one hour before bedtime. Nabilone could be titrated up based on effect. “They had seven weeks of treatment, and then a two-week washout period, followed by seven weeks of the other treatment. So half of the subjects got cannabis first, and then the other half received placebo first,” Dr. Philbrick noted. The average dose was 3.0 mg on placebo and 2.0 mg on nabilone.

The authors saw reductions in recurrent distressing dreams, based on Clinician-Administered PSTD Scale (CAPS) scores: The mean reduction was –3.6 in the nabilone group and –1.0 in the placebo group ((P=0.03). Mean global improvement was also measured, based on the Clinical Global Impression of Change, and some key differences emerged: Scores of 1.9±1.1 (much improved) and 3.2±1.2 (minimally improved) were documented in the nabilone and placebo groups, respectively ((P=0.05). Five of 10 patients in the nabilone group were much improved compared with one of nine on placebo, the investigators reported. A study by Greer et al ((J Psychoactive Drugs 2014;46[1]:73-77) “was interesting,” Dr. Philbrick said. “This study followed New Mexico’s approval of medical cannabis for PTSD. As part of New Mexico’s criteria, patients had to have a personal history of significant improvement with cannabis, meaning recreational use, and show lack of harms or problems during that cannabis use, which is incredibly subjective,” she noted. A problem with the study, Dr. Philbrick added, was the way in which the investigators evaluated benefit and harm from previous use. “The investigators basically asked the patient: ‘Think of a time when you were on cannabis; how did you feel?’ The patient would answer the questions, and then the researcher would ask: ‘Think of a time that you weren’t on cannabis; how did you feel?’ Not incredibly scientific,” Dr. Philbrick said. Not surprisingly, Dr. Philbrick said, “when people were on cannabis they had a CAPS score of 22.5 compared with 98.8 on placebo, which was a greater than 75% reduction in CAPS symptom scores.” CON

Large retrospective studies have disfavored the use of CBD or cannabis for PTSD. Two VA studies ((J Clin Psychiatryy 2015;76[9]:1174-1180;

J Affect Disord d 2016;190:439-442) found that people who started and/or continued cannabis had worse PTSD symptoms than those who never used cannabis or who stopped use. “These were the first large-scale studies to show that cannabis products may not be safe for people with PTSD,” Dr. Lee said. “The investigators also found higher rates of violence and alcohol and drug use in patients who continued to use cannabis.” In a third, smaller study, “researchers found that the weekly cannabis users [higher dose] had greater severity of weekly PTSD symptoms, especially early in treatment,” Dr. Lee said ((J Clin Med d 2017;6[2]:pii: E14). Adverse events were a big concern in the PTSD studies, Dr. Lee noted. In addition to worsening depression, psychosis, tolerance, addiction and maladaptive coping, other adverse effects included neurocognitive impairments, short-term memory and judgment impairment, and problems with motor coordination. “Nabilone, which has some CB1 receptor activity, did reduce CAPS scores, which is the scale that is used to measure PTSD symptoms, but had a huge rate of adverse events,” Dr. Lee said. “I am not sold on whether cannabis has a place for PTSD,” she concluded. “Plant-derived CBD may lead to downregulation of endocannabinoid system, worsening PTSD/anxiety symptoms, neurocognition and coordination. I do believe that a lot of people do get relief from using cannabis for their sleep difficulties, especially when we don’t have a lot of other options, for example, hypnotics. But we need more data on efficacy beyond nightmare and sleep issues in PTSD.” FINAL VERDICT

“Current evidence suggests that CBD products may be more harmful than helpful for PTSD/anxiety,” Dr. Silvia said. “Nabilone may be effective, but larger studies are needed. Lastly, we know there’s a high comorbidity of substance abuse in these patients. That layered on top of a cannabinoid might really muddy the waters and potentially create a dangerous situation.” —Nikki Kean Drs. Silvia and Philbrick reported no relevant ﬁnancial relationships. Dr. Lee reported ﬁnancial relationships with Otsuka Pharmaceutical, Shire, Takeda and TrueLearn.

18 Q & A

Pharmacy Practice News • July 2019

Advertorial

The following advertorial is provided by Pentec Health and is designed to support the advertisement presented below.

Q&A with Daniel Martins, Executive Vice President Of Outsourcing Facility Services, Pentec Health The FDA allows for two types of compounding: sterile-to-sterile or bulk. How are these two methods different?

method is maintaining sterility throughout the collection and repackaging (filling) process. The other method is to use bulk Active Pharmaceutical Ingredient (API) to formulate a solution that is then sterilized just prior to filling.

The difference is the starting material. One method uses commercially available sterile products that are then repackaged into unit doses and/or different final containers. The trick to this

Which type of compounding does Pentec Health utilize and why? Pentec Health utilizes bulk API as a starting

material for several reasons. First, bulk API has a confirmable potency and expiry pedigree which helps to ensure the quality of this starting material (which is how/why traditional pharmaceutical manufacturers use the same). Second, when using bulk API, pharmaceutical recalls do not affect us and, in fact, we can help alleviate drug shortages by becoming an alternate resource. Third, using bulk API simplifies the formulation

process by reducing the amount of manipulations associated with using commercially available starting materials. Finally, our unique products are more concentrated than commercially available products and you cannot make concentrated products from more dilute products.

What are the regulations surrounding bulk compounding? From a 503B perspective, bulk compounding is permissible as long as the API appears on the “503B Bulks list”, for which the FDA has found a clinical need. Furthermore, the compound cannot be a copy of a commercially available product per the FDA final guidance on drugs that are “essentially a copy”. This excludes drugs that are on shortage.

Are there any advantages of bulk compounding? The main advantage of bulk compounding is the scientific history of safety and efficacy as API has been utilized by the pharmaceutical industry for over 100 years. API is readily available and has less shortages of supply when compared to commercially available starting materials. From the cGMP standpoint, it requires fewer manipulations because one bulk stock solution can be utilized over hundreds of smaller, commercially available product units, which reduces the risks associated with trying to maintain sterility. Bulk API is more stable in its pure form, which allows better control of on-demand inventory.

Are there advantages of sterile-tosterile compounding? Sterile-to-sterile compounding does give more flexibility in product offerings, as there is no limitation from the 503B bulks list. Additionally, compounding from commercially available products can be perceived as lower risk for those with a traditional 503A, USP <797> background. However, some disadvantages may include: limited access to product (especially during times of shortage), shorter expiry dating/unknown stability, and the increased amount of manipulations (this type of compounding is only safe when sterility is maintained). Pentec Health believes that the cGMP controls that are required when formulating from bulk should also apply to compounding from commercially available products.

How does Pentec Health ensure the safety of their products?

We’re like an elevator. We eliminate steps for pharmacists. Less steps means our product is easier and faster to use. Yet, provides safety and accuracy to make your processes more effective and efficient. Pentec’s 503B combines validated automation and process quality controls to make concentrated, single-dose products you can trust. We offer the peace of mind of a manufacturer with the efficiency of an outsourcing provider – enabling safe accurate medication, when it’s needed, where it’s needed, the way it’s needed. Less waste means greater value. To learn more please visit pentechealth.com.

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We have been categorized as a manufacturer in the State of PA, and we operate under cGMP compliance (CFR 21, Parts 210 & 211, which is well above what is required of 503Bs). As such, each and every process is validated and has the support of microbiological and analytical testing to ensure the highest quality of every batch. All of this is documented with Certificates of Analysis and Certificates of Conformance that are shipped with each and every order. Mr. Martins possesses more than 20 years of quality and operations oversight experience in various cGMP-regulated industries and a history of noteworthy corporate compliance from his involvement in well over 50 inspections by multiple regulatory agencies.

Clinical 19

Pharmacy Practice News • July 2019

Oncology

Darolutamide Shows Promise for Treatment of nmCRPC

he investigational androgen receptor inhibitor darolutamide is poised to shake up the treatment paradigm for men with high-risk nonmetastatic (M0) castration-resistant prostate cancer (nmCRPC), according to results from the ARAMIS trial. Interim results from the phase 3 trial, presented at the 2019 Genitourinary Cancers Symposium (abstract 140) and simultaneously published in The New England Journal of Medicine (2019;380[13]:1235-1246), showed that darolutamide (Bayer) doubled median metastasis-free survival (MFS) (18.4 vs. 40.4 months; hazard ratio [HR], 0.41; P<0.0001) and was associated with a 29% reduction in the risk for death compared with placebo ((P=0.045).

‘New Standard of Care’ “We believe that darolutamide should become a new standard of care for men with high-risk M0 CRPC,” said Karim Fizazi, MD, PhD, the head of the Department of Cancer Medicine at the Institute Gustave Roussy, in Villejuif, France, who presented the study at the symposium. “Pain progression was delayed and quality of life was meaningfully preserved with darolutamide compared with placebo.” nmCRPC is defined as a rising prostate-specific antigen (PSA) level, despite ongoing androgen deprivation therapy, and no detectable metastases by conventional imaging. The cancer is associated with a high risk for progression and cancer-specific death. Apalutamide (Erleada, Janssen) and enzalutamide (Xtandi, Pfizer) have been shown to improve MFS in patients with nmCRPC, but they are associated with increased rates of fatigue, falls, fractures and other adverse events (AEs) compared with placebo (Eur ( Uroll 2019;75[2]:285293). Darolutamide differs structurally from apalutamide and enzaluatide and is characterized by low blood–brain barrier penetration, which may result in less central nervous system toxicity and improved tolerability. Darolutamide shows a high affinity for the androgen receptor and has promising in vivo activity and a low potential for drug–drug interactions. Results from the phase 1/2 trials, ARADES (Lancet ( Oncoll 2014;15[9]:975985; Eur Urol Focus 2017;3[6]:606-614) and ARAFOR ((Eur Uroll 2016;69:834-840), showed that treatment with darolutamide was associated with PSA decreases of 50% or more in 65% to 83% of chemotherapynaive patients with mCRPC and responses

(complete and partial) by RECIST criteria in 30% of chemotherapy-naive mCRPC. No clear AEs related to darolutamide were detected in the trials. ARAMIS enrolled men with nmCRPC and a PSA doubling time of 10 months or less. The investigators stratified patients by PSA doubling time (≤6 months) and whether they had received osteoclast-targeted therapy, and randomly assigned them 2:1 to receive 1,200 mg

darolutamide plus androgen deprivation therapy (n=955) or placebo (n=554) twice daily. The median PSA doubling time was 4.5 months and only 5% of patients used bone-targeting agents. After a median follow-up of 17.9 months, the investigators found darolutamide was associated with a 59% reduced risk for the primary end point of distant metastases or death (HR, 0.41; 95% CI, 0.34-0.50; P<0.0001). The MFS was improved regardless of

PSA doubling time, use of bone-targeting agents, Gleason score or age. At three years, darolutamide was associated with improvement in overall survival, with a 29% reduction risk for death. The survival probability with darolutamide was 83%, versus 73% with placebo (HR, 0.71; 95% CI, 0.50-0.99; P=0.452). In addition, the median time to pain progression was 40.3 months with darolutamide see DAROLUTAMIDE, page 20

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Pharmacy Practice News • July 2019

Oncology

Adolescent, Young Adult Cancer Survivors Face Treatment Sequelae continued from page 1

Oeffinger et al reported that by age 35, 23% of survivors experience at least two significant toxicities related to the type of therapy they received ((N Engl J Med d 2006;355[15]:1572-1582). In the short term (less than five years), these risks include cardiac effects, pulmonary toxicity and psychosocial issues. In the long term, toxicities include secondary malignancy, osteoporosis, hypertension and endocrine conditions. Oeffinger et al found that treatment-related toxicities leading to death were responsible for 18% of the excess risk for death in children with cancer. Death was most commonly caused by secondary malignancy and cardiac and pulmonary toxicities.

Long-Term Toxicities Given the potential short- and longterm side effects of therapy, decisions made by physicians, pharmacists and family members during treatment can have a meaningful impact on toxicities. “Pharmacists must consider therapy differences both at protocol planning/ design stages and while providing direct patient care,” Dr. Sciasci said. Certain chemotherapy regimens, such as high doses of cisplatin, have been shown to impair hearing, which can be detrimental to patients’ neurocognitive development. “The decreased ability to hear leads to decreased interaction with peers and overall decreased learning abilities,” he said. Even though research has demonstrated that interventions such as addition of sodium thiosulfate or amifostine may help reduce the harm of chemotherapy to hearing (N ( Engl J Med d 2018;378[25]:2376-2385), the addition of amifostine has not proven to be beneficial if cisplatin is combined with high-dose craniospinal-directed radiation therapy, Dr. Sciasci noted.

DAROLUTAMIDE continued from page 19

and 25.4 months with placebo (HR, 0.65; 95% CI, 0.53-0.79; P<0.0001). No meaningful differences in AEs were detected between the groups, and the only AE occurring at a rate over 10% was fatigue. “Darolutamide has a very favorable safety profile,” Dr. Fizazi said. “We

One example of a decision that can influence long-term outcomes is the choice of glucocorticoid in pediatric patients with acute lymphoblastic leukemia (ALL). In a study comparing dexamethasone with prednisone for treatment of ALL in children and adolescents, dexamethasone conferred a survival advantage in children but not adolescents ((Lancet Oncol 2010;11[11]:1096-1106). Adolescents who received dexamethasone experienced significantly more toxicities than those given prednisone.

Although much of the toxicity of dexamethasone is bone-related and develops when patients are still receiving cancerdirected therapy, dexamethasone also has been associated with significant neuropsychological toxicities, Dr. Sciasci noted. “When you combine the hormonal issues and life changes that adolescents may already be experiencing, the addition of steroids like dexamethasone can lead to a lot of behavior disorders.” Fortunately, he said, interventions are available. In one study, patients who experienced significant changes in mood or behavior with dexamethasone bursts had improved neuropsychological scores when hydrocortisone (10 mg/m2 per day) was added to their regimen ((J Clin Oncol 2016;34[19]:2287-2293). The addition of physiologic hydrocortisone did not affect overall bone or metabolic toxicities. Ms. Mably, the pharmacy director at UW Health, in Madison, Wis., said survivors are at greater risk for distress, anxiety, depression and fear of recurrence, and should be monitored regularly, especially during times of stress, and referred to mental health services as necessary. “We shouldn’t always try to keep these patients in the cancer center,” she said. Three classes of medications are

useful for treating anxiety, depression or distress, according to Ms. Mably: selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines. SSRIs and SNRIs take two to six weeks to exert their full effect, she said. “It’s also important to remember that SSRIs are helpful with menopausal symptoms seen in some young adults, and when pain occurs concurrently.” Because of their fast onset of action, benzodiazepines are useful, she added, especially when dealing with acute anxiety episodes. “Benzodiazepines can be tried while waiting for the full effect of SSRIs or SNRIs to kick in, but always remember to [use] the lowest effective dose and decrease the dose once the full effect of the other drugs occurs,” she said. It’s also important to avoid the concomitant use of benzodiazepines and opioids; the combination can cause respiratory depression—an important drug-drug interaction (DDI) to heed, given that many cancer patients are treated with opioids for cancer-related pain, according to the FDA (bit.ly/2NbvQvH). “Pharmacists should also monitor for DDIs such as psychotropic drugs with cytochrome P450 enzymes and tamoxifen,” Ms. Mably said. The emphasis for pharmacists may be on prescription medications, said Ms. Mably, but nonpharmacologic interventions are important, too. “As pharmacists, we sometimes forget about nonpharmacologic treatment strategies,” she said. Therapies such as mindfulness training, exercise, meditation and yoga have been shown to help with psychological stress. “It’s also important to assure survivors that these types of feelings are common and that they are not alone in this.” Increased use of immunotherapies and targeted agents has reduced the burden of additional chemotherapy exposure in

didn’t find any increase in side effects, such as falls, fractures, cognitive disorders, seizures and hypertension compared to placebo.” Drug discontinuation rates were similar in the two groups, about 9%. “Grade 3/4 adverse events were rarely observed in the trial, which is an important finding for a vast population of asymptomatic men.” Quality of life scores favored darolutamide for pain and urinary symptoms.

