Pharmacy Practice News - May 2021 by McMahon Group

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The Best-Read Pharmacist’s News Source

pharmacypracticenews.com

OPERATIONS & MGMT

The case for mobile cleanrooms ........................

Retired pharmacists could expand COVID-19 vaccinator pool ................ 6 CLINICAL

Vancomycin and the move to AUC-based dosing ................................

Affordable alternatives to pricey ethanol locks ..................

A plan for predicting CAR T-Cell toxicity ..............................

POLICY

The cost equation for CSTDs: debating the data .............................

REVIEW ARTICLES

Parenteral Nutrition Therapy Assessment Tools and Guidelines See insert after page 18

Lean Thinking For CSTDs See page 32

Coalition Slams White Bagging Push by Payors

Volume 48 • Number 5 • May 2021

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Testing, vaccinations part of services offered

Pharmacy Colleges Pitch In on COVID-19

ayor-mandated “white bagging” is jeopardizing patient safety and exacerbating supply chain problems for hospitals and health systems, the ASHP and 61 health systems and group purchasing organizations recently told FDA Commissioner Janet Woodcock, MD, in a letter requesting a meeting to discuss the practice. White bagging typically involves clinician-administered drugs given to nonhospitalized patients—often infusion-based drugs that patients cannot take safely on their own. Historically, hospitals have purchased these drugs in advance and held them in stock, and when a patient needs the drug, the hospital compounds and administers the medication and is reimbursed by the medical plan. Under white bagging, payors move these drugs from

rom coast to coast, colleges of pharmacy have been spearheading COVID-19 testing and vaccination initiatives, both on and off campus. Pharmacy faculty at the University of South Carolina , in Columbia, were among the first in the country to develop saliva-based polymerase chain reaction (PCR) COVID-19 testing. Stephen Cutler, PhD, the dean and a professor at USC College of Pharmacy, said that innovation began in January 2020, when two of the college’s faculty were watching the as yet unnamed coronavirus

Continued on page 34

Continued on page 12

Pharmacists at the Medical College of Wisconsin Pharmacy School, in Milwaukee, help with COVID-19 testing and vaccinations.

At Seattle Children’s:

Patients and covered entities feeling the pinch

Algorithm Drives More Appropriate PN Use in Children

Manufacturers’ 340B Restrictions On Contract Pharmacies Draw Ire

ocusing on patient safety and engaging front-line dietitians in the development of an algorithm for appropriate use of pediatric parenteral nutrition allowed Seattle Children’s Hospital to achieve a significant, sustained reduction in PN usage and reduced the likelihood that PN contributed to central line–associated bloodstream infections (CLABSIs). After implementing a four-step quality improvement project on Continued on page 19

eginning last summer, several drug manufacturers announced they would no longer extend 340B drug pricing to contract pharmacies. The manufacturers said the restrictions are part of a much-needed adjustment to a program that has seen “egregious markups” and other abuses. But the pharmacies caught up in the crossfire say the policy is having unintended consequences, including compromised patient care. Many individuals with diabetes, for example, are having to pay steep price increases for their insulin or switch to less expensive— and potentially less effective—products.

Cleanrooms and Sterile Compounding See pages 4, 5, 30

Affected 340B facilities say they also are worried about the financial fallout if the restrictions continue. “This is a very problematic time to cut these [contract pharmacy discounts],” said Jessica Galens, PharmD, the assistant chief pharmacy officer, business services, at UCSF Medical Center. “Hospitals are all suffering financially and because these savings are no longer available to us, it means that we can’t even think about expanding services to people in need when we’re just trying to keep our doors open.” Continued on page 28

Indicated for all persons suspected of exposure to rabies

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REDEFINING HRIG ADMINISTRATION 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.

#1 Prescribed HRIG in the US

References: 1. Cabasso VJ, Loofbourow JC, Roby RE, Anuskiewicz W. Rabies immune globulin of human origin: preparation and dosage determination in non-exposed volunteer subjects. Bull World Health Organ. 1971;45(3):303-315. 2. Aoki FY, Rubin ME, Fast MV. Rabies neutralizing antibody in serum of children compared to adults following post-exposure prophylaxis. Biologicals. 1992;20(4):283-287. 3. Kuwert EK, Werner J, Marcus I, Cabasso VJ. Immunization against rabies with rabies immune globulin, human (RIGH) and a human diploid cell strain (HDCS) rabies vaccine. J Biol Stand. 1978;6(3):211-219. 4. Aoki FY, Rubin ME, Friesen AD, Bowman JM, Saunders JR. Intravenous human rabies immunoglobulin for post-exposure prophylaxis: serum rabies neutralizing antibody concentrations and side-effects. J Biol Stand. 1989;17(1):91-104. 5. Data on ﬁle, Grifols.

October 2020

US-HB3-2000068

Up Front

Pharmacy Practice News • May 2021

Digital

COVID-19 On the Web Here’s a sample of COVID-19 news articles from www. pharmacypracticenews.com. To access full articles, see the URLs below. The Origin of the Species: The Hunt for SARS-CoV-2 Amid a politically charged backdrop, a new World Health Organization report explored several pathways that the

Improving the Journey for Long Haulers

SARS-CoV-2 virus could have entered the human population. Natural zoonotic transmission pathways came up as one of the more likely sources, the report noted. But the authors stressed the need for more study, and outlined best practices for continued research. Access: bit.ly/3ehThxE.

For some patients, SARS-CoV-2 doesn’t just run its course; they continue to experience myriad sequelae after the acute phase of COVID-19. Whether it’s severe cardiopulmonary issues or less serious but still troubling alterations in smell and taste, the symptoms continue to alarm patients for weeks to months after the original illness. These patients are truly in it for the

long haul. Access: bit.ly/3grwOAT.

Virtual SP Care Gains Traction During COVID-19 Going virtual during the COVID-19 pandemic has not diminished the ability of health-system specialty pharmacies to meet their patients’ medication needs and provide quality care, according to the experience of several large centers. Telemedicine, in particular, has helped the facilities improve communication among clinical pharmacy specialists, patients and providers. Access: bit.ly/3sB0xK6.

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.

4 Operations & Management

Pharmacy Practice News • May 2021

Sterile Compounding

Could a Mobile Cleanroom Be a Solution for Your Pharmacy?

etween 2018 and 2020, the Smilow Cancer Network of Yale New Haven Health underwent a major expansion, which included adding new cleanrooms and expanding existing ones at several locations within the network of 14 cancer centers and the flagship Smilow Cancer Hospital. “At the time, we had a total of 22 cleanrooms supporting the network,” said Howard Cohen, MS, RPh, FASHP, who

retired last year as the executive director of oncology pharmacy services at Yale New Haven Health, in New Haven, Conn. “At the Smilow Cancer Hospital, for example, we had a large oncology pharmacy on the eighth floor of the hospital that needed to be totally renovated because it didn’t meet any of the new standards set by U.S. Pharmacopeia Chapters <797> and <800>. It was a very busy pharmacy, compounding 400 to 500

doses a day, and we had no other place to mix our hazardous drugs while it was being renovated. We couldn’t shut down compounding, and we knew that trying to segment the existing cleanroom—compounding in one half while renovating the other half—really wouldn’t work. We’d be risking sterility and a lot of other issues. So we started looking for an alternative.” The solution? A mobile cleanroom. Several vendors, including Germfree and

HyperRAB

-----------DOSAGE FORMS AND STRENGTHS---------300 IU/mL solution for injection supplied in 1 mL, 3 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.

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

3054805 Revised: 11/2019

Cleanroom Design LLC, offer a variety of temporary cleanroom options, with some literally on wheels and able to be parked outside a facility for as long as a facility needs them, and other modular options that can be built off-site and configured for a variety of sizes and layouts before delivery to your institution. “It was the perfect solution for us,” said Cohen, who commissioned Germfree to customize a special version of their standard 53-foot mobile trailer compounding pharmacy for the cancer hospital. “Their usual layout is segmented into two hazardous hoods and two nonhazardous, with anterooms and workrooms. For the oncology pharmacy in the cancer hospital, we went with four hazardous hoods.” Smilow’s specialized unit, located near the loading dock, enabled the hospital to totally take down its existing pharmacy and convert everything to the mobile unit. “We had to go from six biological safety cabinets to two, but we expanded our hours of operation and changed our workflow to accommodate our needs, and relied on other existing cleanrooms throughout the institution to do some of our nonhazardous compounding,” Cohen said.

Strict State Standards Met In addition to the unit at the main cancer hospital, Cohen estimates he used three or four additional mobile cleanrooms over the course of the system’s renovations. “Our state is very strict with its pharmacy standards, and we had both the Connecticut Drug Control Division [which oversees licensing for pharmacies and pharmacists] and the Department of Health in to approve our use of the mobile units, and they were blown away. They said they were outstanding.” The publication of USP’s revised Chapter <800> in 2016, followed by revisions to <797> in 2019—even though implementation has been delayed—kicked off a wave of interest in mobile cleanrooms. “Everybody realized that they were nowhere near compliant and would have to do a significant amount of remodeling to become compliant for hazardous drug compounding,” said Jerry Siegel, PharmD, the vice president at Safe Medication Management Associates and a clinical associate professor at The Ohio State University College of Pharmacy, in Columbus. “To fill their hazardous compounding needs during renovation, many institutions have elected to commission a mobile or modular unit that they can have on-site.” Natural disasters such as hurricanes and earthquakes, as well as the COVID-19 pandemic, also have increased demand for mobile and modular cleanrooms. see MOBILE, page 10