Asked to comment on the study, Lisa Holle, PharmD, an assistant clinical professor at the University of Connecticut School of Pharmacy, in Storrs, said the results of ARAMIS are significant. “Although darolutamide is not yet FDA approved, the results of this study are likely to support approval.” If darolutamide is approved, Dr. Holle said, there would be “three good options for men with nonmetastatic

More Than Just Physical Effects

Helpful Resources On Cancer Survivorship Children’s Oncology Group Survivorship Guidelines https://childrensoncologygroup. org/index.php/ survivorshipguidelines

Texas Children’s Hospital Passport for Care https://www.texaschildrens. org/departments/cancersurvivor-program/ passport-care

The Childhood Cancer Survivorship Study https://ccss.stjude.org

some subgroups of relapsed/refractory patients, but these therapies may bring their own unique long-term effects, according to Dr. Sciasci. “I think we still have a lot to learn about the long-term effects of approaches like CAR-T therapy,” he said. “We know what the risk of infection is, but we don’t necessarily know what happens greater than five years outside of their initial injection. Nevertheless, as use of targeted agents continues to grow, we expect the number of survivors to increase. Hopefully, the reduced exposure to chemotherapy will lead to fewer side effects.” Finally, Dr. Sciasci said many institutions have developed a survivorship or late effects clinic. These clinics help with the transition from pediatric/acutefocused care and help patients develop relationships with family or adult internal medicine practitioners. They can also help address compliance issues that may related to chronic health conditions. —Chase Doyle Dr. Sciasi reported no relevant ﬁnancial relationships. Ms. Mably reported serving on advisory boards for Alnylam Pharmaceuticals, Juno Therapeutics and Stemline Therapeutics.

CRPC: apalutamide, darolutamide and enzalutamide.” The three drugs have yet to be compared head-to-head, she noted, adding that clinicians should select an antiandrogen agent based on patient characteristics and cost. —Kate O’Rourke Drs. Fizazi and Holle reported no relevant ﬁnancial relationships.

An animal attack is traumatic enough…

PROTECT HER FROM RABIES with the potential for fewer injections

HyperRAB® (rabies immune globulin [human]) 300 IU/mL The #1 prescribed human rabies immune globulin (HRIG) you’ve trusted for over 40 years is now available in a high potency formulation

the volume of medication administered in a total dose the concentration of rabies antibodies per mL at the wound site Please see Important Safety Information and brief summary of Prescribing Information for HyperRAB on adjacent pages, or visit www.HyperRAB.com for full Prescribing Information.

HyperRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies. HyperRAB is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products.

22 Clinical

Pharmacy Practice News • July 2019

Cardiology

Stress Testing: Newer Drug Not Necessarily Better Anaheim, Calif.—Encouraging doctors to switch from a newer to an older agent when performing pharmacologic stress testing saved money without increasing adverse effects (AEs) at a Virginia medical center. Until April 2018, doctors at Mary Washington Hospital were prescribing regadenoson (Lexiscan, Astellas) when trying to mimic the effects of exercise on the heart. Regadenoson,

administered via an IV bolus, is relatively easy to use compared with other drugs that require continuous infusions and monitoring. But it’s also more expensive. Searching for alternatives, study author Sarah Yohey, PharmD, a clinical pharmacy specialist at Mary Washington Healthcare (whose pharmacy is managed by Cardinal Health), in Fredericksburg, Va., discovered a 2015 paper that compared regadenoson

with adenosine—an older drug with a shorter half-life—and found that people taking the older drug experienced fewer side effects, such as headache and trouble breathing, and were less likely to require a rescue agent to reverse the drug’s effect, all at a lower cost ((Pharmacotherapy 2015;35[12]:1117-1123). So administrators at Mary Washington Hospital asked doctors there to switch to adenosine.

That decision saved the hospital an average of $4,000 per month, and did not appear to increase the risk for AEs, Dr. Yohey reported at the ASHP 2018 Midyear Clinical Meeting. During the study, she and her colleagues reviewed the electronic health records of 60 consecutive patients treated with regadenoson between February and March 2018, and compared their outcomes with those of 60 consecutive

Indication and Usage HYPERRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies. Limitations of Use Persons who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine. For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis. Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred. Important Safety Information For infiltration and intramuscular use only. Severe hypersensitivity reactions may occur with HYPERRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur. HYPERRAB is made from human blood and may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The most common adverse reactions in >5% of subjects during clinical trials were injection-site pain, headache, injection-site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain. Do not administer repeated doses of HYPERRAB once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine. Other antibodies in the HYPERRAB preparation may interfere with the response to live vaccines such as measles, mumps, polio, or rubella. Defer immunization with live vaccines for 4 months after HYPERRAB administration. Please see brief summary of Prescribing Information on adjacent page or visit HyperRAB.com for full Prescribing Information.

Clinical 23

Pharmacy Practice News • July 2019

Cardiology ‘Anything that we can do to reduce the cost of a patient stay means the hospital may gain revenue on that stay. But improving patient care and outcomes by reducing the amount of reversal is the biggest win in my eyes.’ —Sarah Yohey, PharmD

HyperRAB

-----------DOSAGE FORMS AND STRENGTHS---------300 IU/mL solution for injection supplied in 1 mL and 5 mL single-dose vials.

HIGHLIGHTS OF PRESCRIBING INFORMATION

--------------------CONTRAINDICATIONS--------------------None.

Rabies Immune Globulin (Human) These highlights do not include all the information needed to use HYPERRAB® safely and effectively. See full prescribing information for HYPERRAB. HYPERRAB [rabies immune globulin (human)] solution for infiltration and intramuscular injection Initial U.S. Approval: 1974 ----------------INDICATIONS AND USAGE------------------HYPERRAB is a human rabies immune globulin indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies. Limitations of Use: Persons previously immunized with rabies vaccine that have a confirmed adequate rabies antibody titer should receive only vaccine. For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis. Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred. --------------DOSAGE AND ADMINISTRATION------------For infiltration and intramuscular use only. Administer HYPERRAB within 7 days after the first dose of rabies vaccine. Postexposure HYPERRAB • Administer as soon prophylaxis, 20 IU/kg as possible after along with body weight exposure, preferably rabies OR at the time of the first vaccine, after 0.0665 mL/kg rabies vaccine dose. suspected body weight • Infiltrate the full exposure to dose of HYPERRAB Single dose rabies thoroughly in the area around and into the wound(s), if anatomically feasible. • Inject the remainder, if any, intramuscularly.

-------------WARNINGS AND PRECAUTIONS-------------• Severe hypersensitivity reactions, including anaphylaxis, may occur with HYPERRAB. Have epinephrine available immediately to treat any acute severe hypersensitivity reactions. • HYPERRAB is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. --------------------ADVERSE REACTIONS--------------------The most common adverse reactions in >5% of subjects in clinical trials were injection site pain, headache, injection site nodule, abdominal pain, diarrhea, ﬂatulence, nasal congestion, and oropharyngeal pain. To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics LLC at 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------DRUG INTERACTIONS------------------• Repeated dosing after administration of rabies vaccine may suppress the immune response to the vaccine. • Defer live vaccine (measles, mumps, rubella) administration for 4 months.

patients who received adenosine after April 2018. Patients with pulmonary problems such as asthma and severe chronic obstructive pulmonary disease (COPD) could not receive adenosine, which can trigger lung problems, affecting comparisons between the two patient groups, acknowledged co-author Dustin Spencer, PharmD, MBA, the clinical director of cardiopulmonary diseases at Cardinal Health. “This was one of the limitations we have on the study,” he said. However, the researchers found that patients who received adenosine were no more likely to experience AEs, and were less likely to require rescue agents. “This change in pharmacologic agent for stress testing was a twofold benefit for our health system,” Dr. Yohey said in an interview. “Anything that we can do to reduce the cost of a patient stay means the hospital may gain revenue on that stay. But improving patient care and outcomes by reducing the amount of reversal is the biggest win in my eyes.” It’s not a huge surprise that patients receiving regadenoson needed more rescue agents, Dr. Spencer explained. Since adenosine has a shorter half-life, if patients begin to experience AEs, doctors can simply stop the infusion and reverse its effects. But patients receiving regadenoson, which lingers longer in the body, may need an additional agent to reverse its effects if they are struggling to tolerate the drug, he explained. C. Michael White, PharmD, the head of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy, in Storrs, noted that the study is limited by its observational design and the “big difference” between patient groups. “Even with all these deficiencies, these results are very similar to previous observational studies comparing regadenoson to adenosine where adenosine was shown to be safer,” said Dr. White, who did not participate in the research. “No large-scale randomized trials assessed safety end points, so the best evidence to date, while flawed, is that adenosine is safer.” Dr. Spencer cautioned that adenosine should not be a first choice for all patients. “It’s not that we’re trying to say adenosine is the safest option for all patients. We’re saying that in patients who don’t have COPD or asthma, it appears to be safe to use adenosine.” —Alison McCook

Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871

3052565 Revised: 06/2018

The sources reported no relevant ﬁnancial relationships.

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Pharmacy Practice News • July 2019

Nutrition

Tailoring Nutrition to Special Patient Populations A

one-size-fits-all approach to nutrition support is not a strategy forr success. A far better strateggy is to employ tailored interveentions when feeding a hospiitalized patient who is criticcally ill, morbidly obese, underggoing major abdominal surgery or o on multiple organ support, according to nutrition experts. “You have to adjust your feeding for each one of these special patient populations,” said Steephen McClave, MD, a professor off medicine at the University of LouisL ville in Kentucky. Still, a few key strategiees are nearly universal: Begin feeeding the patient early, not too m much and ideally orally. Dr. McClave recommen nded taking into account baseeline nutrition status, disease seeverity and the presence of sarcopenia before initiating any nutrition therapy. He allso cautioned that a malnou urished patient may be diffficult to recognize. “They can be thin or they can be heavy, and they may or may not have malnutrition.” The three most reliable markers of malnutrition in the ICU are reduced oral feeding prior to admission, weight loss prior to admission and low body mass index (BMI) (Curr Opin Clin Nutr Metab Care 2014;17[2]:177-182). Malnutrition is also a moving target: Critical illness can accelerate the deterioration of a patient’s nutrition status from baseline. “It changes the slope of the malnutrition curve dramatically and drives you toward a state of increased complications and adverse outcomes,” Dr. McClave said. Malnutrition can, in turn, alter a patient’s response in the ICU. It may shift the body’s metabolic response to injury, therefore increasing cellular toxicity and driving inflammatory responses and end organ dysfunction (JPEN ( J Parenter Enteral Nutr 2017;41[2]:188-197).

Age, Comorbidities Also Key Once malnutrition is identified in a critically ill patient, several other factors need to be considered, such as the patient’s age and comorbidities, before determining the optimal therapy. Dr. McClave emphasized the importance of preserving lean body mass, so higher amounts of protein and exercise are critical for patients over 60 years of age, as well as those with burns, obesity or on continuous renal replacement therapy. Bed rest can result in a reduction in the

Taking into account baseline nutrition status, disease severity and the presence of sarcopenia (above) before initiating any nutrition therapy is critical to achieving optimal outcomes.

expression of cell membrane–associated amino acid transporters and other factors associated with a decline in skeletal muscle mass ((JPEN J Parenter Enteral Nutr 2015;39[3]:273-281). Dr. McClave also advised providers to look for the cardiac, pulmonary and neurologic signs of refeeding syndrome, a potentially fatal shift in fluids and electrolytes that can occur in malnourished patients receiving artificial refeeding, as well as to minimize permissive underfeeding and ramp up the infusion rate to goal as soon as possible. “By day 2 or 3, you should have identified and are moving to the goal,” he said. “Expect micronutrient deficiencies,” Dr. McClave added. Although there are multiple schools of thought on micronutrients, including measuring levels in the ICU and correcting any deficiencies or providing supraphysiologic doses, he recommended assuming some deficiencies and empirically providing physiologic doses ((Am J Clin Nutr 2007;85[5]:1293-1300). Enteral nutrition has both nutritional and non-nutritional benefits over parenteral nutrition (PN), Dr. McClave noted. The feeding route is less invasive, poses less risk for infection or metabolic abnormalities, and helps to maintain healthy gut integrity, motility

and immune function, he pointed out. “And by putting proteins in the gut compared to the blood, you get more insulin output.” Phil Ayers, PharmD, the chief of clinical pharmacy services at Mississippi Baptist Medical Center in Jackson, also underscored the advantages of enteral nutrition. “In the majority of critically ill patients, it is practical to use enteral nutrition instead of parenteral nutrition,” he said. “Parenteral nutrition is only indicated if enteral nutrition is not feasible and hypermetabolism is expected to last more than four to five days, or if the patient’s condition precludes the use of the gastrointestinal tract for more than seven to 10 days.” Enteral nutrition, Dr. Ayers added, is contraindicated if the intestinal tract has severely diminished function due to the underlying disease or treatment, such as paralytic ileus, mesenteric ischemia, small bowel obstruction or gastrointestinal fistula.

Feeding Obese Patients Morbidly obese patients are increasingly common in the United States. According to the CDC, the prevalence of obesity was 39.8% and affected about 93.3 million adults in 2015 to 2016 (www. cdc.gov/obesity/data/adult.html).

Despite that prevalence, there is a concerning lack of research on the specialo ized nutritional needs of this pattient population, according to B Beth Taylor, DCN, RDN-AP, who o suggested this gap is at leastt partly to blame for some lingeering misconceptions. “Ju ust because someone is someewhat obese doesn’t mean they have adequate nutrition,” said D Dr. Taylor, a research scientistt in the Department of Reseaarch for Patient Care Services aat Barnes-Jewish Hospital in St. Louis. “We need to feed these patients, but we have to do it cautiously because they have a lot going on.” Nott all obese patients are the same.. Even with the same BMI, patien nts can present very differen ntly. A 25-year-old male footb ball player and an inactive 62-yyear-old woman may both havve a BMI of 40 kg/m2 but havve very distinct nutritional sttatuses. “We can’t just think aabout BMI when thinking about these patients,” Dr. Taylor said. “What else is going on? What comorbidities might they have?” Among those key comorbidities is sarcopenia, which is generally defined as reduced muscle mass and is associated with decreased physical activity and increased obesity. “If they have sarcopenia, you probably need to get more protein in them,” Dr. Taylor said. Probably because of the insulin resistance common in obese patients, amino acids have more difficulty accessing skeletal muscle where they are able to make protein, Dr. Taylor explained. “So, even if you are giving high loads of amino acids, the patient may not be able to utilize it.” Other complications of obesity may influence feeding, such as difficult intubation with the narrowing of the upper airway, decreased mobility, alterations to the gut flora and anabolic resistance. Because of the extra weight and pressure on their lungs, these patients also may have an increased risk for pulmonary edema. “Be cautious with the carbohydrate load up front, as refeeding [syndrome] could result,” she said. Guidelines generally recommend hypocaloric and high protein feeding for obese patients. The goal should not exceed 65% to 70% of target energy requirements as measured by indirect calorimetry, Dr. Taylor noted. If indirect calorimetry is not available, she recommended a weight-based equation of 11 to 14 kcal/kg of actual body

Clinical

Pharmacy Practice News • July 2019

Nutrition weight per day for patients with a BMI of 30 to 50, and 22 to 25 kcal/kg of ideal body weight per day for patients with a BMI greater than 50 (Crit Care Med 2016;44[2]:390-438). Regarding protein, she recommended 2 g/kg of ideal body weight per day for patients with a BMI of 30 to 40, and up to 2.5 g/kg of ideal body weight per day for patients with a BMI of 40 or greater. “The main goals for providing nutrition to obese patients in the ICU are the same as for nonobese patients, but the total energy and protein goals are different. A low-calorie, high-protein approach is recommended,” said Diana W. Mulherin, PharmD, a clinical pharmacist at Vanderbilt Center for Human Nutrition in Nashville, Tenn. Both Drs. Taylor and Mulherin emphasized that enteral feeding should continue to be the standard of care for these patients.

More Customized Menus Philip Barie, MD, a professor of surgery at Weill Cornell Medicine in New York City, discussed feeding before and after major abdominal surgery, and

attempted to clear up some myths. “NPO (nothing by mouth) after midnight is just ridiculous. Here we are, 140 years later, still pursuing the practice,” he said, noting that the origin of the misconception was likely an extrapolation from the higher risk for aspiration posed by use of emergency general anesthesia when the stomach is full. Evidence indicates a shortened fluid fast up to 1.5 hours preoperatively did not increase the risk for aspiration, regurgitation or related morbidity (Cochrane Database Syst Rev 2003;4:CD004423). Surgery is stressful to the body. Among its effects are increased intestinal permeability and decreased intestinal villous height (Nutrients ( 2013;5[2]:208623). Dr. Barie suggested this damage can raise caloric requirements to as high as 30 kcal/kg of ideal body weight. “You should add another 20% during renal replacement therapy to account for losses of urea nitrogen,” he said. As did the other expert, Dr. Barie recommended the start of enteral feeding as early as possible—ideally, 24 hours

after surgery. “Then advance to goal as tolerated over the next few days,” he said. Dr. Barie cited a meta-analysis that found an average reduction of 0.84 days in hospital length of stay with early enteral feeding compared with NPO ( (BMJ J 2001;323[7316]:773-776). Regarding the choice of substrate for feeding, he noted that elemental and semi-elemental formulas require less energy expenditure to digest, but are expensive and therefore most suitable for selected patients with short-bowel syndrome, malabsorption syndrome or low-output enterocutaneous fistula (Chestt 2014;145[5]:1148-1157). Dr. Barie, too, said PN should be reserved for rare cases. Studies have found that withholding PN for at least one week resulted in lower mortality and fewer complications than early PN in both children and adults ((N Engl J Med d 2016;374:1111-1122 and 2011;365:506-517). Todd Rice, MD, an associate professor of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University

Medical Center in Nashville, echoed similar recommendations in his discussion of feeding a patient on multiple organ support. Dr. Rice suggested beginning enteral feeding early and at a low dose for these patients and then moving toward goal between days 4 and 8. Research indicates starting enteral nutrition within 24 hours improves survival ((Intensive Care Med 2009;35[12]:2018-2027). Dr. Rice further advised optimizing protein at between 1 and 2 g/kg of body weight per day, adding, “Providing at least a little nutrition into the gut has positive effects.” —Lynne Peeples Dr. McClave reported financial relationships with Abbott, Cardinal Health, Fresenius Kabi, Nestlé, Nutricia and Pfizer; Dr. Ayers with Fresenius Kabi and Janssen Pharmaceuticals; Dr. Taylor with Abbott, Baxter, Medtronic and Nestlé; and Dr. Rice with Avisa Pharma and Cumberland Pharmaceuticals. Drs. Barie and Mulherin reported no relevant financial relationships. This article is based in part on presentations made at the 47th Annual Congress of the Society of Critical Care Medicine in San Antonio.

Another Challenge:

Surviving PN Shortages T

ailoring nutrition to special populations can’t work if providers don’t have ready access to nutrition products in the first place. So it’s important to have a strategy for dealing with the short-supply issues that continue to challenge clinicians. The first step is to understand just what’s at stake, according to Beverly Holcombe, PharmD, a clinical practice specialist for the American Society for Parenteral and Enteral Nutrition (ASPEN). In 1988, three patients died after a nationwide shortage of multivitamins affected the composition of PN (MMWR Morb Mortal Wkly Rep 1989;38[3]:43-46). More than 30 years later, Dr. Holcombe noted, key nutritional product shortages persist—hence the need for proactive strategies for combating them. Here is a sampling of such steps that nutrition experts have shared with Pharmacy Practice News in our recent coverage of this issue: Meet often. At Nationwide Children’s Hospital, in Columbus, Ohio, a pharmacist and pharmacy technicians who are responsible for inventory control meet weekly about parenteral nutrition (PN) shortages, according to Steven Plogsted, PharmD, a clinical pharmacy specialist in the nutrition support service. One of their tasks, he said, is to maintain a document that forecasts what shortages might be on the horizon, perhaps as a result of a recent manufacturing issue. Shortage plans often include determining which patients can receive nutrition by mouth, performing an inventory count and trying to consolidate inventory, and rationing some products, if possible. Although zinc is a trace element critical for growth and wound care, during shortages providers sometimes reduce the amount they give to older children, ensuring that neonates are getting what they need. Prioritize. Determining which patients get priority during PN shortages is another important management task, according to Diana W. Mulherin, PharmD, a clinical pharmacy specialist at the Vanderbilt

Center for Human Nutrition, in Nashville, Tenn. Among adults, priority is given to those with high fluid or electrolyte needs and those who rely entirely on PN for nutrition, Dr. Mulherin noted. Once priorities, alternative agents and other key strategies are set, the shortage plan is communicated to the informatics team so they can quickly make changes to the computerized provider order entry system. Keep the lines of communication open. For patients receiving PN at home, home infusion pharmacies should communicate frequently with the prescriber, Dr. Mulherin said. For instance, a recent shortage in sodium phosphate prompted the United States to temporarily approve imports of sodium glycerophosphate from Europe. But sodium glycerophosphate has a different sodium content than sodium phosphate; some amino acids contain additional sodium and/or phosphate. These differences in content “can significantly affect the stability of the PN formula or change the intended electrolyte provision, which can be dangerous if not accounted for,” she said. Be careful with imported PN products. If providers need to rely on imported nutrition products or components, Dr. Holcombe advised that they review the “dear health care provider” information that comes with the formulations, because the products may have key differences that affect use. Secondary shortages. Also remain vigilant about the tendency of a shortage to lead to secondary shortages after providers hoard supplies or use up supplies of a substitute product, Dr. Plogsted noted. For instance, after a recent shortage of a bundle of trace elements, there was a subsequent shortage of the individual elements that providers had bought to overcome the loss of the bundle, he recalled. Push back if institutions try to continue giving some patients less of a rationed drug after shortages resolve to cut costs, he

added. “Just because you didn’t see negative outcomes during the shortage period, doesn’t mean they aren’t there.” Keep talking! Whatever the coping strategy is, its success may well hinge on maintaining the lines of communication between the prescriber and home infusion pharmacies, Dr. Mulherin stressed. That way, “PN orders are accurate and reflect the exact ingredients in the PN formulation,” she said. “It is also imperative that any substitutions for short-supply nutrition products be discussed with prescribers beforehand.” Use available resources. ASPEN maintains a page dedicated to nutrition shortages that includes advice for navigating shortages in individual components (bit.ly/2TKgc8x). And don’t hesitate to consult the manufacturer that’s facing a shortage, Dr. Holcombe said. “The manufacturers are fabulous resources.” —Alison McCook The sources reported no relevant ﬁnancial relationships.

26 Clinical

Pharmacy Practice News • July 2019

Infectious Disease

UTIs: Go Slow continued from page 1

Furthermore, pediatric patients; solidorgan transplant patients, particularly renal transplants; and patients undergoing elective nonurologic surgery (mostly hip and knee replacements and prosthetic cardiac devices) have been added to the list of populations that should not receive UTI testing, unless they encounter other symptoms, according to the updated guidelines.

Elizabeth Dodds Ashley, PharmD, an associate professor of medicine in the Infectious Diseases Division at Duke University School of Medicine, in Durham, N.C., applauded the guideline’s conservative approach about which populations should be screened. “We know that once you obtain a urine culture, it is really hard not to treat a positive result,” she said. “Therefore, having a better and more limited guideline as far as who should undergo screening cultures is very helpful to us in order to limit this unnecessary therapy.”

The 2019 guideline replaces the initial 2005 published guideline. “However, none of the 2005 recommendations needed to be changed,” said principal writer Lindsay Nicolle, MD, a professor emeritus at the Rady Faculty of Health Sciences, University of Manitoba, in Winnipeg. “Any new studies, which have been published in the interim, simply confirm those previous recommendations.” Overall, the 2005 guideline and additions to the 2019 guideline recommend that most people with ASB “do not benefit by treating ASB with antibiotics,”

Dr. Nicolle said. “Such treatment is not recommended because of the side effects from the antibiotics, the antimicrobial resistance issue and potential cost.” There are only two groups with probable ASB for which treatment and screening are recommended: pregnant women and patients undergoing endourologic surgery. “We have reaffirmed the recommendation of the 2005 guideline that pregnant women should be screened sometime early in their pregnancy and then treated for ASB, if it is present,” she said. “This is based on some studies conducted back in the 1960s and 1970s, which suggested that such a protocol provided a tremendous benefit for preventing pyelonephritis later in pregnancy.” Conversely, a more recent study in the past few years from the Netherlands indicates that for low-risk pregnant women, there may not be benefits for screening or treatment. “But we believe there needs to be further studies undertaken in other pregnant populations, including highrisk women as well as low-risk women,” Dr. Nicolle said. “There is some controversy about the issue at the present time.” Likewise, for elective nonurologic surgery, “there has been a practice among many surgeons to routinely obtain either a urinalysis or a urine culture prior to the surgery and then to treat that,” Dr. Nicolle said. “However, our recommendations suggest that there are no benefits for obtaining samples and treating; therefore, there is no need to screen or treat ASB prior to these elective surgeries.” In addition, given the limited quality and amount of data available for treating elderly residents in retirement communities and health care facilities, UTI testing is recommended only if there is deterioration in clinical status with localized genitourinary symptoms, such as frequency or dysuria, consistent with a UTI. “Otherwise, you should first carefully consider all other potential causes of infection and monitor the patient, because symptoms like urine odor and confusion in the elderly are often caused by other conditions that should be ruled out,” Dr. Nicolle said. “We hope that identifying this issue will encourage investigators to more rigorously evaluate clinical presentations in elderly populations.” Dr. Nicolle anticipates that the updated guideline will assist in bolstering antibiotic stewardship efforts and decreasing the use of antibiotics for UTIs in cases of which there won’t be any benefit to the patient. “Clinicians need to be more judicious in administering antimicrobials,” she said.

Clinical 27

Pharmacy Practice News • July 2019

Infectious Disease UTIs are responsible for nearly

10 million doctor visits each year. Source: National Kidney Foundation

Dr. Nicolle noted that some studies conclude that the inappropriate prescribing of antibiotics actually can increase the risk for a UTI and may contribute to other serious infections, such as Clostridioides difficile infection. “The hope is that this revised guideline will give clinicians a chance to go into health care settings where there has not been good evidence for treating ASB, and where we have not tried to cut back on treating the condition because the previous guideline did not address certain populations,” said guideline coauthor Dimitri Drekonja, MD, an associate professor of medicine at the University of Minnesota in Minneapolis.

Can We Talk? One of the intentions of the updated UTI practice guidelines is to foster conversations that will guide those caring for elderly people, who often are admitted to hospitals without specific symptoms but with potentially abnormal urine testing, Dr. Drekonja noted. In such cases, he stressed, it is important to determine whether there is worsening agitation or worsening fatigue due to a UTI, or if these symptoms are due to something else. In the past, people treated the urine test, not the patient. “But now it is OK to simply watch, wait and observe, and not necessarily treat,” Dr. Drekonja said. He added that none of the guideline recommendations should come as a surprise. “Individually in our practices, we have all [held off on UTI testing, where appropriate]. But it’s nice to now have a summary of the evidence and an official recommendation [supporting such an approach].” In fact, the onus should be on demonstrating a benefit from treating ASB, according to Dr. Drekonja. “We know there are harms with antibiotics, so if you are going to use them, you need to show some evidence of benefit before you can consider it,” he said. “Even though sometimes the evidence is weak, if there is no evidence of benefit, the known harms win out in our minds.” Dr. Dodds Ashley, a past president of the Society of Infectious Diseases Pharmacists, said as antibiotic stewards, “we know that treatment of perceived urinary

infections is one of the most common reasons that patients receive unnecessary antibiotics in the community and in the hospital. Overtreatment of ASB is an area of specific focus for many antibiotic stewardship programs.” Dr. Dodds Ashley reiterated that she was encouraged by the guideline authors’ go-slow approach for managing challenging populations, such as older patients who experience a fall. Although UTIs can cause confusion in the elderly, which in turn can lead to falls, other causes of falls should be

considered, she noted. This point was underscored by the guideline authors, who noted that in patients who fall and present with bacteriuria without local genitourinary symptoms or other systemic signs of infection (fever, hemodynamic instability), “we recommend assessment for other causes and careful observation rather than antimicrobial treatment of bacteriuria.” This recommendation, the guideline noted, “places a high value on avoiding adverse outcomes of antimicrobial therapy such as Clostridioides difficile infection,

increased antimicrobial resistance, or adverse drug effects, in the absence of evidence that such treatment is beneficial for this vulnerable population.” “This is one of the areas where the updated guidelines have done a very nice job of not just addressing the urine but also encouraging clinicians to first rule out other possible causes,” Dr. Dodds Ashley said. —Bob Kronemyer The sources reported no relevant ﬁnancial relationships.

Omegaven

(fish oil triglycerides) injectable emulsion

Introducing a Fish Oil Lipid Emulsion for Pediatrics1 A source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis (PNAC) Patients receiving Omegaven achieved age appropriate growth Omegaven treated patients experienced improvement in liver function parameters

CONTRAINDICATIONS Omegaven is contraindicated in patients with known hypersensitivity to fish or egg protein or to any of the active ingredients or excipients, severe hemorrhagic disorders due to a This brief summary does not include all the information needed to use Omegaven potential effect on platelet aggregation, severe hyperlipidemia or severe disorders of lipid safely and effectively. Please see full prescribing information for Omegaven (fish oil metabolism characterized by hypertriglyceridemia (serum triglyceride concentrations triglycerides) injectable emulsion for intravenous use at www.fresenius-kabi.com/us. greater than 1,000 mg/dL). INDICATIONS AND USAGE WARNINGS AND PRECAUTIONS Omegaven is indicated as a source of calories and fatty acids in pediatric patients with • Risk of Death in Preterm Infants due to Pulmonary Lipid Accumulation: Deaths in parenteral nutrition-associated cholestasis (PNAC). preterm infants after infusion of soybean oil-based intravenous lipid emulsions have Limitations of Use: been reported in medical literature. Autopsy findings in these preterm infants included Omegaven is not indicated for the prevention of PNAC. It has not been demonstrated that intravascular lipid accumulation in the lungs. The risk of pulmonary lipid accumulation Omegaven prevents PNAC in parenteral nutrition (PN)-dependent patients. with Omegaven is unknown. Preterm and small-for-gestational-age infants have poor It has not been demonstrated that the clinical outcomes observed in patients treated with clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. This risk due to poor lipid clearance should be considered Omegaven are a result of the omega-6: omega-3 fatty acid ratio of the product. when administering intravenous lipid emulsions. Monitor patients receiving Omegaven DOSAGE AND ADMINISTRATION for signs and symptoms of pleural or pericardial effusion. Prior to administration, correct severe fluid and electrolyte disorders and measure serum • Hypersensitivity Reactions: Omegaven contains fish oil and egg phospholipids, which triglycerides to establish a baseline level. Initiate dosing in PN-dependent pediatric patients may cause hypersensitivity reactions. Signs or symptoms of a hypersensitivity reaction as soon as direct or conjugated bilirubin levels are 2 mg/dL or greater. The recommended may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, daily dose (and the maximum dose) in pediatric patients is 1 g/kg/day. Administer Omegacyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, ven until direct or conjugated bilirubin levels are less than 2 mg/dL or until the patient no rash, urticaria, erythema, fever, or chills. If a hypersensitivity reaction occurs, stop infusion longer requires PN. of Omegaven immediately and initiate appropriate treatment and supportive measures.

OMEGAVEN (fish oil triglycerides) injectable emulsion emulsion, for intravenous intraven use BRIEF SUMMARY OF PRESCRIBING INFORMATION

Please see continuation of Brief Summary of Prescribing Information for Omegaven on the reverse side.