Operations & Management

Pharmacy Practice News • May 2021

Sterile Compounding

Building a Cleanroom Compliance Team I

A Major Undertaking With approximately 335 of Michigan’s pharmacy full-time equivalents participating in compounding or supervision of compounding areas, that was a major undertaking. Most of those staff members completed approximately 24 hours of continuing education on sterile compounding during the team’s first year. All compounders were required to complete a media fill challenge overseen by CCT members to be credentialed. Existing policies and procedures were not robust enough for regulatory compliance purposes, so the CCT purchased draft compounding standard operating procedures from an outside vendor, and then invested significant time in adapting them to Michigan Medicine’s circumstances. The result was eight general compounding policies covering seven areas, each accompanied by associated work procedures, quick tip sheets and documentation forms. Also included were 10 miscellaneous compounding-related policies and four related safety and quality assurance THE MCMAHON GROUP, LLC McMAHON PUBLISHING McMAHONMED.COM Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036 Telephone: (212) 957-5300 CT Office: 83 Peaceable Street, Redding, CT 06896 Copyright © 2021 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News is published bimonthly by McMahon Publishing. POSTMASTER: Send address changes to

policies for medication safety, adverse drug reactions, drug recalls and incident reporting. The team also spent much of the first year focused on centralizing all of the academic medical center’s many records related to compounding. “We were able to centralize all of our certification records, environmental monitoring records and personnel monitoring records,” Tharp said. “These records are Source: HBB Services Solution

n the wake of a series of four audits from different regulatory agencies between June 2016 and August 2017, each resulting in various recommendations, including an FDA Form 483 observation report, Michigan Medicine decided that its network of 21 compounding pharmacy locations needed oversight by a dedicated, in-house team of compounding compliance experts. “Most of the time, compounding compliance in academic medical centers is handled by an administrative leader in the department or the person responsible for supervising the compounding facility itself,” said Bruce Chaffee, PharmD, Michigan Medicine’s director of pharmacy analytics, quality, regulatory and safety. “Before this team was formed, we operated in a very similar way: Each of our compounding areas had a supervisor, and compliance was folded into their duties supervising operations and staff. Some of the work was outsourced, such as sampling being done by a certifier.” To lead the initial four-person compounding compliance team, Chaffee recruited pharmacy manager Jamie Tharp, PharmD, to serve as Compounding Compliance Team (CCT) manager. They then added three more team members: a lead pharmacist with both operational compounding experience and background knowledge in regulatory standards, as well as technical writing skills; and two pharmacy technicians with sterile compounding experience who were also senior enough to have experience with coaching and mentoring. “Our primary focus at the beginning was education, facilities and equipment enhancements, policy revisions and insourcing of our own media fill testing and environmental sampling,” Tharp said. “We spent a lot of our effort during the first year after the team was created in educating all of the compounders across our 21 sites.”

3 Tips for Effective Quality Control

ne key to a successful cleanroom quality control effort is to take a multipronged approach, including the following elements:

1. A dedicated housekeeping team. “Our four housekeepers receive specialized training and only clean pharmacy spaces,” said Bruce Chaffee, PharmD, Michigan Medicine’s director of pharmacy analytics, quality, regulatory and safety. “We have seen significant improvements in the cleanliness of those spaces.” 2. An oversight committee. This group includes pharmacy senior leaders; operational leaders; and representatives from infection prevention, compliance, facilities and systems monitoring, and maintenance. “It’s important to have these checks and balances for tough policy decisions that may not be popular with operations because they change workflow and may be challenging to implement,” Chaffee said.

3. A training space. “What really impressed me was that they were able to keep a decommissioned pharmacy for a training facility where people can practice gowning and garbing, and training and testing can be done,” said Caryn Belisle, RPh, MBA, the director of pharmacy regulatory compliance, quality and safety at Brigham and Women’s Hospital, in Boston. “You see this in the 503B industry, but it’s something most hospital pharmacies can only dream of.”

Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. We endeavor to obtain relevant financial disclosures from all interviewees and rely on our sources to accurately provide this information, which we believe can be important in evaluating the research discussed in this publication. WANT TO SUBSCRIBE? CHANGE YOUR ADDRESS? HERE’S HOW Selected U.S. hospital pharmacists and health care personnel receive Pharmacy Practice News free of charge. If you are a hospital pharmacist and do not

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now in a logically organized database that can easily be searched to answer questions, such as how we managed excursions.” About a year after the CCT was put in place, Michigan Medicine had return visits from the FDA and two other regulators who had audited the facility—the state of Michigan and the Joint Commission. “They were very impressed with the progress we had made,” Chaffee said. “In their interviews, they could clearly see how knowledgeable our staff were, and they were easily able to access all our records in the one-stop shop of our centralized database. They saw what a huge investment of time and effort we had made.” As of April 2021, Michigan Medicine had no outstanding issues in need of regulatory corrective action with any agencies, added Chaffee and Tharp, whose team described their revamped compounding program in the American Journal of Health-System Pharmacy (2020;77[11]:882-891). Based on the initial success of the CCT, Michigan Medicine’s Department of Pharmacy requested that the team be expanded from focusing solely on sterile compounding to include hazardous drug handling and nonsterile compounding. Two more pharmacists and three more pharmacy technicians were added as part of that effort.

Cleanroom Manager ‘Can’t Do it All’ “Having dedicated staff focused on cleanroom compliance, whether it’s one person or a whole team of people like Michigan has, is imperative nowadays,” observed Caryn Belisle, RPh, MBA, the director of pharmacy regulatory compliance, quality and safety at Brigham and Women’s Hospital, in Boston. “You can’t expect your cleanroom manager to do it all. You need someone outside the cleanroom’s day-to-day operations who is focused on quality and compliance. First, it’s just too much for one person to have to keep their eye on, and second, it’s always good to separate your quality from your operations when you are compounding significant amounts of product, either patient-specific or batch.” Internal audits are highly beneficial, Belisle added. “You can observe your trends in environmental monitoring, but you need to also get out of your chair and watch the staff gown and garb, and see how they’re behaving in the cleanroom. At Brigham, we perform monthly quality rounds. We have a team, including our quality assurance coordinator, cleanroom manager, one of our technician trainers and me, observe, talk to front-line staff, watch their performance and get a sense of the challenges they are facing in their day-to-day work.” —Gina Shaw

—G.S. The sources reported no relevant financial disclosures.

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6 Operations & Management

Pharmacy Practice News • May 2021

COVID-19 Pandemic

Expanding the COVID-19 Vaccinator Pool V

accination against COVID-19 in the United States is at an all-time high, but to maintain this pace, the nation still needs more experienced vaccinators to stay ahead of SARS-CoV-2. There still are not enough people vaccinated to reach herd immunity, according to CDC Director Rochelle Walensky, MD. “The key to getting us back to our lives is increasing vaccinations, and to do that, we need more vaccinators,” said acting Health and Human Services (HHS) Secretary Norris Cochran in a statement. The Public Readiness and Emergency Preparedness Act (PREP Act) has expanded its list of people who can administer the vaccines. The act includes pharmacists, pharmacy technicians, pharmacy students and now retired pharmacists. Tom Kraus, MHS, JD, the vice president of government relations at ASHP, said such measures are well-timed. “We are, as a country, going to find ourselves with more vaccine supply coming online, and we’re going to need every potential vaccinator available to be vaccinating patients,” Kraus said. “Anything we can do to get additional vaccinators [on board] is a step in the right direction.”

Retired Pharmacists a Resource Any retired pharmacist who had a valid state practice license within the past five years and is trained to provide intramuscular injections and cardiopulmonary resuscitation (CPR) can volunteer, Kraus explained. If the licensing state does not specify vaccination training, an Accreditation Council for Continuing Pharmacy

Education–approved practical training program of at least 20 hours is required, according to the American Pharmacists Association (APhA). Their CPR certificate should be current, the APhA added. Hospitals, community pharmacies and mass vaccination centers can feel confident in taking advantage of this labor pool because the PREP Act provides liability protections under federal and state law with respect to all claims for loss resulting from the administration or use of COVID-19 vaccines, according to HHS. The PREP Act preempts state laws and regulations by state boards of pharmacy that would restrict or prohibit an active or retired pharmacist from administering the vaccine, but Kraus said he has not heard any concerns about allowing retired pharmacists to practice in this limited capacity. Hospital and community pharmacists have been very engaged in the fight against COVID-19. “Pharmacists in those settings might be running the vaccination program on behalf of a health system, as well as serving as vaccinators,” he said. There are about 300,000 pharmacists nationally, as well as pharmacy technicians, students and now retired pharmacists, so this could be a substantial number of people who can help vaccinate Americans. “This is a potentially significant source of vaccinators, particularly for mass vaccination sites,” Kraus said. On campuses, many schools are “leveraging pharmacists or encouraging their schools of pharmacy to form relationships with health systems or with public

health departments. And most students will have had vaccination training as part of the school curriculum. So that’s another great resource of potential additional vaccinators.” (For more on the colleges of pharmacy COVID-19 response, see page 1.)

Leveraging Pharmacy Students In addition to allowing retired pharmacists to participate, changes to the PREP Act also provided additional flexibility for engaging pharmacy students. Originally, they had to work under a licensed pharmacist, but now they can work under any licensed health care provider. This is going to be pivotal to using these students in mass vaccination and other sites, outside the pharmacy school, Kraus said. Although the vaccines are free, facilities can charge an administration fee. Effective for vaccines provided on or after March 15, 2021, the payment rate will increase from $28.39 to $40. For two-dose COVID-19 vaccines, the rate is $40 per dose, a significant increase over the previous $16.94 for the first payment and $28.39 for the second. ASHP has advocated for reimbursement sufficient to support the additional costs associated with COVID-19 vaccine provision. “With additional resources, providers will be better equipped to provide vaccines safely and quickly to more patients,” Kraus said.