28 Clinical

Pharmacy Practice News • July 2019

Infectious Disease

Antibiotic Stewardship Critical but Difficult in the ICU

ntibiotic stewardship in the ICU should be a critical part of a patient’s care, but it is not easy to practice in this setting because the patients are so vulnerable, the need is immediate, and usually all the information needed to choose an antibiotic is not available. One of the major barriers to a successful antibiotic stewardship program (ASP) is fear of missing the potential pathogen, which drives much of

excessive antibiotic use, according to Richard Wunderink, MD, a professor of medicine in the Division of Pulmonary and Critical Care at Northwestern University Feinberg School of Medicine in Chicago. That lack of information can be a particular challenge early in the course of care. “Cultures usually take about 72 hours, during which time you are working without a clear diagnosis, and therefore

a tendency to continue to cover broadly until the results come back,” said Dr. Wunderink, who is the senior author of a recent article on antibiotic stewardship in the ICU (Chest 2019 Jan 25. [Epub ahead of print]). However, rapid diagnostic tests are helping to provide that information sooner. Bonnie Falcione, PharmD, BCPSAQ ID, a clinical pharmacist in antibiotic management and critical care at

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• Risk of Infections: The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other conditions or concomitant drugs. To decrease the risk of infectious complications, ensure aseptic technique in catheter placement and maintenance, as well as in the preparation and administration of Omegaven. Monitor for signs and symptoms of early infections including fever and chills, laboratory test results that might indicate infection (including leukocytosis and hyperglycemia), and frequently inspect the intravenous catheter insertion site for edema, redness, and discharge. • Fat Overload Syndrome: A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in this syndrome, which is characterized by a sudden deterioration in the patient’s condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, hepatomegaly, deteriorating liver function, and central nervous system manifestations (e.g., coma). • Refeeding Syndrome: Administering PN to severely malnourished patients may result in refeeding syndrome, which is characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, closely monitor severely malnourished patients and slowly increase their nutrient intake. • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. Serum triglyceride levels greater than 1,000 mg/dL have been associated with an increased risk of pancreatitis. To evaluate the patient’s capacity to metabolize and eliminate the infused lipid emulsion, measure serum triglycerides before the start of infusion (baseline value), and regularly throughout treatment. If hypertriglyceridemia (triglycerides greater than 250 mg/dL in neonates and infants or greater than 400 mg/dL in older children) develops, consider stopping the administration of Omegaven for 4 hours and obtain a repeat serum triglyceride level. Resume Omegaven based on new result as indicated. • Aluminum Toxicity: Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Preterm infants are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with impaired kidney function, including preterm infants, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. • Monitoring and Laboratory Tests: Routine Monitoring: g Monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, coagulation parameters, and complete blood count including platelets throughout treatment. Essential Fatty y Acids: Monitoring patients for laboratory evidence of essential fatty acid deficiency (EFAD) is recommended. Laboratory tests are available to determine serum fatty acids levels. Reference values should be consulted to help determine adequacy of essential fatty acid status. • Interference with Laboratory Tests: The lipids contained in Omegaven may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase, bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. Lipids are normally cleared after a period of 5 to 6 hours once the lipid infusion is stopped.

www.OmegavenUSA.com 1.888.386.1300 1.800.551.7176 (option 4) nutrition.medinfo.USA@fresenius-kabi.com

to 6 months) of treatment, and 3 (2%) were taken off the waiting list because cholestasis resolved. One hundred thirteen (60%) Omegaven-treated patients reached DBil levels less than 2 mg/dL and AST or ALT levels less than 3 times the upper limit of normal, with median AST and ALT levels for Omegaven-treated patients at 89 and 65 U/L, respectively, by the end of the study. Median hemoglobin levels and platelet counts for Omegaven-treated patients at baseline were 10.2 g/dL and 173 x 109/L, and by the end of the study these levels were 10.5 g/dL and 217 x 109/L, respectively. Adverse reactions associated with bleeding were experienced by 74 (39%) of Omegaven-treated patients. Median glucose levels at baseline and the end of the study were 86 and 87 mg/dL for Omegaventreated patients, respectively. Hyperglycemia was experienced by 13 (7%) Omegaven-treated patients. Median triglyceride levels at baseline and the end of the study were 121 mg/dL and 72 mg/dL for Omegaven-treated patients respectively. Hypertriglyceridemia was experienced by 5 (3%) Omegaven-treated patients. The triene:tetraene (Mead acid:arachidonic acid) ratio was used to monitor essential fatty acid status in Omegaven-treated patients only in Study 1 (n = 123). The median triene:tetraene ratio was 0.02 (interquartile range: 0.01 to 0.03) at both baseline and the end of the study. Blood samples for analysis may have been drawn while the lipid emulsion was being infused and patients received enteral or oral nutrition. Postmarketing Experience The following adverse reaction has been identified with use of Omegaven in another country. Life-threatening hemorrhage following a central venous catheter change was reported in a 9 month-old infant with intestinal failure who received PN with Omegaven as the sole lipid source; he had no prior history of bleeding, coagulopathy, or portal hypertension. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Prolonged bleeding time has been reported in patients taking antiplatelet agents or anticoagulants and oral omega-3 fatty acids. Periodically monitor bleeding time in patients receiving Omegaven and concomitant antiplatelet agents or anticoagulants.

USE IN SPECIFIC POPULATIONS • Pregnancy: There are no available data on Omegaven use in pregnant women to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with fish oil triglycerides. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. • Lactation: No data available regarding the presence of fish oil triglycerides from Omegaven in human milk, the effects on the breastfed infant, or the effects on milk production. ADVERSE REACTIONS Lactating women receiving oral omega-3 fatty acids have been shown to have higher levels The most common adverse drug reactions (>15%) are: vomiting, agitation, bradycardia, apnea of omega-3 fatty acids in their milk. The developmental and health benefits of breastfeeding and viral infection. should be considered along with the mother’s clinical need for Omegaven, and any potential adverse effects of Omegaven on the breastfed infant. Clinical Trials Experience • Pediatric Use: The safety of Omegaven was established in 189 pediatric patients (19 days to The safety database for Omegaven reflects exposure in 189 pediatric patients (19 days to 15 years of age). The most common adverse reactions in Omegaven-treated patients were 15 years of age) treated for a median of 14 weeks (3 days to 8 years) in two clinical trials. vomiting, agitation, bradycardia, apnea and viral infection. Adverse reactions that occurred in more than 5% of patients who received Omegaven and with • Geriatric Use: Clinical trials of Omegaven did not include patients 65 years of age and older. a higher incidence than the comparator group are: vomiting, agitation, bradycardia, apnea, viral infection, erythema, rash, abscess, neutropenia, hypertonia and incision site erythema. OVERDOSE Patients had a complicated medical and surgical history prior to receiving Omegaven In the event of an overdose, fat overload syndrome may occur. Stop the infusion of Omegaven treatment and the mortality was 13%. Underlying clinical conditions prior to the initiation of until triglyceride levels have normalized and any symptoms have abated. The effects are Omegaven therapy included prematurity, low birth weight, necrotizing enterocolitis, short bowel usually reversible by stopping the lipid infusion. If medically appropriate, further intervention syndrome, ventilator dependence, coagulopathy, intraventricular hemorrhage, and sepsis. may be indicated. Lipids are not dialyzable from serum. Twelve (6%) Omegaven-treated patients were listed for liver transplantation (1 patient was REFERENCES: listed 18 days before treatment, and 11 patients after a median of 42 days [range: 2 days to 1. Omegaven Prescribing Information, Fresenius Kabi USA, LLC. 2018. 8 months] of treatment); 9 (5%) received a transplant after a median of 121 days (range: 25 days

Fresenius Kabi USA, LLC Three Corporate Drive, Lake Zurich, IL 60047 Phone: 1.888.386.1300 www.fresenius-kabi.com/us

UPMC Presbyterian Hospital in Pittsburgh, said she is excited about rapid diagnostic and laboratory testing to reduce inappropriate antibiotics. “However, the coordination of these technologies to bring them to the bedside, particularly in the ICU, is going to make the difference going forward,” she stressed. Rapid diagnostics continue to evolve, Dr. Falcione said. Accelerating the ability to grow the bacteria, which historically has been the ratelimiting factor, “will enable us to truly move forward by minimizing the time to identification of the bacteria, along with the phenotype.” Still, rapid test results aren’t always available to guide therapy, and in such cases, empiric treatment can still be effective—provided they are evidencebased, noted Dr. Falcione, also an associate professor of pharmacy at the University of Pittsburgh Schools of Pharmacy and Medicine. “We know that the time to appropriate antibiotic use in critically ill patients, particularly those with septic shock, makes a difference,” she said. “So, the more we can identify appropriate empiric regimens specific to patient populations and subpopulations, the better we will be at identifying those regimens and starting them on time.”

Renal Clearance A Consideration In addition to selecting an appropriate drug, other key factors are proper dosing, method of administration and frequency. “ICU patients are particularly vulnerable to augmented renal clearance,” Dr. Falcione said. “Based on their IV fluid requirements, ICU patients may also end up with larger volumes of distribution.” Therefore, the same dose that is given to one patient compared with another with a similar body habitus may not result in the same drug concentration where the infection occurs, she noted. Yet another key consideration is proper de-escalation of antibiotics—a particular challenge in the ICU because these patients are so ill. “Having a plan identified up front helps with adhering to limiting duration to the most appropriate timeline, followed by ongoing monitoring to ensure that the plan continues to be suitable,” Dr. Falcione said.

A Multidisciplinary Approach The literature indicates that the involvement of infectious disease (ID) consultations is another key to success in forging an effective ASP, according to Dr. Falcione. ID consults are particularly important with complex patients, such as

Clinical

Pharmacy Practice News • July 2019

Infectious Disease the cause or rule out certain organisms, thus not continue to cover empirically for those infections,” Dr. Wunderink said. Another way to optimize ASPs is to share clinical outcomes. By doing so, “one learns there is a natural variation among physicians,” Dr. Wunderink said. For instance, discovering that other clinicians stopped antibiotics at a certain time or did not use broad-spectrum antibiotics for some patients who fared well is valuable in helping clinicians understand how they are managing a patient compared with their peers. those with a history of multidrug resistance. The ID consult can help determine the duration of therapy for complicated patients. These consults can also assist in establishing and coordinating management and monitoring for longer term plans once the patient leaves the ICU, for ideal continuity of care. Sarah Doernberg, MD, an associate professor of medicine at the University of California, San Francisco School of Medicine, and the medical director of antimicrobial stewardship at UCSF, agreed that a team approach to ASPs is critical—particularly so when incorporating the results of rapid testing into antibiotic treatment decisions. “Various studies of rapid diagnostics have shown that without having a pharmacist or other ID specialist, or both, helping clinicians integrate the information quickly, the fact that it is recorded in the medical record six hours later does not necessarily change antibiotic behavior in six hours,” she said. “We also need physicians to become more comfortable with the uncertainly in the ICU and figure out strategies for how stewardship can be executed in this really high-stake setting and leading to good patient outcomes.”

—Bob Kronemyer The sources reported no relevant ﬁnancial relationships.

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Tech Can Help In such hectic settings, technology can be a boon, according to Dr. Wunderink. He cited, as an example, computerized decision support that offers automated prompts to reassess antibiotics, check patterns of resistance for particular pathogens and consider results from previous treatments. These types of automated notifications hold promise for enhancing stewardship programs, he noted. A case in point are antibiotic time-outs, which can be triggered by the electronic health record and remind a clinician that it is time re-evaluate the need for a particular antibiotic. “After a designated number of hours of treatment with a particular antibiotic, it makes sense to re-evaluate, once the dust settles in a critically ill patient,” he said. Other crucial times to reassess are when results of cultures and diagnostic tests return. “This is an opportunity to reassess antibiotic usage, by helping us to either exactly define the infection and

That willingness to scrutinize one’s own prescribing patterns is crucial to ensuring a dynamic and effective ASP, Dr. Wunderink stressed. After all, he noted, “we are partly to blame for the development of drug-resistant pathogens because of our use of antibiotics, especially in situations where we do not practice good antibiotic stewardship.”

of commercially insured patients pay $0 OOP costs per dose of Neulasta® Onpro®1,*

*Data based on quarterly SHS medical claims data of 20,862 commercial medical claims collected at the national level between January 2017 and December 2017. Physician service claims and hospital claims were included in this analysis. Neulasta® OOP is calculated using the sum of deductible, V «>Þ] > ` V ÃÕÀ> Vi >vÌiÀ Ì i w > «>ÞiÀ has paid their share of the cost. Each claim represents a single dose of Neulasta®.1

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References: 1. Data on file, Amgen; [1]; 2019. 2. Data on file, Amgen; [2]; 2019. 3. Data on file, Amgen; [1]; 2018. 4. Data on file, Amgen; [2]; 2018.

30 Clinical

Pharmacy Practice News • July 2019

Biosimilars

Countering the Nocebo Effect

he “nocebo effect” is an under-recognized challenge to the adoption of biosimilars, according to a new consensus report from a multispecialty panel of experts from five European countries who conducted a review of the available evidence on the nocebo effect. The report’s primary focus is on the prevention and management of the nocebo effect of patients with inflammatory bowel disease (IBD) who are

treated with biosimilars ((Aliment Pharmacol Ther 2019;49[9]:1181-1187). “Randomised controlled trials specifically examining the nocebo effect in biosimilar-treated IBD patients were lacking,” the authors wrote. At the time of their consensus meeting, there was only one interventional study examining the nocebo effect in biosimilar-treated patients with IBD, which converted patients with different

immunomodulatory imide drugs from the infliximab originator to infliximab biosimilar, and monitored the nocebo effect rate after a switch back to the original. That study found that the effect occurred in 12.9% of patients with IBD and 12.5% of patients with a rheumatologic condition ((Eur J Clin Pharmacol 2018;74[5]:655-661). Nocebo, as its name suggests, is the opposite of the placebo effect: Negative

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expectations modulate the outcome of a given therapy in a negative way, such as adverse events/side effects or diminished efficacy. “This phenomenon has been demonstrated to potentially be a significant factor in a number of different study designs,” said Gregory Heindel, PharmD, BCPS, a clinical specialist of drug information/policy in the Department of Pharmacy at the University of North Carolina Hospitals, in Chapel Hill. “For example, in a study of men prescribed fin finasteride for benign prosstatic hyperplasia, telling patiients that they might experiencce symptoms of erectile dysfunction substantiallyy increased the percentage of patients who reported that side effect [[J Sexx Med d 2007;4[6]:1708-1712]]. But as the European repo ort noted, there’s a paucity off evidence evaluating adverse effects ff from the nocebo phenomenon when switching to biosimilars.” In 2018, Dr. Heindel and his colleagues published a systematic review of the literature, which found that current scientific evidence is insufficient to confirm a biosimilar nocebo effect, although they noted that higher discontinuation rates in infliximab biosimilar open-label studies support the theory ((J Manag Care Spec Pharm 2018;24[10]:952-959). A trial to thoroughly investigate the nocebo effect in biosimilar adoption would be challenging, Dr. Heindel told Pharmacy Practice News. “A lot of factors would influence the effect,” he said. “Ideally, a trial would have an arm of patients who didn’t know they were switched from the innovator product to a biosimilar, an arm with patients who knew they were switching but did not receive counseling, and a third arm with patients who were provided with counseling that involved positive framing before switching.” Of the 18 biosimilars approved by the FDA, as of spring 2019, only seven had reached the market, including four filgrastim or pegfilgrastim biosimilars, one epoetin alfa biosimilar, and two infliximab biosimilars. “A nocebo effect is potentially bigger in an infliximab product, which patients are on for an indefinite amount of time and in which side effects and disease progression or worsening can be more subjective, compared with a filgrastim, which is

Clinical

Pharmacy Practicce News • July 2019

Biosimilars providers of the available data about biosimilars, and their ability to explain this information effectively to patients, will result in increased patient confidence in their treatment choice. Patient education should not only include sharing of factual information about biosimilars, but also explicitly discussing the possibility of the nocebo effect.” At least one study, while not specifically assessing the nocebo effect, has found that this kind of framing improves biosimilar uptake (Ann ( Rheum Dis 2017;76:557). Dutch patients with rheumatic diagnoses

switching from innovator infliximab to a biosimilar were either simply informed by letter about the transition, or given an “enhanced communication” transition that included training for clinical staff about how to assuage patient concerns. During 230 person-years of follow-up, 36 patients from the enhanced communication group discontinued therapy (16/100 person-years); by contrast, 47 patients without enhanced communication discontinued therapy over 84 person-years of follow-up (56/100 person-years). “We know that educating the patient as

to what a biosimilar is and how it works, and reassuring them that it is essentially the same as the branded product, can make a significant difference in their acceptance of these agents,” Dr. Heindel said. “Even some pharmacists and physicians have misconceptions around the approval process and safety evaluations for biosimilars, and that can get passed down to patients.” —Gina Shaw The sources reported no relevant ﬁnancial relationships.

Approved for use in interscalene brachial plexus nerve block

CHANGE THE FACE OF POSTSURGICAL RECOVERY

prescribed for a fairly short course of time, has fewer side effects, and likely less baseline knowledge and expectation of the product from the patient,” Dr. Heindel said.

A Gastroenterologist’s Take In a recent systematic review, Gary Lichtenstein, MD, the director of the Inflammatory Bowel Disease Center and a professor of medicine at the Hospital of the University of Pennsylvania, in Philadelphia, and his colleagues found that published data from six randomized controlled trials on switching from reference to biosimilar infliximab in inflammatory disorders show no clinically important efficacy or safety signals associated with switching ((Aliment Pharmacol Ther 2019;49[1]:31-40). “We don’t want to bias patients to think that the biosimilar agents are bad or inappropriate when they’ve been evaluated by regulatory agencies with different primary end points from multiple trials,” Dr. Lichtenstein said. “I think the nocebo effect brings up the power of suggestion, and that’s really the concern. Patients may hear about the cost savings associated with biosimilars and think, ‘I’m getting a cheaper drug that’s probably less effective; why would I want that?’” The new consensus report recommends individualized patient communication strategies and positive framing around the use of biosimilars, noting, “The awareness of health-care

Choose long-lasting pain control that can reduce or eliminate the need for opioids1* In an inﬁltration study, EXPAREL signiﬁcantly reduced pain and opioid use vs bupivacaine HCl1†‡ 78% FEWER OPIOIDS

13.6% LESS PAIN

overall opioid consumption (P<0.005)

cumulative pain scores (P<0.04)

10% OF PATIENTS WERE OPIOID FREE WITH EXPAREL VS 0% WITH BUPIVACAINE HCI (P=0.01)

*The clinical benefit of the decrease in opioid cons consumption mption was as not demonstrated in the pi pivotal otal trials trials. † Results from a phase 4, double-blind, randomized, active-controlled, parallel-group study that compared the efficacy and safety of EXPAREL 266 mg (20 mL) (n=70) and bupivacaine HCl (n=69) in a total knee arthroplasty (TKA). Primary end points: area under the curve of visual analog scale pain intensity scores 12 to 48 hours postsurgery; total opioid consumption 0 to 48 hours postsurgery. Rescue opioids for pain were available upon patient request. Rates and types of adverse events were similar between treatment groups. The most common adverse events in the EXPAREL group were nausea, muscle spasms, and vomiting.1 ‡ In patients undergoing a TKA; reductions were measured through 48 hours.1

Indication EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Safety and efficacy have not been established in other nerve blocks. Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia. Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via inﬁltration were nausea, constipation, and vomiting; adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation. If EXPAREL and other non-bupivacaine local anesthetics, including lidocaine, are administered at the same site, there may be an immediate release of bupivacaine from EXPAREL. Therefore, EXPAREL may be administered to the same site 20 minutes after injecting lidocaine. EXPAREL is not recommended to be used in the following patient population: patients <18 years old and/or pregnant patients. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver liver, EXPAREL should be used cautiously in patients with hepatic disease. Warnings and Precautions Speciﬁc to EXPAREL Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. EXPAREL is not recommended for the following types or routes of administration: epidural, intrathecal, regional nerve blocks other than interscalene brachial plexus nerve block, or intravascular or intra-articular use.

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The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days, as seen in clinical trials. Warnings and Precautions for Bupivacaine-Containing Products Central Nervous System (CNS) Reactions: There have been reports of adverse neurologic reactions with the use of local anesthetics. These include persistent anesthesia and paresthesia. CNS reactions are characterized by excitation and/or depression. Cardiovascular System Reactions: Toxic blood concentrations depress cardiac conductivity and excitability which may lead to dysrhythmias, sometimes leading to death. Allergic Reactions: Allergic-type reactions (eg, anaphylaxis and angioedema) are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. Chondrolysis: There have been reports of chondrolysis (mostly in the shoulder joint) following intra-articular infusion of local anesthetics, which is an unapproved use. Methemoglobinemia: Cases of methemoglobinemia have been reported with local anesthetic use. Please refer to brief summary of Prescribing Information on adjacent page. For more information information, please visit www www.EXPAREL.com EXPAREL com or call 1-855-RX-EXPAREL (793-9727). Reference: 1. Mont MA, Beaver WB, Dysart SH, Barrington JW, Del Gaizo DJ. Local infiltration analgesia with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: results of a randomized controlled trial. J Arthroplasty. 2018;33(1):90-96.

Find out more by visiting www.EXPAREL.com and request to meet with one of our representatives.

32 Policy

Pharmacy Practice News • July 2019

Managed Care

Safe Harbor continued from page 1

the pharmacy counter in decades,” Ross D. Margulies, JD, MPH, a senior associate with Foley Hoag law firm in Washington, D.C., told a packed conference room at the AMCP’s Managed Care and Specialty Pharmacy 2019 Annual Meeting. He provided an overview of the proposed rule and what it could mean. For decades, manufacturers and payors, including managed care

Brief Summary (For full prescribing information refer to package insert) INDICATIONS AND USAGE EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Limitation of Use: Safety and efficacy has not been established in other nerve blocks. CONTRAINDICATIONS EXPAREL is contraindicated in obstetrical paracervical block anesthesia. While EXPAREL has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death. WARNINGS AND PRECAUTIONS Warnings and Precautions Specific for EXPAREL As there is a potential risk of severe life-threatening adverse effects associated with the administration of bupivacaine, EXPAREL should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity. Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration. • epidural • intrathecal • regional nerve blocks other than interscalene brachial plexus nerve block • intravascular or intra-articular use EXPAREL has not been evaluated for use in the following patient population and, therefore, it is not recommended for administration to these groups. • patients younger than 18 years old • pregnant patients The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days as seen in clinical trials. ADVERSE REACTIONS Clinical Trial Experience Adverse Reactions Reported p in Local Infiltration Clinical Studies The safety of EXPAREL was evaluated in 10 randomized, double-blind, local administration into the surgical site clinical studies involving 823 patients undergoing various surgical procedures. Patients were administered a dose ranging from 66 to 532 mg of EXPAREL. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, constipation, and vomiting. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration were pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus, tachycardia, headache, insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain. Adverse Reactions Reported p in Nerve Block Clinical Studies The safety of EXPAREL was evaluated in four randomized, double-blind, placebocontrolled nerve block clinical studies involving 469 patients undergoing various surgical procedures. Patients were administered a dose of either 133 or 266 mg of EXPAREL. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, pyrexia, and constipation. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration as a nerve block were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, hypoesthesia oral, pruritus generalized, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, body temperature increased, edema peripheral, sensory loss, hepatic enzyme increased, hiccups, hypoxia, post-procedural hematoma. Postmarketingg Experience p These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes (SOCs): Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin and Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest). DRUG INTERACTIONS The toxic effects of local anesthetics are additive and their co-administration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic cyclophosphamide, flutamide, hydroxyurea, ifosfamide, agents rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Bupivacaine p Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. Non-bupivacaine p Local Anesthetics EXPAREL should not be admixed with local anesthetics other than bupivacaine. Nonbupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. There are no data to support administration of other local anesthetics prior to administration of EXPAREL.

‘On the upside, it is possible pharmacies will experience fewer complaints from Medicare beneficiaries about high out-of-pocket costs. If the rule works, and manufacturer list prices come down, beneficiary out-of-pocket costs could also go down.’ —Ross D. Margulies, JD, MPH organizations, have been entering into agreements to discount drug prices in exchange for formulary placement, volume commitments and administrative services, Mr. Margulies said. But now,

Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior to administration. Water and Hypotonic yp Agents g Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles USE IN SPECIFIC POPULATIONS Pregnancy Risk Summaryy There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Clinical Considerations Labor or Delivery Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has not been studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death. Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Data Animal Data Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity. Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day buprenorphine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation). Lactation Risk Summaryy Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EXPAREL and any potential adverse effects on the breastfed infant from EXPAREL or from the underlying maternal condition. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. Of the total number of patients in the EXPAREL nerve block clinical studies (N=531), 241 patients were greater than or equal to 65 years of age and 60 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical experience with EXPAREL has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease. Renal Impairment Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. This should be considered when performing dose selection of EXPAREL. OVERDOSAGE Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution. Signs and symptoms of overdose include CNS symptoms (perioral paresthesia, dizziness, dysarthria, confusion, mental obtundation, sensory and visual disturbances and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia and asystole). Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,500 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL. Management g of Local Anesthetic Overdose At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. Supportive treatment of

federal policymakers are saying this rebate structure encourages manufacturers, plans and PBMs to raise drug prices and increases costs for consumers at the pharmacy counter.

circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, maybe indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. DOSAGE AND ADMINISTRATION Important Dosage and Administration Information • EXPAREL is intended for single-dose administration only. • Different formulations of bupivacaine are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL. • DO NOT dilute EXPAREL with water for injection or other hypotonic agents, as it will result in disruption of the liposomal particles. • Use suspensions of EXPAREL diluted with preservative-free normal (0.9%) saline for injection or lactated Ringer’s solution within 4 hours of preparation in a syringe. • Do not administer EXPAREL if it is suspected that the vial has been frozen or exposed to high temperature (greater than 40°C or 104°F) for an extended period. • Inspect EXPAREL visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer EXPAREL if the product is discolored. Recommended Dosing in Adults Local Analgesia g via Infiltration The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266mg (20 mL), and is based on the following factors: • Size of the surgical site • Volume required to cover the area • Individual patient factors that may impact the safety of an amide local anesthetic As general guidance in selecting the proper dosing, two examples of infiltration dosing are provided: • In patients undergoing bunionectomy, a total of 106 mg (8 mL) of EXPAREL was administered with 7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue. • In patients undergoing hemorrhoidectomy, a total of 266 mg (20 mL) of EXPAREL was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block. Regional g Analgesia g via Interscalene Brachial Plexus Nerve Block The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg (10 mL), and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair. Compatibility Considerations Admixing EXPAREL with drugs other than bupivacaine HCl prior to administration is not recommended. • Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. • Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. The toxic effects of these drugs are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. • When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, the site should be allowed to dry before EXPAREL is administered into the surgical site. EXPAREL should not be allowed to come into contact with antiseptics such as povidone iodine in solution. Studies conducted with EXPAREL demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of EXPAREL any more than they are by saline. None of the materials studied had an adverse effect on EXPAREL. Non-Interchangeability with Other Formulations of Bupivacaine Different formulations of bupivacaine are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL and vice versa. Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute. CLINICAL PHARMACOLOGY Pharmacokinetics Administration of EXPAREL results in significant systemic plasma levels of bupivacaine which can persist for 96 hours after local infiltration and 120 hours after interscalene brachial plexus nerve block. In general, peripheral nerve blocks have shown systemic plasma levels of bupivacaine for extended duration when compared to local infiltration. Systemic plasma levels of bupivacaine following administration of EXPAREL are not correlated with local efficacy. PATIENT COUNSELING Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Pacira Pharmaceuticals, Inc. San Diego, CA 92121 USA Patent Numbers: 6,132,766 5,891,467 5,766,627 8,182,835 Trademark of Pacira Pharmaceuticals, Inc. For additional information call 1-855-RX-EXPAREL (1-855-793-9727) Rx only November 2018

Because the federal Anti-Kickback Statute makes it a crime to pay or receive anything of value as an incentive or inducement to use a health care service that is reimbursable by a federal health care program, a rebate paid to encourage a Medicare Advantage plan, Part D plan or Medicaid managed care plan to favor a particular drug could be a violation. However, the statute and regulations contain “safe harbors” protecting some arrangements—including those involving drug rebates—from prosecution. On Feb. 6, OIG published a proposed rule amending the discount safe harbor regulation to eliminate protection for price reductions, including rebates offered by pharmaceutical manufacturers to plan sponsors under Medicare Part D, Medicaid managed care organizations or PBMs under contract with them. The rule also would create two new safe harbors. In one, regulations would protect fixed payment service fees paid by manufacturers to PBMs for services written out in advance, based on fair market value and disclosed to the plan and HHS. In the second, the regulations would protect point-ofsale price reductions that are set in advance, applied to the price charged to a beneficiary at the point of sale and are not rebates. If enacted, the proposed amendment could take effect as early as Jan. 1, 2020, but it may not be finalized until as late as November, Mr. Margulies told Pharmacy Practice News. “One critical question that remains,” he said, is if that happens, “will Part D and Medicaid managed care plans really have enough time to come into compliance by January 1, 2020?”

Front-Line Pharmacies Will Be Affected If finalized, the proposed rule could cause a major change to the transaction flow at pharmacies, Mr. Margulies explained. To make up the difference between the plan payment and the purchase price of a drug, pharmacies will need to “charge back” what is owed to the manufacturer. This could create new payment delays for pharmacies, requiring them to hold floats longer than the current payment delays in the system, he said. “On the upside, it is possible pharmacies will experience fewer complaints from Medicare beneficiaries about high out-of-pocket costs,” he said. “If the

Policy 33

Pharmacy Practice News • July 2019

Managed Care

rule works, and manufacturer list prices come down, beneficiary out-of-pocket costs could also go down.” Many letters submitted during the open comment period supported the idea of lowering drug prices but not using this mechanism to do it. They also called for an extension to the effective date beyond next Jan. 1.

The Blue Cross Blue Shield Association noted that although it “[agrees] with the Administration that the status quo is unsustainable,” the group “has significant concerns with any proposal that would curtail the ability of health plans and PBMs to negotiate rebates with drug manufacturers without replacing them with equally

effective tools to address manufacturer pricing power,” wrote Kris Haltmeyer, the association’s vice president of legislative and regulatory policy. “The drug pricing negotiation system in this proposed rule may stifle a powerful tool that payors use today to help lower drug prices and premiums.” However, some pharmaceutical manufacturers, including Novartis, wrote that they support the proposed amendments, but urged OIG to offer more clarification and to not extend the proposed discount safe harbor changes to Medicaid managed

care plans. These beneficiaries already have zero or very low copays. The AMCP will continue to ensure members are updated with the latest information, Ms. Cantrell said. Meanwhile, she advised, Medicare Part D planning for 2020 should continue per an April 5 memo issued by the Centers for Medicare & Medicaid Services, with backup plans if necessary. —Karen Blum The sources reported no relevant ﬁnancial relationships.

AMCP Expresses Concern The AMCP, for one, expressed its concerns that the proposed rule is “not the right approach to lowering out-of-pocket costs for all Medicare beneficiaries and will not result in the automatic lowering of manufacturer list prices,” said the organization’s CEO, Susan A. Cantrell, RPh. “The rebate system is currently an important lever to ensuring affordability of prescription medications and health care premiums for Americans, and it is unclear what would replace this important lever that payors now use to manage overall beneficiary costs.” The organization urged HHS to consider reforms in other regulations and laws that result in higher beneficiary costs, such as Medicaid best price provisions. Many others also weighed in. Michael Looney, the senior vice president of government programs for Prime Therapeutics LLC, a PBM headquartered in Minnesota, said in a public comment that the company has long supported market-based solutions to address increasing drug prices by fostering transparency, increasing competition and promoting value. “The proposed rule will not promote these outcomes,” Mr. Looney wrote. “It would amend protections for rebates, a key tool used by PBMs to leverage negotiations to control drug costs. The rule also could discourage the development of alternative payment models that could promote additional cost savings and quality outcome improvements, and will destabilize premiums for vulnerable populations including lower-income seniors and those with chronic illnesses.” It is “unlikely” that removing the rebate safe harbor will accomplish its baseline goals, wrote Jillanne Schulte Wall, JD, the director of regulatory affairs at the ASHP. “We cannot support the removal of the rebate safe harbor as currently written.”