Setting Up a Mass Vaccination Site

new resource from ASHP outlines the essential elements of successful mass immunization programs and emphasizes evidence-based best practices in the safe handling and preparation of vaccines for mass administration. The pharmacy profession is well-positioned to offer such guidance, noted ASHP CEO Paul Abramowitz, PharmD. “Pharmacists have a deep understanding and expertise regarding the therapeutics, handling, preparation, distribution and monitoring of all vaccines, drugs and biologics.” Drawing from the experiences of health-system pharmacy leaders from across the country who have coordinated vaccination sites responsible for the administration of up to 10,000 vaccines per day, ASHP recommends the following as essential elements of an effective mass immunization effort: Leadership: Centralized leadership—pharmacist, physician and nursing—as well as leaders from operations, medical informatics, logistics, facilities,

Image source: St. Joseph Mercy Ann Arbor.

environmental services and security, are critical. Planning: Scaling mass immunization programs requires deliberate and iterative planning. Pharmacy leadership supports the planning of vaccine storage and accountability, ancillary supplies, vaccine preparation and medication waste. Communication, coordination and collaboration: External communication amplifies awareness of successful mass immunization efforts. A public relations

Kraus hopes that as the pandemic winds down, both state and federal legislators recognize the contributions that pharmacists are making in the areas of testing, medication management and vaccine delivery. The best way to do that, he noted, is by passing provider status legislation. “There is no doubt that over the past year, we have seen both state governments and the federal government turn to pharmacy and say, ‘We need help, and you are a capable provider that we’re going to turn to,’” Kraus said. “ASHP and many of the pharmacy organizations are absolutely in alignment that we should be extending some of the flexibilities and making permanent some of the authorities to maintain the roles that pharmacists are playing” during the pandemic. “If the federal and state governments want pharmacists to be a provider they can turn to, they also need to make sure there’s a payment mechanism that’s going to work to support those services. The pandemic actually has been a case study that demonstrates the value that pharmacists bring as providers.” For information from HHS about volunteering to administer COVID-19 vaccines, visit bit.ly/3taDGGw. —Marie Rosenthal The sources reported no relevant financial disclosures.

team can ensure the public is aware that the mass immunization site is active and share resources for scheduling appointments. Regulatory and reporting compliance: For a mass immunization program to be effective, it must comply with state or local health department requirements related to COVID-19 vaccine reporting and personnel credentials. Supply chain management: Vaccine and ancillary supply accountability, storage and security will avoid loss or waste of scarce resources. Pharmacy leaders can support efforts to train and supervise personnel who handle and prepare vaccine doses. Vaccine safety: Safe vaccine handling and preparation practices will promote efficiency and reduce the risk for harm. Vaccine doses should be prepared in a dedicated location away from patient administration areas, restrooms or other environmental factors that may affect air quality. Staff resources: Personnel should be trained and assigned roles according to their qualifications. Staff also should receive resources to support organized workflows. These elements (bit.ly/3t4w8Fd) should be a welcome resource for the growing numbers of pharmacies that already have become sites for COVID-19 vaccinations. More than 20 national and regional pharmacy program partners were participating as of late April, according to the CDC (bit.ly/3evSXLF). —M.R.

Safety. Performance. Ergonomics. Ease of use. We’ve advanced them all. With the BD PhaSeal™ Optima System: the next generation of hazardous drug protection ion Discover the difference at bd.com/optima BD, the BD Logo, Advancing the world of health and PhaSeal are trademarks of Becton, Dickinson and Company or its afﬁliates. © 2021 BD. All rights reserved. BD-29972 (03/21)

8 Operations & Management

Pharmacy Practice News • May 2021

Part 1 of a 2-Part Series

COVID-19 Pandemic

“Nothing will ever be the same after COVID-19” seems to be the general feeling among pharmacists, but just how different the new normal will be depends on many factors, according to the ASHP COVID-19 2020 National Survey and the industry-sponsored 2020 Hospital Pharmacy Operations Report. Both surveys paint a picture of how pharmacists worked during the pandemic, what they think the future holds, as well as technology’s role in their profession. In this first of a two-part series, Pharmacy Practice News discusses shortages, staffing and operational concerns. Part 2 will explore the important role technology plays in the pandemic, as well as trends affecting future pandemic preparedness.

How Did You Respond to the ‘Black Swan’ Event? I

s your organization prepared for a black swan event? That was a question posed during a session at the ASHP 2019 Midyear Clinical Meeting. Who knew that three months later, the audience would find out? A “black swan” event is a rare and unpredictable occurrence that has significant consequences for an organization (bit.ly/3dnoLmz-PPN). The irony of that ASHP session was not lost on Jennifer Symon, RPh, MBA, the director of clinical solutions at Kit Check. “It’s interesting that the [presentation] from 2019 talked about black swans, those unexpected events that are not controllable, and then look what happened in 2020.” One of the responses to the pandemic Symon and her colleagues documented in the company’s own practice survey was a behavior she referred to as “futureproofing.” They found that back-up plans “weren’t enough or they were lacking processes, and everything was just stresstested by the pandemic,” she said, referring to findings from the company’s 2020 Hospital Pharmacy Operations Report (HPOR). “Some things worked out and some things didn’t.” Such stressors—from drug shortages to staffing shortfalls—were significant and also borne out by the ASHP COVID-19 2020 National Survey, noted Michael Ganio, PharmD, BCPS, the group’s senior director of Pharmacy Practice and Quality.

Shortages of Drugs, PPE The pandemic brought about not only drug shortages, but insufficient supplies of personal protective equipment (PPE), and once again demonstrated the fragility of the U.S. supply chain—another concern cited by many respondents to the ASHP National Survey. Such sentiments are not unfounded. During one spike in the pandemic, the FDA identified 20 drugs for which either the active ingredients or finished product were solely sourced from China. Putting more pressure on the supply chain, India, also a major supplier of drug products to the United States, announced at the time that it would suspend some drug exports. Even if the products could get out of China and India, there was no guarantee that they would make it to the United States because air travel was suspended. Many products, including drugs and PPE, are shipped in the belly of passenger planes, and companies had to find alternative shipping methods. That, combined with the surges seen in ICUs, particularly in New York City,

Detroit and New Orleans, and the fact survey respondents said they planned that it was not clear “how difficult to increase inventory of selected onresupplying those drugs would be, hand medications permanently. The PPE shortage for personnel led to some angst,” Gaino explained at the 2021 Montana Pharmacy Asso- involved in patient care made a lot of ciation and HealthSystem Academy headlines during the pandemic, but its Combined Virtual CE Conference, in effects on sterile compounding also were acute. The ASHP survey asked about Helena, held in April. Once the United States issued stay-at- changes that were implemented as a home recommendations, patients were result of the PPE shortage, and found that encouraged to get a larger supply of 71.3% of respondents reported conservdrug refills, which stressed the sup- ing, reusing or adopting an alternative ply chain even more. “The outpatient garb in sterile compounding operations; side was not spared either, as the CDC and other agencies were recommending that patients go get refills,” Ganio said. Drug recalls were another stressor, according to the HPOR survey, which found that 25% of hospital pharmacists thought recalls were exacerbated by COVID-19, and 79% reported that each recall required up to 10 staff hours to manage. In addition, the survey found that 62% of hospitals experienced more than 10 different drug shortages in their pharmacy at any given time. The ASHP COVID-19 2020 National Survey also asked about shortages affecting specific drug classes administered in the ICU, as well as albuterol metered-dose inhalers, which did not fit into a particular of hospital pharmacists saw drug class but were given to staffing reductions and COVID-19 patients. Just over 60% of respondents said they experienced a shortage of inhalers; 57.5% saw a shortage of sedatook a pay cut. tives and analgesics; 42.8%, of Source: ASHP COVID-19 National Survey neuromuscular blocking agents; 34.1%, of corticosteroids; 23.7%, of investigational COVID-19 treatments; 49.3% restricted entry into buffer rooms to minimize PPE use; 22.1% delayed perand 5.5%, of dialysis solutions. Before the pandemic, most hospitals sonnel sterile-compounding competenhad a just-in-time inventory model—a cies; 9.5% increased environmental monistrategy that worked thanks to daily deliv- toring in response to having to reuse PPE; eries from wholesalers. The ASHP survey 9% eliminated use of selected PPE due to asked what steps pharmacists took to man- the shortage; and 9% delayed certificaage the shortages. As a result of the threat tion of engineering controls. “We found 70% were reusing or conto the supply chain, Ganio told Pharmacy Practice News, 90.6% of respondents said serving PPE in some way, which makes they “increased the day’s supply they sense given how significant the shortwere carrying of specific drugs, which I ages were,” Ganio said. think was a significant finding.” In addition, 25.9% of respondents Staff Shortages expanded the use of premade or Pharmacy leadership had to deal with ready-to-mix systems; 18.5% expanded staff changes, according to both surveys. the use of outsourcing vendors; and The HPOR survey found that 43% of 8.2% increased the day’s supply of all pharmacies had to manage staff shortmedications. “We [also] wanted to ages and that it was a leading issue that know if any of these changes were will need to be addressed. permanent,” he said. Indeed, 42% of The ASHP survey found that 54.7% of

54%

15.9%

respondents saw staffing reductions and 15.9% saw salaries cut, but 10.6% hired temporary staff to meet increased demand and 31% didn’t experience any of these changes. “The reductions were early on and in response to the census being low,” Ganio said. “There were a couple of areas that were surging [initially], but the rest of the country went into this sort of lockdown prevention of surges, and so elective procedures were being canceled and preventive [care] visits were being canceled.” As hospitals resumed more normal

43% of hospitals reported staff shortages. Source: Kit Check survey

operations—for instance, 97% of hospitals resumed all elective procedures by the summer of 2020—that required some rehiring of staff. In addition, pharmacists were involved with COVID-19 testing and vaccinations, which also led to increased staffing, although some of that could have been temporary, Ganio said. Overall, the nation’s drug experts became an important part of the fight against COVID-19, not only for testing and vaccinations, but also to help physicians understand and prescribe the many off-label and experimental medications that were used during the pandemic. Hydroxychloroquine, tocilizumab (Actemra, Genentech), famotidine, baricitinib (Olumiant, Lilly) and ivermectin (Stromectol, Merck) were all used off-label see PRACTICE SURVEYS, page 10

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10 Operations & Mangement

Pharmacy Practice News • May 2021

Sterile Compounding

MOBILE continued from page 4

“When Katrina hit, a whole hospital system was knocked out; if a cleanroom gets flooded, it could take months to get back online again,” Siegel said. “Most recently with COVID-19, there was a need for rapid increase in cleanroom capacity in some areas.”

A Solution During HVAC Renovation In March, the Dayton VA Medical

This custom USP <800> mobile pharmacy was used by Moffitt Cancer Center to prepare medications for 200 patients per day during its facility renovations in 2020.