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34 Policy

Pharmacy Practice News • July 2019

Finance

Pressure on PAPs continues

Ensuring Access to Meds Remains a Moving Target Baltimore—Rapid changes being proposed and implemented in Medicare programs are forcing patient assistance programs and health systems to pay attention and sometimes get creative to ensure their patients have affordable access to prescribed medications, according to speakers at CBI’s Patient Assistance and Access Programs 2019 conference. “All of us are grappling with changes on a daily basis, and the hits just keep on coming,” said Jennifer Snow, the vice president of reimbursement policy insights for Xcenda, a health care consulting company, during a talk on the evolving health care landscape. “You never know what’s going to come up on a Thursday afternoon.” Today, more patients are considered underinsured or functionally uninsured, meaning they have insurance but it doesn’t cover their medications, Ms. Snow said. Coupled with an increase in formulary exclusions, utilization management and prior authorizations, there is added pressure on patient assistance foundations and patient representatives to help out, she said. As of this past January, the Centers for Medicare & Medicaid Services (CMS) permits step therapy for Part B drugs in Medicare Advantage plans, so these plans are now allowed to require that one drug be tried before another. There also has been a shift in Part D drugs, so those costing over $670 per month fall in a specialty tier with a cost sharing for patients of 25% to 33%, said Ms. Snow, and there is no out-of-pocket maximum for Part D. Furthermore, an out-of-pocket “cliff” requires that unless some new legislation

is passed, beneficiaries will face an additional $1,200 more in their out-of-pocket spending threshold before they hit catastrophic coverage. “That’s going to be a big stretch for a lot of beneficiaries,” Ms. Snow said. “The good news is there could be ways to help them moving forward, but in the meantime the pressure on PAPs [patient assistance programs] continues.” The federal government’s May 2018 release of a blueprint to reduce drug prices has accelerated a focus on possible Medicare reforms, said Emily Gibb, the senior director of public policy for GlaxoSmithKline and president of the company’s patient access foundation. The blueprint is focused on increasing competition, improving negotiation in the health care system, policy proposals for lowering list prices of pharmaceuticals, and decreasing out-of-pocket costs for patients, she said. (For one health system’s approach to patient assistance, see sidebar at right.) Several Medicare proposals and reforms (see sidebar below) have been floated, according to Ms. Gibb. “Think of a kaleidoscope: that is what is being proposed for Medicare,” she said. “There is not a one-size-fits-all solution because of the complexity of the benefit, and because pharmaceuticals are reimbursed in Medicare Parts B and D, as well as through Medicare Advantage plans. There are a number of potential changes that together could reform the system if implemented.” —Karen Blum

One Health System’s Strategy For Making Rx Costs Less Toxic

ome health systems have become creative in how they gain access to expensive medications for their patients. Melissa Paige, an oncology/infusion patient access principal coordinator at the University of Virginia Health System in Charlottesville, discussed some patient scenarios indicating the hoops she and her colleagues jump through to help their Medicare patients get access to free medications. For a Medicare Part D patient taking an oral medication, for example, Ms. Paige filled out the manufacturer application for financial assistance and did a preauthorization, noting the patient’s copay would be $2,172 for the first two months alone. There were no foundation grants available to pay for the drug. Next, they called the manufacturer and found out the patient had to spend 3% of their prescription out-of-pocket costs just on themselves. At that point, the patient had spent only $200 and was required to spend an additional $500 to qualify for assistance. Then the team reached out to a specialty pharmacy provider and asked it to fill just enough of the prescription to hit $500. They submitted receipts to the manufacturer and obtained approval for the patient to receive the medication free of charge. Ms. Paige offered some tips for others looking to help their patients: • Act fast on every patient. • Always fill out the manufacturer application to get hub support. • If there is a grant available, enroll your patient. • Use patient assistance as a last resort. • Work with your field reimbursement managers and tell them what’s going on and what barriers you see. Let them know whether another manufacturer is helping and offers a competitive product.

The sources reported no relevant ﬁnancial relationships.

6 Plans for Avoiding a Medicare Meltdown Implementing out-of-pocket spending caps in Medicare Part D. Currently, people who have Medicare Advantage have out-of-pocket caps but those with Part D or not in traditional Medicare have no cap. Manufacturers generally have been supportive of the idea, Ms. Gibb said. This may help patients who take a medication that falls in one of the specialty tiers. Passing manufacturer-negotiated rebates through to patients at the pharmacy counter (point-of-sale). This proposed rule from the Office of Inspector General and the Department of Health and Human Services would apply to people with Medicare Advantage, Part D and Medicaid managed care organizations. Instead of manufacturers negotiating

rebates with a pharmacy benefit manager or payor in exchange for formulary coverage, rebates only would be negotiated in order to be passed through to the patient as a chargeback with the pharmacy at the point of sale. Value-based insurance designs for management of chronic conditions. The Center for Medicare & Medicaid Innovation has adopted some value-based insurance design models for Medicare Advantage plans that are being expanded to all 50 states by 2020, Ms. Gibb said. If a service is deemed to be high value (which in the case of chronic conditions could include medications) and patients adhere to these services, they could see lower cost sharing.

—K.B.

Expanded use of utilization management tools. There is a potential to expand utilization management tools to Medicare Part B for medical benefit products and to the six protected classes of drugs taken by patients with HIV, psychiatric conditions and others. Allowing manufacturer coupons and copay assistance in Medicare. This suggestion, quoted in the blueprint, has been discussed for many years, Ms. Gibb said. Implementing a real-time benefit tool. This one, proposed for Medicare Part D, would help patients understand their true out-of-pocket costs, as well as a number of pricing reforms have been floated. —K.B.

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36 Policy

Pharmacy Practice News • July 2019

Reimbursement Matters

The Push for Transparency trans·par·en·cy: frankness, openness, candidness, honesty, directness, forthrightness, unreservedness, plain-spokenness, straightness, straightforwardness, ingenuousness, innocence, guilelessness, simplicity

or the past several months, there has been a deluge of proposals addressing the Trump administration’s broad prescription drug pricing blueprint. A common theme of the plans is the concept of transparency. Others focus on proposed efforts such as requiring that all negotiated drug discounts are channeled to patients at the point of sale instead of to PBMs, while still others focus on tweaking or rewriting myriad rules.

disclosure must be in “legible” text at the end of the advertisement, much like the list of side effects. The concept, as expressed by Alex M. Azar II, the secretary of the HHS, is that patients have “a fundamental right to know” whether a product recommended to them costs $50 or $5,000 before investing in a doctor’s appointment. “If a drug company is afraid that their prices are so excessive and abhorrent that they will scare patients away from using

choose a plan with more favorable cost sharing requirements.” The HHS stated it believes “patient counseling, care planning and navigation and shared decision making are valuable to patients and important for delivering high-quality care. We also agree that pharmacists may be able to provide information on drug pricing and patient coinsurance to patients, and advise patients on the availability of less expensive drugs in the event cost is a barrier to medication adherence.” In acknowledgment of those factors, the agency wrote that it will “consider a counseling code for future rulemaking in the appropriate benefit categories as allowed by statute” to reimburse phar-

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

Bonnie Kirschenbaum, MS, FASHP, FCSHP

• which size and configuration of packaging is chosen by the pharmacy (injectable meds are the most complicated); • route of administration; • drug delivery method; • manufacturer, if the product has multiple sources or is generic; and • how the drug is documented as given (or not). Think about how you would respond if the DTC ad WAC price of a product was $1,000 and your posted price was $2,000.

Commentary From AHA C

Health care systems and their hospitals cover a broad swath of practice sites, many of which will be affected by any changes enacted. Taking a proactive approach to designing a strategy to thrive in this environment will serve you well. This column focuses on transparency as it relates to determining your response to a final rule, released May 8 (bit. ly/2F6RBpS), requiring pharmaceutical manufacturers to be forced to share the list price (also known as WAC) for their products in all DTC television advertisements for drugs covered by Medicare or Medicaid. The rule will apply to any pharmaceutical covered by Medicare costing $35 or more per month or per course using the list price, and is effective 60 days after the May 10 Federal Register (bit.ly/2E0G4bk). Television advertisements also will include a disclaimer stating, “If you have insurance that covers drugs, your cost may be different.” Drugmakers must update the price they disclose in the advertisements every quarter, which will be the product’s monthly cost or the price for a course of treatment if it is not a long-term medication. The

their drugs … they ought to look inside themselves and think about whether they should be lowering their prices.” Mr. Azar also described the list price as “what consumers would be accustomed to pay because it’s close to an insurance plan’s average copayment for these drugs.” The latest government figures show that the prices of the 10 most widely advertised drugs range from $488 to $16,938 per month or for a usual course of therapy (bit.ly/2F9FhoJ). According to the APhA, the DTC ad final rule has implications for pharmacists beyond virtually guaranteeing patients will approach pharmacy with more questions than answers on why their drugs cost what they do. In the Federal Registerr rule discussion, the APhA recently reported (bit.ly/2IGCR1X), many commenters told the HHS that pharmacists are the best source of education on the cost of drug therapies, and that “[knowing] the WAC may also help a beneficiary begin a conversation about less expensive alternatives, prompt them to ask their pharmacist if a lower-cost option is available, or encourage them to

macists and other providers who help patients control their drug costs.

How Transparent Are You? Online posting of standard charges began with CY2019 rules. Under current law, hospitals are required to establish and make public a list of their standard charges. To encourage price transparency by improving public access to charge information, CMS guidelines specifically require hospitals to make public a list of their standard charges via the internet in a machine-readable format, and to update this information at least annually or more often as appropriate. What is your department’s and your facility’s response in this ongoing and ever-growing wave of transparency? Is your CDM or your pricing structure contributing to problems? This is not transparency if the final patient charge is affected by: • how the drug is ordered; • whether or not the product is profiled; • where the product is administered (inpatient unit vs. procedural area); • how the drug is entered into the pharmacy system;

Other bills under discussion also a aimed at improving transparare eency in the drug supply chain to rreduce prices. Some bills would rrequire certain drug manufactureers to submit documentation to the HHS 30 days before increasing the price of a qualifying drug (H.R. 2296); justify increases estimated 2 to cosst at least $26,000 per year or per trreatment (H.R. 2069); and report on pro oduct samples provided to certain health h care providers (H.R. 2064). Others w would require all drugmakers to accuraately report ASP price data for Part B druggs to the CMS or face civil monetary peenalties (H.R. 2087), and PBMs to publiccly report on the aggregate rebates, discou unts and price concessions they negotiate with drugmakers (H.R. 2115). Bill H.R. 2376 would require the FTC to conduct a study on competition in the drug supply chain, and H.R. 2757 would eliminate generic drug copayment requirements for Part D beneficiaries who receive low-income subsidies. (See the AHA summary at bit.ly/2Ifv10c). Look for more on these practice-changing decisions in upcoming columns. ■

A Reimbursement Lexicon AHA, American Hospital Association; APhA, American Pharmacists Association; ASP, average sales price; CDM, charge description master; CMS, Centers for Medicare & Medicaid Services; DTC, direct to consumer; FTC, Federal Trade Commission; HHS, Department of Health and Human Services; PBMs, pharmacy benefit managers; WAC, wholesale acquisition cost

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38 Operations & Management

Pharmacy Practice News • July 2019

Ambulatory Care

Transitions of Care Workflow Shows Its Worth Boston—A pharmacist-led comprehensive medication management (CMM) program for post-discharge transitions of care can reduce hospital readmissions and costs, according to a study from Intermountain Healthcare in Salt Lake City. Three Intermountain primary care clinics established a transitions of care workflow, which embedded an ambulatory care pharmacist or resident with a primary care provider and nurse care

manager. The group wanted to investigate whether telephone-based CMM would decrease 30-day readmission rates. Intermountain had several reasons for launching the program, said Alex Boyd, PharmD, an ambulatory care resident at the health system. The Hospital Readmission Reduction Program reduces payments for all Medicare patients to hospitals that exceed average 30-day readmission rates for certain disease states, he

said during a poster presentation (poster 10-M) at the 2019 ASHP Summer Meetings & Exhibition. Penalties for 2017 alone are estimated to be $528 million, for 29% of U.S. hospital systems. “We know Medicare beneficiaries are at high risk for readmission, about 20%,” Dr. Boyd said. “[CMM] is a standard of practice that professional organizations such as the American College of Clinical Pharmacy have really been pushing to

standardize how ambulatory care pharmacists are approaching their practice. We also have billing opportunities for transitional care management, or TCM. This allows billing for everything that’s going on in between the acute patient stay and the transition to community care.” The study included patients 18 years of age or older who were at high risk for readmission, including those with three or more emergency department (ED)

Operations & Management

Pharmacy Practice News • July 2019

Ambulatory Care

Post-discharge telephone follow-up with patients reduced hospital readmissions by

22%. Source: ASHPSM19 Poster 10-M

visits in the previous six months or three or more hospital admissions in the previous 12 months. During the intervention, a pharmacist called the patient within two days of discharge to review the discharge summary and check for correct indication, effectiveness, safety and adherence. Any interventions and recommendations were communicated to the primary care provider prior to the follow-up visit. The team compared patient outcomes between 35 patients receiving the CMM intervention and 195 patients from other clinics who did not. Baseline

characteristics were similar between the groups. The study found that five patients in the intervention cohort (14.3%) were readmitted versus 71 (36.4%) in the comparator group, for an absolute risk reduction of 22% ((P=0.009). Of those admitted, three were ED visits and two were inpatient admissions. The estimated cost of an ED visit was $299 and that of inpatient admission was $4,448. Overall, the team prevented eight hospital readmissions at a cost savings of $22,307. In the intervention group, the team identified 71 drug therapy problems at

discharge, with an average of 2.03 issues per patient. There were 52 issues related to indication and effectiveness, 11 to adherence and eight to safety. Pharmacists could make medication changes related to diabetes, hypertension and hypercholesterolemia. For other conditions, they submitted recommendations to the patient’s primary care provider. The project also tracked pharmacist time on the service, noting that pharmacists spent on average about a halfhour on each call. Patients were happy with the service, Dr. Boyd said: “Patients are pretty winded by the time they get discharged from the hospital. The discharge summary, no matter what hospital you look at, is complicated.”

VA Health’s Approach The Audie L. Murphy Memorial Veterans’ Hospital in San Antonio, part of the Veterans Health Administration, also has had success with a transitions of care program. There, a clinical pharmacy specialist holds an in-person meeting with a patient while they are still in the hospital to perform medication reconciliation and offer medication education. Then, within two to three days of discharge, the same pharmacist conducts a follow-up telephone visit to identify any medication errors, offers additional education and assists in facilitating follow-up with a primary care provider. Results of their pilot, published late last year ((Fed Pract 2018;35[12]:42-50), showed that the 30-day readmission rate among 388 patients receiving the intervention was 15.6%, compared with 21.9% among another 1,189 similar patients included as controls. Approximately 35% of patients had at least one pharmacistrecommended change in their treatment while they were still in the hospital; the most common recommendation was discontinuation of at least one medication. Patients “appreciate the time that someone actually spends with them,” going into detail about key elements of their medication regimens, said Rebecca Rottman-Sagebiel, PharmD, a geriatric clinical pharmacy specialist with the program. During the sessions, a pharmacist works with patients to identify potential medication-related problems, “and also teaches them how to use resources, such as Pillbox, or alarm clocks to keep them on track,” Dr. Rottman-Sagebiel said. The idea behind the program was to have a true transition from hospitalization through discharge, added Sara Espinoza, MD, a geriatrician and internist with the VA program. “Often there were errors that could be improved even before patients went home.” —Karen Blum The sources reported no relevant ﬁnancial relationships.

40 Operations & Management

Pharmacy Practice News • July 2019

Leadership in Action

Further Thoughts on What Makes a Great Boss ‘Your capacity to grow determines your capacity to lead.’ —Dan Kathy

hen I started as a young pharmacist supervising pharmacy technicians, I couldn’t even spell emotional intelligence—Daniel Goleman’s view of self-awareness and how it relates to being an effective leader. But I had a good heart and wanted to serve people, no doubt due, at least in part, to years of Sunday school lessons as a child. As I grew into leadership roles as a supervisor, an associate director, a pharmacy director and a pharmacy vice president, I discovered that leadership was like a puzzle and I was learning where the pieces fit, one piece at a time. Articles I’ve written in Pharmacy Practice News for the last dozen years exposed me to many leadership books, and several additional puzzle pieces fell into place. There are many overlapping themes in the books I’ve read, but Mark Miller’s “The Heart of Leadership: Becoming a Leader People Want to Follow” (Berrett-Koehler Publishers Inc.; 2013) and “The Secret of Teams: What Great Leaders Know and Do” (Berrett-Koehler 2011) carry particular resonance for me. I think it’s because, as I noted in my first column on these books (May 2019; bit.ly/2MWLTx1), Miller has captured the importance of starting with heart and character. This is the foundation on which other pillars of leadership are built. Miller cites five “Heart” characteristics that he believes—and I agree—are essential to effective leadership (box). I explored these attributes at length in my last column, so I’m going to hone in on a few that I feel are crucial and offer some added thoughts on why you may want to take them to heart during your own leadership journey.

Think ‘Others First’ Thinking of others first does not come naturally; humans tend to be selfish. The good news is that we can change. Putting others first can become easier as time goes on, partly because our brains are “neuroplastic”—they have the ability to

adapt and change if a different way of thinking is practiced long enough. So it’s important and possible to cultivate a new way of thinking. What are the practical applications of this mindset? Think of those who you are mentoring. What skill sets are you instilling in them? How can you put them in situations where you give them authority and responsibility and you become hands off and coach only if they need it? Your function is to add value to others. Are you training your folks so your department can run without you? As the leader, that is your ultimate goal. When you unleash people, you will find they get excited about the opportunity and often do functions, develop programs and projects better than you could. Multiply this by the number of people in your department who you can give autonomy to and you will have a highly functioning, successful team. This is applicable to all of those you interface with, including your family. Another practical idea is to ask your staff to develop their personal life plan. A year from now, ask how your department helped them achieve their plan. Perhaps they were able to buy a house or complete an academic course, or learn a new skill they could apply outside of work. And don’t forget the value and power of simple gestures, such as a smile, a thank-you, birthday wishes, asking a waitress her name, then calling her by name expressing thanks for her service. In short, be an encourager. Make a pact with yourself that you will try to add value to everyone you meet today. Being a leader who thinks “others first” changes you. It will even change how you drive.

Hunger for Wisdom Leaders become predatory about learning—they seek it out. They read, listen to podcasts, attend seminars and learn from mentors. Wisdom helps

determine how you behave around people; it helps you make the hard choices. I recently told someone they needed to dismiss a poor performer. Ample improvement opportunities had been provided. Now the leader was frustrating the rest of the staff by not removing this nonperformer. He made the tough decision, and the entire department was better for it. It’s also important to be ever-vigilant about the attitude yyou p project, j , because people resist pessimistic leadeers. So I would encourage you u to develop a mindset that looks for positives—even in n mistakes. Encouragemen nt of people is highly m otivating. Look for oppo ortunities to praise peop ple. Create a culture of optimism, beginn ning with you. Thiis improves relaationships with h departments and the C-suite. But this iss n’t only about your co-workers; it’s also crucial to remain positive with patients desp pite their circumstances, to help foster feelings of hope about their illness. There are numerous examples of better medical outcomes wh hen patients have a positive outlook. Remember, optimism is contaagious.

Take It to Heart If these observations on leadership resonate, I encourage you to take a look at my May column, wherre I first outline some of thee basics behind these concepts. pts. But even if you take only one thing away from either column, remember this: Developing a strong character and then leading from the heart is the foundation of success for you and your team. Certainly, learning and practicing principles of the heart have served

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, FASHP, FMSHP, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at ernestanderson1130 @gmail.com.

Ernest R. Anderson Jr., MS, RPh, FASHP, FMSHP

Leadership Character’s 5 Attributes H – Hunger for wisdom E – Expect the best A – Accept responsibility R – Respond with courage T – Think “others first” Source: “The Heart of Leadership.”

me well for decades and has given me the privilege of pouring myself into the lives of several individuals who I have had the pleasure of leading. It has been a rewarding labor of love. May you find equal success! ■

If you missed any recent issues of Pharmacy Practice News, visit www.pharmacypracticenews.com.

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42 Technology

Pharmacy Practice News • July 2019

Risk Stratification

Tool May Predict, Prevent Hospital Readmissions H

ealth-system pharmacists generally know the value they bring in the form of medication reconciliation and education. However, what if there was a way to accurately identify those patients at increased risk for readmission due to medication errors and target them for a pharmacy-led intervention? The 30-day readmission prediction models being used in many health systems—including LACE (an acronym describing length of stay, acute admission, Charlson Comorbidity Index score and emergency department visits)— have proved largely insufficient (Sur( gery 2019;165[5]:882-888). Hence, new tools are needed.

was used to guide TOC processes on an internal medicine team at Detroit Medical Center (DMC). They derived the risk index based on a retrospective review of 40,668 patient admissions, with a focus on 10 variables (box). To ensure the program continued to identify those who might be at risk, the HATRIX research team continued to validate the HATRIX score in a large patient cohort (N=121,277) in three-month increments over 2.5 years ((Am J Health Syst Pharm 2019;76[7]:444-452). After 10 iterative validations, they reported, the odds ratios for each of the 10 HATRIX variables “shifted significantly ((P<0.05), reflecting changes in the risk factors that conferred

admission and discharge, patient education on medication and disease state management, and a post-discharge telephone follow-up counseling session within seven days of hospital discharge Following a five-month trial, 374 participants were included in a study designed to assess the accuracy of HATRIX in predicting hospital readmissions in high-risk patients. Among those who received medication reconciliation from the pharmacy-led TOC, there was a 48% reduction in 30-day readmission rates compared with controls. Readmission rates for TOC patients were 11.4% versus 21.7% for the non-TOC group ( =0.04). Furthermore, on multivari(P

a TOC program partly on predicting risks for drug-related adverse events makes sense. Indeed, one of the greatest benefits of a pharmacist-led TOC program, she noted, is its ability to identify and resolve medication-related problems associated with care transitions and provide medication education to patients and their caregivers. As part of their role in such programs, pharmacists can obtain medication histories on admission, initiate medication reconciliation when patients are transferred, provide education, and perform medication reconciliation and counseling at discharge—many of the same functions that were part of the HATRIX approach ((Am J Health Syst Pharm 2014;71[8]:648656), Dr. MacDonald added.

Leadership Key

10 Variables Included in HATRIX Risk Assessment 1. Previous readmissions within 12 months 2. Congestive heart failure 3. Chronic kidney disease 4. Pulmonary heart disease 5. Anemia 6. Liver disease 7. Essential hypertension 8. Receipt of anxiolytics 9. Receipt of antiarrhythmic agents 10. Length of stay

Enter HATRIX, or the Hospital AllCause Thirty-Day Readmission Index, a 10-variable risk index that can be embedded in a health system’s electronic health record (EHR) and serve as a guide for the appropriate implementation of pharmacist-led transitions of care (TOC).

Better Models Needed “Most reported predictive models in the literature are derived on a single patient cohort,” explained Joshua N. Raub, PharmD, a clinical pharmacist specialist in internal medicine, Detroit Receiving Hospital and University Health Center, and a member of the HATRIX research team. “This [is] a limitation … because the risk factors and their significance in predicting readmission are only analyzed once,” noted Dr. Raub, whose team won an ASHP Best Practices Award at the 2018 Midyear Clinical Meeting for their research. At the ASHP meeting, Dr. Raub and his colleagues described the results yielded by HATRIX during a multidisciplinary pilot program in which it

the greatest risk for readmission.” Despite these changes, the HATRIX’s diagnostic properties were maintained throughout the study and achieved an overall accuracy of more than 80%. The next step was to prospectively test HATRIX used as part of a TOC pharmacist’s daily practice, Dr. Raub noted. Once the model was embedded in the EHR at DMC, a clinical pharmacist led the integration of TOC activities “into the daily workflow on one of two academic internal medicine teams.” On one of the teams, patients with a high HATRIX score were targeted for medication reconciliation and education with the pharmacist, whereas patients treated by the other team that did not use the HATRIX score intervention served as controls. In the experimental group, the TOC pharmacist identified patients on an adult internal medicine service who were calculated to have the highest risk for readmission by the HATRIX model; TOC interventions were then performed on those patients. TOC interventions included medication reconciliation at

ate analysis, pharmacist-led TOC was independently associated with reduced 30-day readmission rates ((P=0.041).

Adapting to Changes No tools for predicting risk will work if they remain too static, and HATRIX is no exception. “During our iterative validation process, we were surprised that risk factors both lose and regain their significance in predicting 30-day readmission over 2.5-years,” Dr. Raub said. “This confirmed our hypothesis that prediction models are susceptible to clinical practice changes. Now, we hope to implement HATRIX in other specialty services such as ICU or ambulatory care to validate its use in a broad patient population. HATRIX is unique to our system and our patients, and [we hope it will] serve as a blueprint for others to derive and validate their own prediction indexes.” Nancy C. MacDonald, PharmD, a TOC coordinator at Henry Ford Health System, also in Detroit, who was not part of the HATRIX team, agreed that focusing

But these initiatives often require champions to succeed—a point underscored by several studies showing that systems in which pharmacists take a leadership role experience significantly fewer preventable adverse drug events. ASHP has suggested that health-system pharmacists take on that leadership role by helping to design and manage patientcentered medication reconciliation systems, educate patients and other clinicians about the medication reconciliation process, and serve as patient advocates throughout care transitions ((Am J Health Syst Pharm 2018;75[5 suppl 1]:S1-S5). However, for pharmacists, undertaking a leadership role is not an easy feat. That’s why Dr. MacDonald and others believe that the HATRIX findings are so important; the model allows clinical pharmacists in the acute care setting to proactively identify high-risk patients in what is often a resource-limited environment. “In talking to people throughout the country, many institutions still struggle with how to incorporate transitions-ofcare activities into their daily workflow,” Dr. MacDonald said. “Unfortunately, not all health systems have the resources or staff to perform transitions-of-care activities which improve patient and health-system outcomes. One of the things the HATRIX study helps to do is to show us where to start. “How do we or should we use tools to identify the high-risk patients and populations at our institution? Where should pharmacy resources be allocated to make the biggest impact clinically and financially for our patients? What’s the financial impact to the health system of the changes in outcomes we’re achieving?” —Brian Dunleavy The sources reported no relevant ﬁnancial relationships.

Technology 43

Pharmacy Practice News • July 2019

Digital Health

Is AI the Next Big Thing for Predicting ADEs? “Siri, can I prescribe these two medications together safely?”

sking Apple’s artificial intelligence (AI) engine such a high-stakes question about drug safety may seem too risky for clinicians today. But it may well serve as a model for the future, if new research into the ability of AI to predict adverse drug-drug interactions pans out. Marinka Zitnik, PhD, a postdoctoral fellow in computer sciences at Stanford University, in California, and her colleagues have laid out an AI system for predicting side effects from drug combinations. The system, called Decagon, could help clinicians make better decisions about which drugs to prescribe and help researchers find better combinations of drugs to treat complex diseases.

The researchers’ work is based in part on examining how drugs affect the underlying cellular machinery in the body. They composed a massive network describing how the more than 19,000 proteins in the body interact with one another and how different drugs affect these proteins. Using more than 4 million known associations between drugs and side effects, the team then designed a method to identify patterns in how side effects arise based on how drugs target different proteins. To do that, the team turned to deep learning, a kind of AI modeled on the brain. Deep learning looks at complex data and extracts from them abstract, sometimes counterintuitive, patterns in the data. In this case, the researchers designed their system to infer patterns about drug interaction side effects and predict previously unseen consequences from taking two drugs together. But just because Decagon finds a pattern doesn’t necessarily make it real, so the group looked at whether its predictions came true, and in many cases, they did. For example, there was no indication in the team’s data that the combination of atorvastatin and amlopidine could lead to muscle inflammation, yet Decagon predicted correctly that it would. Although it did not appear in the original data that led to the drug’s approval, a case report from 2017 suggested the drug combination had resulted in muscle inflammation. That example was confirmed in other cases,

too. When the investigators searched the medical literature for evidence of 10 adverse events predicted by Decagon but not in their original data, they found that five of the 10 have been confirmed recently, lending further credence to the system’s predictions. “It was surprising that protein interaction networks reveal so much about drug

side effects,” said Jure Leskovec, PhD, a member of Stanford Bio-X, Stanford Neurosciences Institute and the Chan Zuckerberg Biohub, in California. Decagon only considers adverse events associated with pairs of drugs, but in the future the team hopes to extend their results to include more complex regimens, Dr. Leskovec said.

“The possibilities of this type of screening sound good,” said Matthew Grissinger, RPh, the director of error and reporting programs at the Institute for Safe Medication Practices, in Horsham, Pa. However, he cautioned, its success would depend on several factors, not the least of which is how it handles alert fatigue, given how prevalent a problem it is in most health systems. —Marie Rosenthal, David Bronstein The sources reported no relevant ﬁnancial relationships.

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BRIEF SUMMARY OF PRESCRIBING INFORMATION: These highlights do not include all the information needed to use Smoflipid safely and effectively. See full prescribing information, including Boxed Warning, for Smoflipid available at www.smoflipid.com SMOFLIPID (lipid injectable emulsion), for intravenous use WARNING: DEATH IN PRETERM INFANTS See full prescribing information for complete boxed warning. • Deaths in preterm infants have been reported in literature. (\[VWZ` ÄUKPUNZ PUJS\KLK PU[YH]HZJ\SHY MH[ HJJ\T\SH[PVU PU [OL S\UNZ 7YL[LYT HUK SV^ IPY[O ^LPNO[ PUMHU[Z OH]L WVVY JSLHYHUJL VM PU[YH]LUV\Z SPWPK LT\SZPVU HUK PUJYLHZLK MYLL MH[[` HJPK WSHZTH SL]LSZ MVSSV^PUN SPWPK LT\SZPVU PUM\ZPVU. INDICATIONS AND USAGE Smoflipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in Smoflipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. DOSAGE AND ADMINISTRATION • For intravenous infusion only into a peripheral or central vein. • Recommended dosage depends on age, energy expenditure, clinical status, body weight, tolerance, ability to metabolize, and consideration of additional energy given to the patient. • The usual daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day.

• Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL. WARNINGS AND PRECAUTIONS (also see BOXED WARNING) • Hypersensitivity Reactions: Monitor for signs or symptoms. Discontinue infusion if reactions occur. • Infection, Fat Overload Syndrome, Refeeding Syndrome, and Hypertriglyceridemia: Monitor for signs and symptoms; monitor laboratory parameters including serum triglycerides. • Aluminum Toxicity: Increased risk in patients with renal impairment, including preterm infants. • Parenteral Nutrition-Associated Liver Disease: Increased risk in patients who receive parenteral nutrition for extended periods of time, especially preterm infants. Monitor liver function tests, if abnormalities occur consider discontinuation or dosage reduction. ADVERSE REACTIONS (also see Warnings and Precautions) Most common adverse drug reactions (>1%) from clinical trials were nausea, vomiting, hyperglycemia, ﬂatulence, pyrexia, abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device related infection. To report suspected adverse reactions, contact Fresenius Kabi USA, LLC, at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters.

Website: www.smoflipid.com To Order: 1.888.386.1300 Med Info Phone: 1.800.551.7176 (option 4) Med Info Email: nutrition.medinfo.USA@fresenius-kabi.com

DOSAGE FORMS AND STRENGTHS Smoﬂipid is a lipid injectable emulsion with a lipid content of 0.2 grams/mL in 100 mL, 250 mL, and 500 mL. CONTRAINDICATIONS • Known hypersensitivity to ﬁsh, egg, soybean, or peanut protein, or to any of the active ingredients or excipients.

44 Technology

Pharmacy Practice News • July 2019

Data Breaches

For Cybersecurity, Size Doesn’t Matter Las Vegas—Small pharmacies, whether focused on specialty, home infusion or other trade channel, should not believe that because of their size, they are not at risk for cyber threats. Organizations without the finances and on-site information technology expertise to ensure the security of their data and assets may have internal weaknesses that make them more prone to having high-value health care information reach the wrong hands, Daniel Eliot, the director of small business education at the Washington, D.C.–based National Cyber Security Alliance, said at the MHA 2019 Business Summit.

“Cybersecurity is first and foremost a people issue,” he asserted. “No matter how much good technology you have in place, if you don’t have good processes and behaviors in place, it won’t matter.” Indeed, the health care industry is “rife with error and misuse” of information systems and “is the only industry vertical that has more internal actors behind breaches than external,” Mr. Eliot said. Rather than being motivated by malice, employees often inadvertently share internal information by, for example, responding to a phishing email, he noted. “People are your strongest asset, but you need to teach them good behav-

from employee-owned and controlled devices,” he suggested. Data also can be safeguarded by requiring two-factor authentication and using data encryption as well as encrypted devices, he added. Moreover, storing data in multiple locations and multiple formats means that if access to network computers is lost, organizations can still access their data through a separate device, he said. “I encourage organizations to follow the 3-2-1 rule: Keep at least three copies of your data, and store two backup copies on different storage media, with one of them located off-site,” Mr. Eliot said.

Strengthening Your Cybersecurity For software:

For email:

• Update your software. • Create clear rules for what programs employees can install and what data they can keep on their work computers. • Install antivirus and antispyware software. • Limit data or system access to what individuals require to perform their jobs.

• • • • • •

For Wi-Fi:

For mobile devices: • Delete unnecessary apps and update existing ones. • Download apps from trusted sources only, and look for apps with many positive reviews. • Secure devices with passcodes or other strong authentication requirements, such as a fingerprint. • Activate “find device” and “remote wipe” in case your device falls into the wrong hands. • Configure app permissions, as they often don’t default to the most secure settings.