Center, in Ohio, put a mobile cleanroom in place to serve its sterile compounding needs during an approximately sixmonth project to upgrade the HVAC (heating, ventilating, and air conditioning) systems in its existing cleanroom to ensure <797> compliance. “We had options for a couple of different models,

one of which resembles a semi-truck trailer on wheels that is parked in place. That’s designed to be even more mobile,” said William “John” Van Schepen Jr.,

PharmD, Dayton VA’s pharmacy program manager for sterile compounding and hazardous drugs. “We chose a unit that is a little larger, resembling a

PRACTICE SURVEYS continued from page 8

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at some point, and remdesivir (Veklury, Gilead), convalescent plasma and certain monoclonal antibody therapies, as well as COVID-19 vaccinations, all received emergency use authorizations from the FDA. Managing these medications required a whole new level of practice for pharmacists, and there were many unknowns, Ganio noted. The ASHP survey found that to cope with these new clinical challenges, 78.5% of pharmacies said they developed algorithms or guidelines for offlabel medications. In addition, 54.9% opened COVID-19 compassionate- or investigational use studies to ensure access to medications such as remdesivir. Many smaller hospitals do not routinely participate in investigational studies, so this was new territory for many of them. The rapidly changing pace of research on emerging COVID-19 therapies was another challenge for front-line pharmacists. In a given week, a study—often not peer-reviewed—would claim one off-label medication was favorable, and the day after its release, another study would refute it. “There were a lot of clinical, really fast-moving components to COVID-19 treatment,” Ganio said. “So, our clinicians were really forced to use their pharmacology knowledge.” —Marie Rosenthal

Visante consultants bring you expertise in all areas of hospital and health system pharmacy: • • • •

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• Supply Chain Strategies • Drug Diversion Programs • Drug Compounding Excellence

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Surveys by the Numbers ASHP surveyed 1,437 pharmacy directors at general and children’s medical/surgical hospitals. Usable responses were received from 269 survey participants. The survey results will be published in the American Journal of Health-System Pharmacy.

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The Kit Check survey report (bit.ly/ 3sBfCLw) is based on input from 191 hospital pharmacy leaders, and 43% have at least 20 years of experience. Both surveys were sent in the fourth quarter of 2020 and closed in December.

Operations & Management

Pharmacy Practice News • May 2021

Sterile Compounding

4 Questions to Ask When Considering a Mobile Cleanroom 1. What’s Your Budget? Building a cleanroom suite from nothing costs about $2.5 to $3.5 million, depending on the size, said Jerry Siegel, PharmD, the vice president at Safe Medication Management Associates and a clinical associate professor at The Ohio State University College of Pharmacy, in Columbus. “For these mobile and modular units, the cost is between $800,000 to $1.2 million for a bigger unit, and you can get a very small onehood mobile unit for $150,000. Leasing costs somewhere between $35,000 and $50,000 a month.” 2. Buy or Lease? Most hospital pharmacies—including Yale New Haven Health and Dayton VA Medical Center—have chosen to lease their mobile cleanrooms, but if one or more are needed for an extended period, buying may be more economical. “Larger hospital chains that are planning to go through renovations at multiple locations may elect to purchase,” said Jeff Serle, the senior vice president of engineering for Germfree. “They are very mobile and can be fully repositioned in two to three weeks, including certification for

shipping container, which is brought in and placed with a crane. Our unit runs via power and water from the building, as compared to the trailer units, many of which have their own onboard generators and water tanks.” So far, the mobile unit has worked quite well, Van Schepen said. “It took a full week to do the setup, training and certification, but we’ve been using it every day since then for all of our hazardous compounding and hazardous drug storage, as well as some nonhazardous compounding,” he said. “We’ve had no issues with meeting our usual volume.” Challenges have included space, communication and new standard operating procedures. “First, it’s obviously a lot smaller than a normal cleanroom would be, so we have to be more efficient in our use of space, particularly counter space,” Van Schepen said. “We don’t have our normal phones in there, so we’ve had to use things like Vocera and Microsoft Teams to communicate. We’ve also had to establish procedures for delivering preparations once they’re made and restocking in order to minimize traffic and keep things as clean as possible.” Van Schepen advised other pharmacies considering a mobile cleanroom to start the process early. “With something as big and complicated as this, delays are bound to happen,” he said. “Be as flexible as you can. You can’t budge on the regulations, of course, but be flexible in the areas you can be.” —Gina Shaw The sources reported no relevant financial disclosures beyond stated employment.

use. Then they can be safely shut down and stored for periods of time, and you have an asset afterward in situations like disaster recovery.” 3. Modular or Mobile? Even within the “mobile” world, there are different options. “You have ‘on wheels’ and ‘not on wheels,’” Siegel said. “You can also have a vendor build you what’s called a relocatable mobile cleanroom. They will build it off-site to your specifications, put it on a truck, and bring it to your site and hook it up. One mobile

tissue lab that I worked with had five of these modular units hooked together; they were each delivered singly and put together once they arrived.” Cleanroom Design LLC built two modular cleanrooms for a facility in Boston. “They slid them inside the space through a loading dock door, and now they’re part of the permanent structure inside,” said president Brian Clark. “They can be connected like building blocks, where you just add on and on if needed.” 4. How Soon Do You Need It? Choosing

between modular or mobile also may be affected by a facility’s time line. Mobile units typically can be installed without construction permits, which can take six months or longer, depending on the state. “If you need a permit within six months, you’ll be hard-pressed,” Clark said. “It can be done but it’s challenging. But with mobile cleanrooms, for example, we have three right now in the factory that came back off lease that we could deliver in three to four weeks. Our longest lead time for mobile would be three to four months.” —G.S.

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SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) 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. Contraindications: Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL.

WARNING: DEATH IN PRETERM INFANTS • Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm infants and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion.

Please see Brief Summary of Prescribing Information including Boxed Warning for SMOFlipid on the next page.

12 Operations & Management

Pharmacy Practice News • May 2021

COVID-19 Pandemic

Colleges Pitching In continued from page 1

spread through China and make its way toward Europe. “At the time, they were doing work with cancer screening using real-time PCR testing,” Cutler said. “As they were seeing the virus leak out of China, they thought the technology they were using could be employed to test for COVID-19, with saliva.” Their hunch ultimately translated to the Saliva Assay Free Expedited (SAFE)

test, which demonstrated a high level of accuracy in detecting SARS-CoV-2, doing so within 24 hours at a lower cost than nasopharyngeal swab testing, Cutler said. The College of Pharmacy received Clinical Laboratory Improvement Amendments certification, and the test is under review for emergency use authorization (EUA) by the FDA. Their efforts also captured the attention of South Carolina

SMOFLIPID (lipid injectable emulsion), for intravenous use BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR HEALTHCARE PROVIDERS This brief summary does not include all the information needed to use SMOFlipid safely and effectively. Please see full prescribing information, including Boxed Warning for SMOFlipid (lipid injectable emulsion), for intravenous use at www.FreseniusKabiNutrition.com.

te Coat WARNING: DEATH IN PRETERM INFANTS at UConn • Deaths in preterm infants after infusion of intravenous lipid emulsions year pharmacy students celebrate have been reported in the medical literature. Pharmacy into advanced pharmacy practice

• Autopsy findings included intravascular fat accumulation in the lungs. experience rotations. third-year stu- infants and low-birth-weight infants have poor clearance of • Preterm iversity of intravenous lipid emulsion and increased free fatty acid plasma levels ) School following of Phar-lipid emulsion infusion. ked the next s—moving on to AND USAGE INDICATIONS SMOFlipid is indicated in adults as a source of calories and essential fatty acids ver, unlike previts in for theparenteral annual nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. ny weren’t able Limitations of Use ds, orThe otherwise omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in her face-to-face. SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous ct that we are lipid emulsions. today does AND ADMINISTRATION DOSAGE ical imporThe recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk vent stands for,” Package mD, the deanforofadmixing only and is not for direct infusion. Prior to administration, transfer to a separate PN container. dents, friends CONTRAINDICATIONS ng this winter’s Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the eremony. active ingredients or excipients. fessional rite of Severe hyperlipidemia or severe disorders of lipid metabolism with serum pharmacy stu-> 1,000 mg/dL. triglycerides dvanced pharWARNINGS AND PRECAUTIONS rience rotations • Death in Preterm Infants: (see BLACK BOX WARNING) white• Hypersensitivity pharmaReactions: SMOFlipid contains soybean oil, fish oil, and egg ing the School which may cause hypersensitivity reactions. Cross reactions phospholipids, have been observed between soybean and peanut oil. Signs or symptoms the UConn seal ame. of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, hite Coat Cersweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, tions of profespyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately al behavior and and undertake appropriate treatment and supportive measures. of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can have •aRisk chance support microbial growth and is an independent risk factor for the development n Association of of catheter-related bloodstream infections. The risk of infection is increased in Oath patients of a Pharwith malnutrition-associated immunosuppression, long-term use and he first time. poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions or drugs. t of professionFat Overload Syndrome: This is a rare condition that has been reported with dent• pharmasaid. intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome ss of the vircharacterized by a sudden deterioration in the patient’s condition including chool fever, plans anemia, leukopenia, thrombocytopenia, coagulation disorders, fatty liver infiltration (hepatomegaly), deteriorating liver ypicalhyperlipidemia, in-perfunction, and central nervous system manifestations (e.g., coma). White Coat Cere-

• Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, meantcharacterized to bring by the intracellular shift of potassium, phosphorus, and ore they head as the patient becomes anabolic. Thiamine deficiency and fluid magnesium may also develop. ctions,retention so hold-

es the most

Henry Cohen, PharmD, the dean of the Touro College of Pharmacy, in New York City, with students involved in the school’s COVID-19 outreach program.

Governor Henry McMaster, who worked with the South Carolina General Assembly to award the college $16.6 million to expand use of the test and share it

• Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum. During prolonged PN administration in patients with renal impairment, the aluminum levels in the patient may reach toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, including preterm infants, who receive parenteral intakes of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products. • Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction. • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. • Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. • Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. ADVERSE REACTIONS Most common adverse drug reactions >1% of patients who received SMOFlipid 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. Less common adverse reactions in ) 1% of patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis. The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Infections and Infestations: infection. Respiratory, Thoracic and Mediastinal Disorders: dyspnea. 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 Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters. USE IN SPECIFIC POPULATIONS • Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women. • Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients. • Hepatic Impairment: Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure. OVERDOSE In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid infusion until triglyceride levels have normalized. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum. REFERENCE: 1. Deckelbaum RJ, et al. Biochemistry (Mosc). 1990;29(5):1136-1142.

—D.W.

ported no relevant ancial disclosures.

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

with other institutes of higher learning. “We’ve helped other institutions work with the test from soup to nuts, including setting it up and running it to applying for state certification and FDA emergency use authorization,” Cutler said. SAFE has been used roughly 100,000 times in students, staff and faculty at USC, as well as some individuals in the community and at other universities, Cutler said. The college also is sequencing positive cases they find using the SAFE test.

Touro College of Pharmacy In New York City, clinical pharmacists, pharmacy professors and graduate students at Touro College of Pharmacy have been testing and vaccinating patients on and off campus. Henry Cohen, PharmD, the dean of the College of Pharmacy, said they initially used the type of PCR-based saliva testing pioneered at the University of South Carolina but switched to nasal swab antigen testing (BinaxNOW, Abbott) in October 2020 because the test produces results with 93% sensitivity and 98% specificity within 15 to 30 minutes. In addition to detecting individuals infected with SARS-CoV-2, pharmacy staff, students and faculty can make use of testing encounters to educate patients and combat vaccine hesitancy, Cohen noted. “It’s also a great chance to present the latest evidence on vaccine efficacy and safety and to tell people about social distancing, mask wearing and other preventive measures,” he said.

Medical College of Wisconsin Pharmacists in academia have brought their specialized knowledge to campuswide COVID-19 testing and vaccination efforts at the Medical College of Wisconsin (MCW) Pharmacy School, in Milwaukee. Kristin Busse, PharmD, an assistant professor in the Department of Clinical Sciences at MCW, led the operational aspect of MCW’s vaccination program, partly because of her experience handling the institutional use of novel and experimental agents. “We’ve managed it basically like an investigational drug, providing all the necessary documentation for preparation, storage and usage, and making sure we have a very strong audit trail of use of the vaccine,” Busse said. Before any COVID-19 vaccines were approved, Busse and her colleagues

Operations & Management

Pharmacy Practice News • May 2021

COVID-19 Pandemic developed training materials, recruited the initial cadre of volunteers and built their vaccine distribution plan in partnership with an affiliated hospital. “We developed workflow processes ranging from vaccine receipt and secure storage to vaccine distribution to clinic, record keeping and vaccine allocation requests,” she said. To accommodate the storage needs of the Pfizer/BioNTech messenger RNA– based vaccine (BNT162b6), they borrowed –80° C freezers from their basic science colleagues at MCW, “which made on-site inventory management easier, [considering] the five-day expiration dating under refrigeration,” she noted. The advanced planning paid off, and Busse and her team hit the ground running when the Pfizer/BioNTech vaccine received its EUA on Dec. 21, 2020. The next day, they began immunizing campus staff, faculty and students, and have administered 13,000 doses since then. They have the capacity to immunize 80 patients per hour and have had a single-day record of 690 COVID-19 vaccinations. The scale and complexity of the operations have required a multidisciplinary effort, Busse noted. “Pharmacy students and faculty were first to respond to the call for vaccinator support, but clinical research personnel soon followed in both vaccinator and nonvaccinator roles, and medical students and faculty joined the ranks of vaccinators as the clinic continued into late February and March.” Additional personnel from departments around the campus helped staff the record-keeping and clinic support roles, she said. “Dose preparation was always overseen by a licensed pharmacist, but technical support to draw up doses of vaccine relied heavily on basic science lab faculty and staff, as well as veterinarians who run our biomedical resource center.” Busse emphasized the importance of optimizing operations post-launch. She said her team gathers each week to find ways to improve their processes, and early on, they found that asking patients to complete paperwork in line was creating a bottleneck. “So we used tables spaced 6 feet apart to complete paperwork prior to check-in,” Busse said. “That’s one of a number of small efficiencies that have worked well.” For pharmacy students involved in the vaccination clinic, learning how to interact with patients and seeing what it takes to run the clinic have been invaluable, Busse noted. The pharmacy students also have gained confidence through this experience. “Vaccinating is repetitive and allows students to get really comfortable with a process and gain experience with each patient they vaccinate, for example, by answering new and repeated questions.”

UConn School of Pharmacy Pharmacy students at the University of Connecticut (UConn) School of Pharmacy, in Storrs, have spent thousands of hours at vaccination clinics around the state, not only immunizing but training more than 800 health-system and hospital providers in proper COVID-19 vaccine administration and participating in state-run contact tracing. Jill Fitzgerald, PharmD, the director of experiential learning and continuing professional development at UConn, said playing a central role in the clinic’s

operations has been a profound experience for students. Many have said they have developed “a sense of helping the state’s citizens maintain good health and in reducing the impact of the pandemic, and patients and families have expressed gratitude for all the professionals working to get as many people vaccinated as possible.” The efforts of colleges of pharmacy— both students and faculty—will have an “immeasurable impact on our profession,” Fitzgerald added. “The exposure of pharmacists in arenas other than community

pharmacy is raising public awareness that our profession can make enormous contributions in keeping our citizens healthy.” Cohen, of Touro College of Pharmacy, agreed. “If there’s a silver lining for the profession of pharmacy with this terrible pandemic, it’s that it has put us in the spotlight and shown others how we can play an integral role in managing [COVID-19].” —David Wild The sources reported no relevant financial disclosures.

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14 Clinical

Pharmacy Practice News • May 2021

Infectious Disease

Staying ahead of the curve:

Vancomycin and the Move to AUC-Based Dosing D

osing practices for vancomycin remain notoriously uneven, which is one of the reasons why updated 2020 guidelines on the antibiotic are still so important to heed, several ID experts told Pharmacy Practice News. The guidelines represent a significant change in practice (Pharmacotherapy 2020;40[4]:363-367). Under the new recommendations, dosing vancomycin using trough-only monitoring—as has been the standard for the past decade— is no longer recommended. Instead, a more individualized approach is urged, using the 24-hour area under the curve to minimum inhibitory concentration ratio (AUC24:MIC). The stakes in following the guidelines are high, stressed Timothy Gauthier, PharmD, BCPS-AQ ID, the antimicrobial stewardship clinical program manager at Baptist Health South Florida, Miami/ Fort Lauderdale area. “Individualized dosing is important for maintaining steady-state levels of vancomycin, maximizing efficacy, avoiding inadequate dosing that can lead to antibiotic resistance, and minimizing toxicities such as acute kidney injury,” Gauthier said. “In the 11 years since the original guidelines were released, an emerging body of evidence has come out that it is safer and more effective to use the AUC/MIC-based dosing, particularly with invasive MRSA [methicillin-resistant Staphylococcus aureus] infections.” Katherine Yang, PharmD, MPH, a health sciences clinical professor in the Department of Clinical Pharmacy at the UCSF School of Pharmacy and an infectious diseases clinical pharmacist in the UCSF Medical Center, in San Francisco, who specializes in the treatment of multidrug-resistant infections, praised the revised guidelines. “Many pharmacists had already been doing this approach instinctively, looking at what the MICs are versus the existing dosing, but it’s important that this is being formalized with clear guidelines on how to implement the new dosing,” she said. “It’s an opportunity for more evidence-based dosing in an area where we actually have data on both efficacy and safety. In a lot of drugs for which we do therapeutic monitoring, the levels don’t always correspond so well with efficacy or safety, but here we have strong data, and that’s exciting.” But putting AUC/MIC-based dosing into practice has proven more challenging. The debut of the revised guidelines in March 2020 occurred just as the first wave of the COVID-19 pandemic was beginning to slam U.S. hospitals. With ID pharmacists in many institutions overwhelmed by the demands of the

Trough-only targeting has become less accurate due to “MIC Creep.” Source: Matthew Song, PharmD. www.linkedin.com/pulse/bayesian-derived-vancomycin-aucmic-easy-accurate-tdm-matthew

pandemic, not all hospitals and health systems have made the shift to the new dosing and monitoring strategy. An April 2020 survey of hospital pharmacists by InsightRx found that 86% were still using trough-based methods. Gauthier said he doubted that figure has moved much in the past year. “It is not a small change to move toward [AUC/ MIC dosing],” he said. “Depending on the size of your hospital, if vancomycin use is low, this may not be a high-priority item.” He added that the debate over vancomycin dosing “blazes on,” based on a recently published pro/con debate by major leaders in the infectious disease space (Clin Infect Dis 2021 Mar 19; doi: 10.1093/cid/ciaa1743). “Clearly, AUC/ MIC dosing is not something everyone universally agrees on,” Gauthier said. Even at a large institution such as UCSF, with a major antimicrobial stewardship program, the process has been slow. “We would have been much further in our implementation by now, but everybody was scrambling to go into high-COVID gear,” Yang said.

Opportunity for Education The concept of AUC is probably not intuitive for most nonpharmacist providers, Yang noted. “There is a lot of opportunity here for pharmacists to educate the rest of the team on what this means, what pharmacokinetics [PK] and pharmacodynamics [PD] are, and why they matter,” she said. “Infectious disease physicians may be more familiar with these concepts, but for generalist physicians who are writing for vancomycin, it’s really a switch for them not to do traditional drug monitoring based on trough levels.

There also will be some education required for the nursing staff on when to draw levels and how many, as well as opportunities forr working closely with thee microbiology lab. It’s a nice way to bring all thee team members together.”” Patient populationss for which vancomy-cin dosing is a particu-larly sensitive issue include those who aree critically ill and alreadyy at risk for acute kidney ney injury, which is one of the most significant toxicities associated with vancomycin. “High levels of vancomycin within the body can exacerbate acute kidney injury, leading to even higher vancomycin levels and a potentially dangerous cycle,” said Drayton Hammond, PharmD, a clinical pharmacy specialist in the medical intensive care unit at Rush University Medical Center, in Chicago. “This is a population that we would particularly worry about, in which it’s tougher to dose medications, and where these revised guidelines are particularly important. Other patients where this is the case are those who are obese, who may need a slightly higher concentration in the body to allow for appropriate blood levels of vancomycin—but that also potentially poses a risk of toxicity.” Implementing the revised guidelines can involve pharmacists developing a homegrown Excel spreadsheet for their institution or purchasing a commercial product from an outside vendor. There also are free online dosing calculators,

such as one offered by DoseMeRx (doseme-rx.com/vancomycin/dosingcalculator). “Is it the right thing for your site to get some sort of PK/PD dosing tool, or is it better to develop your own Excel sheet? There’s no one answer; it’s unique to your institution,” Gauthier said. “But if you don’t have the resources to develop your own tool, and you aren’t satisfied with any of the free online tools, there are multiple precision dosing tools on the market, some of which will integrate with your existing hospital software.” Pharmacists are critical to every step of this process, Gauthier said. “We need to work with physicians to understand the needs of the patients being treated at our facilities, and to communicate opportunities from the pharmacy standpoint. This goes beyond simply the dosing and monitoring of vancomycin to appropriate use. Can we assist in performing antibiotic timeouts to see if vancomycin antibio is needed anymore? We understand n the dynamics of how we produce the doses, dose how we send them to the floor, and how the nurses are administering them. Logistically, we are well in positioned to advise prescribers on p ttheir best approach, given a speccific clinical scenario.” —Gina Shaw Gauthier reported a financial relationship with DoseMe by Tabula Rasa. Hammond reported no relevant financial disclosures.