“Small businesses need to be connected to the internet; the challenge is to make their data safe while they do so,” he said. According to an investigation conducted by Verizon, health care organizations account for 24% of all breaches in the United States (vz.to/2Rzk8Zw). Combine that with the fact that 58% of all breach victims are small businesses, as the Verizon report noted, and small pharmacies have good reason to take their cybersecurity seriously. “The problem is, small businesses often don’t have the sophisticated staff and financial resources to invest in security infrastructure,” Mr. Eliot said.

People, Process, Technology While they may not be able to build a cyber-fortress, small businesses can follow some relatively simple steps to enhance the safety of their “people, processes and technology,” Mr. Eliot said.

Maintain strong, unique passphrases. Turn on two-factor authentication. Don’t use personal email for company business. Verify the legitimacy of any email request with the sender. Teach staff to identify malicious emails. Implement policies for personal email use on company networks.

• • • •

Physically secure Wi-Fi equipment in the office. Use a virtual private network (VPN) when using public Wi-Fi. Do not connect to unknown, generic or suspicious networks. Turn off Wi-Fi and Bluetooth when not using them.

For social networks: • Limit who has administrative access to the organization’s social media accounts. • Set up two-factor authentication. • Configure privacy settings to limit the amount of data shared. • Avoid third-party apps that seem suspicious, and limit data they can access. • “Take care with what you share:” For example, what is in the background of a photo taken at work?

iors so that they can identify malicious threats and avoid mistakes,” he emphasized. “Make sure you develop policies and procedures and train your staff during the onboarding process as well as on an ongoing basis.”

Know Your Assets Ensuring staff follow safe behaviors requires first identifying data assets and building measures to protect them, Mr. Eliot said. These assets range from software, such as customer relationship management systems and email, to electronic health records and physical devices. Once the assets have been identified, organizations can take some easy steps to protect them and limit the impact of an attack or a data breach, Mr. Eliot said (sidebar). “For instance, establish Bring Your Own Device (BYOD) policies and procedures to limit the amount of risk that can be brought into the organization

Source: Daniel Eliot, National Cyber Security Alliance.

Limit Access He said one common mistake organizations make is providing too much data access to employees who may not need it. “Limit access to what people need to do their job—that even applies to the CEO,” he said. “And make sure people can’t just walk around your workplace and access your systems. Think of cybersecurity down to the physical layout of your office. How easy is it for someone to access your medical records or the server closet?”

Detect, Respond and Recover In case an attack does occur, Mr. Eliot encouraged attendees to develop strategies to promptly detect, respond to and recover from problems and threats. Signs that an attack has occurred range from obvious ransomware notifications to customer feedback that indicates “something unusual is happening

with, for example, your online portal or your customer service process,” he said. Developing and following can help mitigate the impact of an attack and might include steps like disconnecting from the network when necessary, contacting IT and legal leadership as well as local law enforcement, and complying with any state data breach laws, Mr. Eliot explained. “By failing to prepare, you are preparing to fail,” Mr. Eliot cautioned.

Document Lessons Learned After an attack, document lessons learned from the incident to improve policies and procedures as well as refine your training and retrain employees, he said. All off these measures can help prevent anotheer breach or attack, he said. Chris Schreiber, a solutions architect at FireEyee, a cybersecurity company headquarteered in Milpitas, Calif., who was nott involved in the MHA presentaation, believes small pharmaciess face several challenges in seecuring their data. Echoing Mr. Eliot, he said they often do M not have their own security n sspecialists, and “staff wear multiple hats and try to run a business at the same time, which reduces their ability to w crreate a strong defense.” Having weak defenses makes H smalll pharmacies vulnerable to commo on phishing and ransomware attacks, Mr. Schreiber said. Howeverr, like Mr. Eliot, he said there are some simple measures smaller pharmaciees should take to protect themselves. “You can use a cheap computer to do all your emailing and another sy system to run your pharmacy, which would limit the amount of damage done if a phishing email is opened or a ransomware attack takes place,” Mr. Schreiber said. If a ransomware attack were to occur, a strong data backup approach, as Mr. Eliot outlined, would reduce the likelihood that a pharmacy would have to submit to the demands of a ransomware attack. Doing so would only increase the likelihood of further attacks, Mr. Schreiber emphasized. For more information on easily available measures, Mr. Schreiber urged readers to review the Department of Health and Human Services’ publication on cybersecurity risks and best practices for the health care industry (bit.ly/2x5Glpc). —David Wild The sources reported no relevant ﬁnancial relationships beyond their stated employment.

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Atopic i Dermatitis i i iin the h Specialty i l World ld T

herapy for atopic dermatitis (AD), a chronic inflammatory skin disease that usually starts in infancy or early childhood, entered the specialty pharmacy space over the past two years with the approval of dupilumab (Dupixent, sanofi-aventis), an injectable biologic approved in March 2017 for adults with moderate to severe AD and, as of March 2019, for adolescents aged 12 to 17 years with moderate to severe AD. Dupilumab is still being studied in the younger pediatric population. But this agent is only the beginning, according to Jeffrey Dunn, PharmD, MBA, the vice president for clinical strategy and programs and industry relations with MagellanRx Management. “The pipeline for AD on the specialty side is fairly crowded, and soon this indication is going to be a big specialty category.” At least 12 other biologic agents are under development for AD, including nemolizumab, which specifically targets a cytokine that causes itching. But all these targeted therapies are likely to be expensive. The lowest price found on GoodRx for a 30-day supply of dupilumab is around $3,000, or $36,000 per year. Price tags like these will have a significant impact due to the prevalence of AD: Approximately 18 million U.S. adults (7.2%) and 9.6 million children (13%) have the condition, according to the National Eczema Foundation, with 3.2 million children affected by moderate to severe AD. “The situation is likely to be similar to what happened with psoriasis 10 years ago, when we had the specialty biologics enter that category. How are we going to afford this and manage utilization?” Dr. Dunn asked. “With really expensive biologics now entering large categories like AD and asthma [dupilumab was also approved for moderate to severe asthma in adults and adolescents in October 2018], it’s becoming an affordability issue, and as payors, we don’t have a lot of arrows in our quiver to manage these trends. We are likely to see significant usage of step therapy, preferred agents and a drive toward some form of rebates in the future.” The American Academy of Dermatology (AAD) has not yet issued new guidelines for the management of AD since the approval of dupilumab and another less expensive topical agent, crisaborole (Eucrisa, Pfizer), in December 2016. “The AAD last updated their guidelines in 2014, so until we have new guidance from them, the obvious question is, where do these two new agents fit,” said Kimberley Benner, PharmD, a professor of pharmacy practice at Samford University

‘The pipeline for AD on the specialty side is fairly crowded, and soon this indication is going to be a big specialty category.’

—Jeffrey Dunn, PharmD, MBA

McWhorter School of Pharmacy, and a pediatric clinical pharmacy specialist at Children’s of Alabama, both in Birmingham. Dr. Benner authored the chapter on AD in the “Handbook of Nonprescription Drugs: An Interactive Approach to SelfCare” (bit.ly/2X2ejpk) and is preparing an update to that chapter. “Although the guidelines aren’t out yet, the combination of the cost and the fact that dupilumab is a subcutaneous injection, which younger people may not want to take, suggests to me that it’s not going to be high up on the AAD’s list,” she said. “In Europe, for example, they have recommended a stepwise approach that includes education and trigger avoidance first, followed by failure of topical agents and then other systemic therapies that have been around for a while, such as cyclosporine and methotrexate. We have seen this before with disease states like psoriasis and IBD [inflammatory bowel disease]: Patients may have to fail older, cheaper and, unfortunately, more toxic therapies before they can qualify for new, more expensive therapies that may have less toxicity.” Although still more expensive than the topical steroids and broad immunomodulators that have until recently been the mainstay of AD treatment, crisaborole is much less costly than dupilumab, with the lowest GoodRx price for a 30-day supply listed at around $635, or about $7,600 annually. “Crisaborole, which was also just approved for children 2 years of age and older, can inhibit AD lesions topically, does not require injection, and has almost no warnings other than local hypersensitivity,” Dr. Benner said. “I would expect that when the new guidelines are issued, it will fall in right after topical steroids.”

Rebates May Drive Utilization The advent of specialty drugs in the AD category also means that AD will likely enter the rebate space, “whatever that looks like in the future,” Dr. Dunn said. “Just like psoriasis has become part of the autoimmune rebate bundle, along with rheumatoid arthritis and Crohn’s disease, the specialty AD drugs likely will, as well. When you talk about these diseases, 80% to 90% of the total cost of care is on the drug side. So pharma has forced us to focus on maximizing rebates—these aren’t clinical categories anymore; they’re rebate categories. It’s

potentially going to get extremely complicated. We will need specialty pharmacies to focus on care management and patient education in order to help drive appropriate utilization.” Although the availability of novel agents is an exciting advance, particularly for patients with refractory moderate to severe AD, Dr. Benner cautioned that it should not supplant nonpharmacologic and lifestyle approaches including trigger avoidance, skin hydration and barrier protection. “It’s essential to know your AD triggers and avoid them; such triggers often include skin irritants like fragranced detergents, certain fabrics, and soaps and household cleaners, as well as common allergens like pollen and pet dander,” she said. “There is a triad of AD, asthma and food allergies, and I commonly see young patients who have all three. Working

to limit exposure to allergens can help improve control of the other conditions.” Nonpharmaceutical topical treatment of AD typically focuses on rehydrating the skin with emollients like petroleum jelly. “Selecting specific products that work the best for your patient often involves a lot of trial and error,” Dr. Benner said. “Often patients may prefer the creams, but ointments are thicker and more lipophilic, which means they penetrate the skin better and act as more of a dermal barrier to slow water loss. Pharmacists can help with the selection of some of these creams and ointments, as well as the newer ceramide skin care agents, which have been found to significantly increase skin hydration by providing barrier protection.” —Gina Shaw The sources reported no relevant ﬁnancial relationships.

Web-only: The link between food allergies and atopic dermatitis. See expanded version at www. pharmacypracticenews.com.

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Making Site of Care Optimization a Success Orlando, Fla.—Payors will increasingly use site of care (SOC) optimization strategies, pushing patients to receive high-cost specialty infusion drugs in settings outside of hospitals, according to a panel of experts at the 2019 annual meeting of the National Home Infusion Association. This trend bodes well for home infusion providers, said David Franklin, MSA, the president of Advanced Care Consulting in Ray, Mich. “I work with a lot of providers, and most of them are seeing a significant uptake in their business.” The ultimate goal of SOC strategies is to have every patient cared for in the least expensive setting that meets clinical guidelines, Mr. Franklin said, “which actually makes a lot of sense.” Panelists offered advice on tactics that infusion companies can use to take advantage of this trend and boost their trade. About 83% of payors either already have or in the next 12 months will institute an SOC policy, according to data from the 2018 EMD Serono Specialty Digest, said Dale Schott, MHA, a market development manager at Janssen Biotech. This includes major insurers such as Aetna, Humana and UnitedHealthcare. “As we look at the market today, we think we’re about halfway through the site of care shift out of hospitals,” he said. The push is being driven largely by the cost of specialty drugs, Mr. Schott said. By the end of 2020, about 50%

of the overall drug spend will be in specialty drugs, according to data from a 2018 Magellan Rx Management Employer Market Insights report (bit. ly/2vt03KT) (Figure). Strategies for SOC optimization used by payors include “hard” shifts that decline approving patients to receive infused medications in the hospital as well as “soft” shifts that offer incentives to the physician or patient for choosing a more cost-effective care setting. Currently, insurers using only soft steers will add in hard steers, Mr. Schott said. In additional trends, payors may expand SOC strategies to include partially covered lives and additional products, he said. These strategies generally are rolled out gradually, Mr. Franklin noted, with payors first identifying a subset of the most expensive therapies and starting to request prior authorizations for those therapies. When hospitals ask for their patient to be treated there, insurers deny the request and try to redirect patients to a non-hospital ambulatory infusion clinic or the home. Once this first tier is in place and operational, he said, they add additional therapies.

Limiting Factors There are several factors that can restrict a patient’s SOC, Mr. Franklin said. If patients are not ambulatory, for example, or are taking medications that

Specialty

Traditional

2017

39%

61%

2018

43%

57%

2019

46%

54%

2020

48%

52%

Figure. Specialty drug growth drives SOC. Source: 2018 Magellan Rx Management Employer Market Insights report (bit.ly/2vt03KT).

have potential for medical reactions, they are better served in a clinical setting. But overall, this shift provides a good opportunity for home infusion companies to tout their expertise to payors, many of whom look at infusion sites as either hospitals or “everything else,” Mr. Franklin said. Home infusion companies should talk to payors about what they are and explain that they are much less expensive than a hospital setting, he said. To stand out among other providers, “let them know what therapies you provide and the service area you cover, particularly if that includes any rural areas,” where there tends to be a scarcity of options, Mr. Franklin said. If you specialize in pediatrics or oncology, let the payors know. Make sure to mention

Health Systems Also Can Benefit From SOC

ealth system–affiliated infusion providers can take advantage of site of care (SOC) optimization to retain patients within their system, said Tim Affeldt, PharmD, the director of specialty and infusion operations at Fairview Pharmacy Services in Minneapolis. Fairview is affiliated with the University of Minnesota, which has 12 hospitals and offers more than 100 specialties throughout its health system. Most health plans are targeting the same 25 to 30 drugs, he said, and the majority of shifts to home infusion are for infliximab and IV immunoglobulin. Fairview became interested in SOC strategies about three years ago, when one of its payors started a soft strategy, and decided to jump on board. Dr. Affeldt and his colleagues had to work proactively with providers, payors and patients to launch their own SOC strategy. Providers expressed concern that home infusion was “less safe” than physician-supervised sites and that they might lose communication about their patients’ status. The pharmacy took steps to allay those concerns, including creating infusion intake teams to handle prior authorizations and embedding pharmacy technicians in every infusion center to serve as a point of contact. They also talked to providers about the safety of home infusion, trained nurses in IV medications, and asked them to document data points such as vitals, how many times it took to get a line, and any adverse reactions in patients’ electronic health records within an hour of being in the home.

The team also spoke proactively with every payor, explaining they had a centralized intake team in place to handle referrals and it could be a valuable home infusion partner. In addition, they talked to patients to gauge their comfort level in moving to the home setting, often having home infusion nurses sit and talk to patients while they received infusions in the hospital. Although some patients were excited to hear they could be treated at home, others expressed concern that they didn’t want young children seeing them hooked up to medical equipment, or losing social opportunities by going to a center. The team set up some “community-based chairs” in infusion centers outside the hospital as a stepping stone for patients who were hesitant, as an interim option to make them comfortable. The team also is surveying patients about their experience and what could be improved. Along the way, the system found that its hospital-based infusion centers still remained full, Dr. Affeldt said. “You move one patient to home, that chair gets filled immediately by another. The thought that the system was going to lose all this revenue when we shifted patients to the home is actually not true. You just expand, allowing the capacity of your infusion centers to speed up.”

that home infusion is one method of preventing hospital-acquired infections.

Independents Benefit Site of care optimization also can benefit independent home infusion providers, said Logan Davis, PharmD, MBA, the director of franchise development at Vital Care Home Infusion Services in Mississippi. Strategies to try include establishing partnerships with local facility sites of care, payors and manufacturers. When working with local facilities, Dr. Davis said, make sure to take good care of their patients and follow up on all communications. “These facilities are going to have patients that can’t come into an infusion center for whatever reason, and you want to leave a positive impression on them.” Whether your referrals come from a payor or a facility, make sure to follow standard protocols to obtain prior authorizations and any relevant medical history, including how patients did during their last infusion. Make sure also that your nurses have competency in the specific therapeutic areas for which you expect to get patients, he said. Drug manufacturers, too, have a stake in the SOC shift, Mr. Schott said, because they want to ensure patients have access to their products. His company had to develop a new contracting strategy to support the shift of patients being treated outside of a hospital. In 2014, the company had relationships with about 14 home infusion providers; today it’s more than 125, he said. “I think a lot of manufacturers are in the same boat. They’re looking at SOC optimization and how to ensure access to [their] products, and they’re looking at home infusion as a key stakeholder in that market.” —Karen Blum

—K.B. Dr. Affeldt reported honoraria from AbbVie and Janssen Pharmaceuticals.

The sources reported no relevant ﬁnancial relationships other than their stated employment.

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