3 Steps In Guidelines-Based Vancomycin Dosing

Draw two vancomycin levels: one trough concentration and one peak steady-state concentration, one to two hours post-infusion.

Use a Bayesian software program to monitor the AUC.

Maintain a Bayesian-derived AUC/ MICBMD (broth microdilution) of 400 to 600 mg*h/L for serious infections.

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16 Clinical

Pharmacy Practice News • May 2021

Infectious Disease

Targeting Stewardship Efforts in the Emergency Department

ntimicrobial stewardship efforts focused on the emergency department (ED) have the potential to decrease antibiotic resistance and improve antibiotic and antifungal use and outcomes, according to Nicole Acquisto, PharmD, an emergency medicine clinical pharmacy specialist at the University of Rochester Medical Center (URMC), in New York. The ED is a target-rich but challenging

environment for antimicrobial stewardship. “Antibiotics are the fourth-largest drug class used in the ED as of 2016— which is improved over 2010 when they were the second-largest drug class used,” Acquisto said, citing the National Hospital Ambulatory Medical Care Survey. “We know that between 30% and 50% of outpatient antibiotic prescriptions in the ED are inappropriate, and that approximately 16% of all ED

visits for adverse drug events involved antimicrobials [Infect Dis Clin North Am 2020;34(1):109-127].” Despite the multiple barriers to effective antimicrobial stewardship posed by the unique environment of the ED, including high patient volume, overcrowding, pressures for throughput and disposition, and limited time with patients, Acquisto said, it’s an important fix. “Research has shown that

ED-initiated therapies, including antibiotics, are often continued upon hospital admission,” said Acquisto, an associate professor in URMC’s Departments of Pharmacy and Emergency Medicine. “When inappropriate antibiotics were prescribed in the ED, only 19% of patients then had appropriate antibiotics on admission. On the other hand, when antimicrobial therapy was optimized in the ED, 83% of patients had appropri-

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ate treatment when they were admitted [Am J Emerg Med 2019;37[5]:839-844].” She cautioned that typical hospitalbased antimicrobial stewardship strategies, such as de-escalation or discontinuation of therapy, scheduled antimicrobial evaluations at 48 to 72 hours, and preauthorization for antimicrobial approval, may not be feasible in the high-throughput, short-duration environment of the ED. Instead, she recommended that EDs focus on the CDC Core Elements for Outpatient Antimicrobial Stewardship Programs, which are intended for the ED and urgent care settings (MMWR Recomm Rep 2016;65[No. RR-6]:1-12). The CDC guidelines recommend focusing on one or more of the following high-priority scenarios for interventions, Acquisto noted: • where antibiotics are overprescribed (e.g., with acute sinusitis, uncomplicated bronchitis or asymptomatic bacteriuria); • where they are prescribed appropriately but the condition is overdiagnosed; • where antibiotics are indicated but the wrong dose, drug or duration is prescribed; • where watchful waiting or delaying prescribing is appropriate but underused; and • where antibiotics are underused, such as for sepsis. “Establish a collaborative team with the ED and the antimicrobial stewardship program and identify one or

Clinical

Pharmacy Practice News • May 2021

Infectious Disease two disease states to target initially, or identify an area with high failures,” Acquisto said. “Maybe certain antibiotics are always prescribed at the wrong dose. Maybe you’re not meeting an antibiotic administration goal in a certain time period. Start with smaller interventions focused on specific antibiotics or specific disease states.” ED-specific stewardship guidelines could fall into several primary areas. “First, you can drive appropriate antimicrobial use,” she said. “It’s important that these guidelines address when and

‘We know that between 30% and 50% of outpatient antibiotic prescriptions in the ED are inappropriate, and that approximately 16% of all ED visits for adverse drug events involved antimicrobials.’ —Nicole Acquisto, PharmD 75%, reduced antibiotic exposure from 8.7 to 5.7 days, and reduced antibiotic adverse events from 28% to 19% [Pediatr Emerg Care 2009;25(11):748-750;

J Pediatric Infect Dis Soc 2014;3(2):112118; JAMA 2009;302(10):1059-1066].” In the unique setting of the ED, Acquisto concluded, collaboration

beyond the ED team is necessary for success. “Initiatives should focus on empiric antimicrobial treatment—decision to treat and right drug, dose and duration; prompt administration; and prevention of emergency department returns and readmissions.” —Gina Shaw Acquisto reported no relevant financial disclosures. Portions of this article are based on a session on novel antimicrobial stewardship programs held during the 2020 virtual annual meeting of the American College of Clinical Pharmacy.

We’ve Got You

when not to treat, and when and when not to test. For example, you don’t want clinicians doing a urine dip on a patient who comes in with a mechanical fall, who is then hydrated and discharged without antibiotics. That dip may end up [yielding a positive] culture, and now potentially another outpatient or inpatient provider may see that result and initiate treatment. It’s really important not to have frivolous testing.”

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Dialing in Antibiograms Acquisto also stressed the importance of understanding the difference between community and inpatient antibiograms. “Historically, the ED was lumped in with inpatients, which reduced our ability to use narrow-spectrum antibiotics. By pulling out and separating the community antibiogram, it’s possible to include antibiotics that may not be able to be used in the inpatient setting,” she explained. “That also means that your ED formulary may be slightly different.” A number of studies also have shown that the availability of rapid diagnostic testing can significantly decrease inappropriate antibiotic use in the ED. “Rapid strep tests in children with pharyngitis in the ED, for example, have been found to reduce antibiotic use from 41% to 23%. Rapid influenza tests reduced antibiotic use from 23% to 11% and increased antiviral use from 19% to 56%,” she said. “A procalcitonin algorithm for lower respiratory tract infection reduced antibiotic use from 88% to

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18 Clinical

Pharmacy Practice News • May 2021

Nutrition

Affordable Alternatives to Ethanol Lock Therapy E

thanol lock therapy—the use of dehydrated alcohol in central line catheters to prevent catheter-related bloodstream infections (CRBSIs)—has been used widely for pediatric patients on home parenteral nutrition (PN). But with ethanol locks becoming exponentially more expensive, clinicians are employing creative alternatives, a speaker said at the ASPEN 2021 Nutrition Science and Practice Conference. Problems started as a result of the FDA’s Unapproved Drugs Initiative (UDI), implemented in December 2020, through which drugs marketed prior to current safety and efficacy requirements needed to be reviewed again, said Ruba Abdelhadi, MD, CNSC, the director of nutrition support at the University of Missouri-Kansas City School of Medicine. Products such as ethanol locks (dehydrated alcohol), neostigmine methylsulfate, vasopressin and selenium had been grandfathered into use but are no longer approved, Abdelhadi said. Then, through the UDI, Belcher Pharmaceuticals in 2018 received orphan drug designation for an injection of dehydrated alcohol, with exclusivity through 2025. The company has been charging $1,000 per milliliter, according to published data from Vizient,

increasing the wholesale acquisition cost by 668%. (Belcher did not respond to repeated requests for comment.)

‘Disastrous Impact’ “The impact of the ethanol shortage has been disastrous for our patients on home PN,” Abdelhadi said. The UDI “really backfired. It was supposed to be a safety initiative, but now it’s putting our patients in danger of developing CRBSIs.” There are other options that clinicians can consider depending on patient profiles, Abdelhadi said: Using ethanol locks with less frequency. Some studies demonstrated a significant reduction in CRBSIs using ethanol locks three days per week (J Pediatr Surg 2010;45[6]:1287-1293) or once weekly (Nutr Clin Pract 2013; 28[2]:226-231) instead of daily. Using different concentrations. Many centers use 70% ethanol, but in a recent survey by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Intestinal Rehab Special Interest Group, two centers reported using either 50% or 20% ethanol.

Using antimicrobial locks. This could be done as a preventive strategy for patients with long-term hemodialysis catheters, limited venous access and a history of recurrent central line–associated bloodstream infections (CLABSIs), or those at increased risk for severe sequelae from a CLABSI. Check with your antimicrobial stewardship program at your institution first, Abdelhadi advised. Using other agents shown to reduce CRBSIs that reduce bacterial burden. These agents include tetrasodium EDTA or taurolidine-citrate solution. Abdelhadi also encouraged clinicians to advocate for their patients by informing legislators about this issue, urging the FDA to regulate pharmaceutical products to avoid shortages, asking the FDA to expedite the approval of competing drugs

Table. UDI-Related Price Spikes for Five Drugs

Drug

Regulatory History

Price Increase

Effect on U.S. Drug Spending (annualized, millions) Before UDI After UDI

Dehydrated Alcohol 98% to Dehydrated Alcohol 99%

• Dehydrated alcohol 98% injection solution was first introduced in 1993 for relief of intractable chronic nerve pain • UDI Status: Received 7-year orphan indication.

• $1,295 ➞ $9,950 • WAC increase of 668% on package of 10

215a

Neostigmine Methylsulfate

• Developed in 1931; gained formal FDA approval in 2013 • UDI Status: de facto exclusivity

• $157.90 (prior to UDI) ➞ $987.50 (peak during exclusivity) ➞ $173.40 (current) • WAC increase of 525% on package of 10, then gradually decreased to 9.8% above prior WAC price

60.6

205.8b

Selenium 40 mcg/mL to Selenious Acid 60 mcg/mL

• Parenteral selenium first introduced in the 1980s; received formal FDA approval as injection on April 30, 2019 • UDI Status: five-year NCE exclusivity through April 2024

• $443.25 ➞ $8,575 • WAC increase of 1,190%c on package of 25

8.52

84.9d

Tralement (trace elements injection)

• Parenteral trace elements were introduced in the 1970s; Multitrace-5 was first marketed in 1993. • Tralement received formal FDA approval on July 2, 2020. • UDI Status: five-year NCE exclusivity through April 2024

• $312.50 ➞ $537.50 • WAC increase of 72% on package of 25

34.1

58.7e

Vasopressin to Vasostrict

• Developed in 1928; granted formal FDA approval in 2014 • UDI Status: Patent approved as innovation through 2035

• $283.25 ➞ $4,939 • WAC increase of 1,644% on package of 25

30.8

791c

looking to reenter the market, and asking professional society advocacy groups for support. The NASPGHAN Intestinal Rehab Special Interest Group, for example, partnered with the American Academy of Pediatrics to send a letter to the editor of the Journal of Pediatric Gastroenterology and Nutrition, stating the need to “rapidly regain access” to ethanol or other agents used internationally, Abdelhadi said (J Pediatr Gastroenterol Nutr 2020;70[6]:e140-e141). “There’s not necessarily a shortage of these products, but they’re so expensive that we’re having to pull out our drug shortage management toolkit to try to figure out how to use less,” said Erin R. Fox, PharmD, the senior director of drug information and support services at the University of Utah, in Salt Lake City. “It’s really unfortunate.” Abdelhadi’s suggestions to preserve costs are reasonable, commented Steven Lucio, PharmD, BCPS, the senior principal of pharmacy solutions at Vizient. “These products were pretty narrowly defined in terms of their use,” he said. “You might have some ways to manage it, but by and large you don’t have great ways to completely avoid the increased costs.” Additional product categories also were affected by the UDI, Lucio said. For example, in 2014, Par Pharmaceuticals received FDA approval for its vasopressin injection Vasostrict, with patent protection through 2035; the company raised the price by as much as 1,644% for a 25-count package (Table). In most cases, manufacturers going through the UDI process did not conduct new clinical studies but did test purity of the products and reviewed studies already published in the medical literature, summarizing what the drug has done, Lucio said. This makes the price spikes “appear even more egregious,” he stressed. “The increases, as well as the duration of time that competition is removed, seems disproportionate to the work being done.” Given the potential for regulators to revisit the decision on the UDI, Vizient has shared recommendations to support findings of safety and efficacy for unapproved drugs while avoiding the unintended consequences of this initiative, Lucio said: “We’re very much waiting to see what transpires.” —Karen Blum

Estimated annual U.S. health care spend since UDI based on 2020 spend.

Estimated 2021 annualized U.S. health care spend since UDI.

Average annual health care spend, 2014-2019.

Calculated to account for concentration change.

NCE, new chemical entity; UDI, Unapproved Drugs Initiative; WAC, wholesale acquisition cost

Estimated 2020 annualized U.S. health care spend since UDI.

Source: Vizient (bit.ly/3cYIx7J)

The sources reported no relevant financial disclosures.

Clinical

Pharmacy Practice News • May 2021

Nutrition

Pediatric PN Algorithm continued from page 1

appropriate initiation, weaning and discontinuation of PN at the hospital, the number of PN orders written per day declined from an average of 45 to 32, said Amber Pulido, PharmD, BCPS, BCNSP, a parenteral nutrition program pharmacist at the medical center. In addition, PN, which had been the most prevalent risk factor for CLABSIs, present in 49% of cases at the medical center, dropped to the fifth most prevalent risk factor, present in 29% of cases, Pulido reported at the virtual ASPEN 2021 Nutrition Science and Practice Conference (abstract 947414). In 2018, Pulido and her colleagues noted that growth in PN use was challenging the limits of their ordering system. They hypothesized that overprescribing of PN due to inappropriate initiation and/or duration was causing the high utilization. “Overprescribing of PN increases costs, compromises PN component supplies in an era of frequent shortages, and increases the risk of errors and complications including CLABSIs,” she said. One issue they observed was a hesitancy to prescribe enteral nutrition for children who didn’t want to eat but had a working GI tract, Pulido said. “It was perceived as more gentle to the patient to receive PN, when in actuality there’s a lot of risks associated with that.” I n t e r ve n t i o n e f f o r t s b e g a n i n February 2019, with an educational campaign. During monthly meetings of dietitians and pharmacists who wrote PN orders, the team first reviewed ASPEN consensus guidelines on when PN is appropriate (JPEN J Parenter Enteral Nutr 2017;41[3]:324-377) and discussed with them how the recommendations applied to their hospital patient population. One tip they gleaned: PN is indicated if an infant is going to be NPO for three days. They also provided education on the hospital’s goal to reduce CLABSIs and how PN is a risk factor for these infections, and conducted focused case reviews of recent PN patients who had contracted CLABSIs. Next, to ensure appropriate initiation, Pulido’s team asked dietitians to report all new start PN orders so they could audit them according to recommended clinical practice guidelines (JPEN J Parenter Enteral Nutr 2002;26 [6]:377-381). They also conducted random sample audits of active PN orders, looking for ongoing appropriateness, and celebrated prevented

inappropriate PN starts through monthly team meetings and weekly huddles among the dietitians.

The investigators recruited two internal multidisciplinary teams to help establish an algorithm for appropriate weaning and discontinuation of PN. One team drafted guidelines, and the other affirmed and validated those standards in relation to the hospital’s recent

YES

A Similar Plan

YES

Do NOT order a PN providing <20% PN goal kcalc

If oral intake is unable to advance to goal within 2-3 days of demonstrating adequate GI function, a feeding tube should be placed to facilitate weaning off PN.

For well-nourished otherwise well infants, consider discontinuation when EN expected to reach ≥ 60% goal kcal in the next 24 hours.

Unless severe malnutrition/malabsorption/very low birth weight.

Figure. Algorithm for appropriate pediatric PN use. EN, enteral nutrition; GI, gastrointestinal; NPO, nothing by mouth; PO, oral Source: JPEN J Parenter Enteral Nutr 2021 Mar;45(S1):S41-S43.

cases. The algorithm divided patients into those who were more nutritionally at risk and those who were more nutritionally stable, with a separate work flowchart for each group. The team implemented their new standards and audited all PN discontinuations, looking for alignment with the new algorithm. Over a five-month period from April to September 2020, more than 90% of PN discontinuations aligned with the algorithm. “Education and engagement were critical to our success with this [quality improvement] project,” Pulido said. “We were able to create a cultural shift where, instead of emphasizing only our patients’ unique needs for our most intense nutrition intervention, we brought into focus patients’ risks from overintervention. Whereas previously we might have talked about costs, workload or the virtues of the gut to try to discourage overprescribing of PN, we found that avoidance of patient harm was a powerful motivator for change.”

The approach that Pulido and colleagues took is reasonable, commented M. Petrea Cober, PharmD, BCNSP, BCPPS, a clinical pharmacy coordinator in the neonatal ICU (NICU) of Akron Children’s Hospital, in Ohio. Cober and colleagues worked on a similar plan regarding the use of starter PN solution for newborns in their NICUs. With multiple NICUs and three neonatology groups, some people’s interpretation of who needed the solution right away was broader than others, Cober said. Pharmacists developed a protocol for which patients most required it (lowbirthweight infants under 1,800 grams) and worked to educate the NICU and neonatology staffs. As a result, orders dropped significantly during the last three months of 2020. The protocol not only avoids potential errors but also helps the pharmacy stock less product, Cober said. Details were scheduled to be presented at the Pediatric Pharmacy Association’s virtual annual meeting in late April. “It’s good to be able to see pharmacists justify protocols at their own institutions,” Cober said. “With drug shortages, if you can judiciously use the products, then you know that the people who truly need it are going to get it.” —Karen Blum The sources reported no relevant financial disclosures.

More on parenteral nutrition: see insert after page 18.

20 Clinical

Pharmacy Practice News • May 2021

Oncology

Spotting Risk Factors Helps In CAR T-Cell Toxicity Fight

himeric antigen receptor (CAR) T-cell therapy is a rapidly expanding, promising treatment for a variety of adult and pediatric cancers, but it brings with it a number of significant toxicities, speakers said during the 2021 Critical Care Congress Virtual Event. The good news is that researchers and clinicians—including pharmacists—are starting to find characteristics that predict the risk for some severe toxicities, and several therapies are under investigation that may eventually decrease their rate and severity, said Julie Fitzgerald, MD, MACP, the co-director of the pediatric sepsis program at Children’s Hospital of Philadelphia. There are about six major toxicities associated with CAR T-cell therapy, said Stephen M. Pastores, MD, the program director of critical care medicine and vice chair of education at Memorial Sloan Kettering

4, as established by the American Society for Transplantation and Cellular Therapy (ASTCT), and includes antipyretics, IV fluids and oxygen (Crit Care Med 2020;48[1]:10-21). Additional treatments include the anti–interleukin-6 (IL-6) receptor antibody tocilizumab (Actemra, Genentech) for grade 2 or greater CRS, and corticosteroids for those with grade 3 to 4 CRS. Siltuximab (Sylvant, EUSA Pharma), a monoclonal antibody to IL-6, and anakinra (Kineret, Sobi), an IL-1 receptor antagonist, may be used in refractory cases. Clinicians also should consider infection and treat sepsis accordingly.

Best Practices Overall best practices include close observation of patients with regular, frequent assessments; having a process for rapid p treatment escalation and communication among ICU, oncology, nursing

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and pharmacy staff; having guidelines for management of complications; and conducting an infectious disease workup and empirical broad antimicrobial coverage in cases of concomitant infection, he said. ICANS typically occurs four to five days after infusion; previous severe CRS is the primary risk factor. Symptoms include encephalopathy, headache, tremor or seizures. The condition is marked by elevated levels of cytokines such as IL-6, interferon gamma and tumor necrosis factor-alpha, as well as elevated C-reactive protein. ICANS grading also is on a scale of 1 to 4, standardized by the ASTCT (Crit Care Med 2020;48[1]: 10-21). In addition, ICANS has an immune effector cell–associated encephalopathy score, ranging from 0 to 10. To calculate this, clinicians give patients cognitive tasks such as naming objects or writing a sentence. see CAR T-CELL, page 22

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22 Clinical

Pharmacy Practice News • May 2021

Oncology

CAR T-CELL continued from page 20

As for CRS, management of ICANS depends on the severity. Patients with grades 1 to 2 receive supportive care, brain imaging to rule out cerebral edema and electroencephalography to rule out seizures. Those with concurrent CRS should also receive tocilizumab. Patients with grades 3 to 4 also may benefit from corticosteroids, such as dexamethasone or methylprednisolone. Regardless of the toxicity, “the main

tenets for treating all patients are rapid recognition, rapid transfer to the ICU, vigilant supportive care and [accounting for the effect] of therapies on the viability of the T cells,” said Fitzgerald, who is also an assistant professor of anesthesiology and critical care at the University of Pennsylvania Perelman School of Medicine, in Philadelphia. “We want to support our patients and reverse their shock and dysfunction while still maintaining efficacy of the antitumor treatment.” The good news, she said, is that certain patient characteristics, such as

cytokine profiles and the degree of tumor burden, may help predict the risk for severe CRS, potentially allowing the identification of patient populations who could be targeted with treatments to prevent CRS.

High Tumor Burden a Red Flag In a study of 213 patients, adolescents and young adults treated with CAR T-cell therapy for leukemia were found to a have a sixfold increased relative risk for ICU admission if they had a high tumor burden, defined as having at least 40%

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bone marrow blasts before treatment, noted Fitzgerald, whose team presented the results at the 2019 annual meeting of the American Society of Hematology; a manuscript is in progress. The risk for ICU admission was 68% in patients with a high tumor burden versus 11% in those with a low tumor burden. Based on the identification of high tumor burden as a risk factor for severe CRS, Fitzgerald’s colleagues developed a separate clinical trial to study whether preemptive tocilizumab administered at the time of first sustained fever could reduce CRS development (J Clin Oncol 2021; in press). In the study, which included 70 children and young adults with relapsed refractory leukemia (55 with low tumor burden and 15 with high tumor burden), those with high tumor burden received one dose of tocilizumab after CAR T-cell therapy, then standard CRS care, while those with low tumor burden received just standard CRS care. Although all patients with high tumor burden still developed some degree of CRS, only 27 developed severe cases— about half the frequency of CRS in historical controls. Use of preemptive tocilizumab had no impact on CAR T-cell expansion or persistence, or long-term outcomes, Fitzgerald noted. Comparing the 15 patients receiving tocilizumab with 26 historical controls, those receiving the drug were less likely to be admitted to the ICU (53% vs. 69%), had shorter ICU length of stay (median, nine vs. 11 days), and had fewer median days requiring mechanical ventilation (six vs. 10) or vasoactive support (four vs. six; P=0.05), she said.

More Refractory CRS Options Additional treatments are being considered for refractory CRS, but they have limited data to support their use and are not yet included in guidelines, Fitzgerald noted. One such therapy is dasatinib (Sprycel, Bristol Myers Squibb), which may act as an on/off switch for CAR T cells and, therefore, for the cytokine storm that results from the expansion of these cells in the body after infusion, she said. CytoSorb (CytoSorbents Inc.), an external device that adsorbs cytokines and other molecules, is another, but it must be used in conjunction with continuous renal replacement therapy or extracorporeal membrane oxygenation. In one case report, a critically ill teenager treated with CytoSorb was ultimately extubated and discharged from the ICU (Crit Care Expl 2020;2[1]:e0071). The device needs further study and is not yet FDA approved for this indication, Fitzgerald noted. (In April 2020, the FDA granted an emergency use authorization for CytoSorb in patients 18 years of age or older with confirmed COVID-19

Clinical

Pharmacy Practice News • May 2021

‘A lot of discussions center on when to initiate steroids, which patients are appropriate for tocilizumab, and if patients are refractory, when do we increase steroids or consider additional treatments like anakinra.’ —Anne Rain Brown, PharmD admitted to the ICU with confirmed or imminent respiratory failure; www.fda. gov/media/136867/download.) Studies also are evaluating the use of anticytokine therapies for ICANS, she said. In one study, four of six adults with large B-cell lymphoma treated with anakinra had a clinical response (Blood Adv 2020;4[13]:3123-3127). Trials also are underway testing itacitinib (a Janus kinase1 inhibitor) for prevention of CRS and anakinra for prevention of ICANS.

of these patients and when we need to escalate therapies and add on [other agents],” she said. “A lot of discussions center on when to initiate steroids, which patients are appropriate for tocilizumab, and if patients are refractory, when do we increase steroids or consider additional

treatments like anakinra.” Some CAR T-cell therapies have “safety switch” products that clinicians can give to shut off the treatment, Brown said, but that involves detailed discussions with the treatment team and patient’s family, and generally is a last

Oncology resort because patients won’t get the benefit of the therapy. “We have to really weigh all the treatments and how they will affect the overall efficacy of the CAR-Ts in curing their disease.” Despite the toxicities, she said, CAR T-cell therapy is considered a groundbreaking treatment offering relapsed patients who would have had no chance of survival up to 50% to 80% cure rates. —Karen Blum The sources reported no relevant financial disclosures.

A Rare but Life-Threatening Toxicity Secondary hemophagocytic lymphohistiocytosis is another toxicity seen in patients undergoing CAR T-cell therapy, Pastores said. This life-threatening hyperinflammatory syndrome, which occurs in less than 5% of patients, also is seen with severe infections. Management depends on the level of organ toxicity, and can include anti–IL-6 therapy with tocilizumab and corticosteroids, similar to CRS regimens. Patients should be monitored closely and also can be treated with etoposide, IV immune globulin (IVIG), anakinra and other therapies (Nat Rev Clin Oncol 2018;15[1]:47-62). Another toxicity related to CAR T-cell therapy that clinicians need to watch for is prolonged cytopenias, which occur in some 30% to 40% of patients, Pastores noted (Leuk Lymphoma 2020;61[4]:940-943). Additional toxicities include the rare tumor lysis syndrome, marked by the release of large amounts of potassium or other elements into the blood after cell death. (The condition can lead to cardiac or renal problems.) Supportive therapies for tumor lysis syndrome include IV hydration and allopurinol or rasburicase (Elitek, Sanofi-Aventis) in patients with elevated uric acid. B-cell aplasia and hypogammaglobulinemia, which can lead to recurrent infections, are expected side effects of CAR T-cell therapy but also need monitoring, Pastores said. IVIG supplementation may be used in adults with recurrent infections (Lancet Oncol 2019;20[1]:31-42).

CAR-ICU Multicenter Effort Anne Rain Brown, PharmD, BCCCP, a clinical pharmacy specialist in critical care at The University of Texas MD Anderson Cancer Center, in Houston, has been part of a multicenter effort called CAR-ICU that has been researching these toxicities. “As pharmacists, we really look to make sure people are familiar with the grading

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24 Clinical

Pharmacy Practice News • May 2021

Oncology

Glucardipase Keeps CNS Lymphoma Rx on Track

new outpatient treatment regimen allowed patients with central nervous system (CNS) lymphoma to continue infusions during the height of the COVID-19 pandemic, and could change the way patients receive care after the current crisis subsides. Researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City found methotrexate could be coupled with repeated doses

‘It’s very interesting and exciting to see what researchers and clinicians are doing to try to move patients from an inpatient setting to an outpatient setting in a way that’s safe.’ —Lisa Holle, PharmD, BCOP

Got a minute? That’s all we need.

of glucarpidase (Voraxaze, aze, BTG International), and patients could safely receive eive the two treatments in an n outpatient setting, according ding to a study presented at the he 2020 Society for Neuro-Oncology logy virtual annual meeting. While the pandemic was surging in New York in thee spring 2020, many patients with ith CNS lymphoma canceled treatments because they were afraid to come to the hospital, missing potentially curative infusions, said Lauren Schaff, MD, a neuro-oncologist and neurologist at MSKCC and lead investigator on the research. “We just felt like that was not in the best interest of our patients and really not acceptable,” she said. Before the pandemic began, the investigators had started examining the safety and efficacy of low-dose glucarpidase to clear methotrexate from patients who received both medications in the hospital (abstract CTNI-61). Schaff and her team wanted to see whether glucarpidase could be given multiple times and stay effective for patients with new or recurrent CNS lymphoma without systemic involvement and renal failure.

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In the study, 12 patients received a total of 65 doses of methotrexate (28 doses of 3 g/m2, 26 doses of 6 g/m2 and 11 doses of 8 g/m2). Twenty-four hours after each methotrexate infusion, patients received glucarpidase, at 1,000 (20 doses) and 2,000 units (45 doses). The researchers found that glucarpidase led to a more than 95% reduction in serum methotrexate levels within 15 minutes 97.7% of the time after administration of 2,000 units of glucarpidase and 75% of the time after administration of 1,000 units. Four of 11 analyzed patients had anti-glucarpidase antibodies that were associated with reduced methotrexate clearance and methotrexate rebound. The researchers also analyzed the cerebrospinal fluid of seven patients and found potentially cytotoxic methotrexate concentrations remained in the fluid one hour and six hours after patients received glucarpidase. Glucarpidase was not detected in the cerebrospinal fluid of the seven patients tested. To Schaff and her team, these findings demonstrated the glucarpidase treatment was safe and did not cross the blood–brain barrier to interfere with the methotrexate response. They also noticed that patients who received glucarpidase could go home earlier than they would have been able to otherwise, Schaff said.

Clinical

Pharmacy Practice News • May 2021

Oncology Glucarpidase yielded

95%+ reduction in serum methotrexate

97.7% of time after dose of 2,000 units and

75% after 1,000 units Source: MSKCC

patients who need access to outpatient treatment as a result of the continuing pandemic and have started enrolling patients into a prospective study of this treatment approach in the outpatient setting. Schaff predicted, “I think certainly there’s going to be a place for this post-pandemic.” —Jillian Mock Holle reported no relevant financial disclosures. Schaff has her name on a patent pending for a lower dose of glucarpidase. BTG Specialty Pharmaceuticals provided the glucarpidase for this study.

When COVID-19 hit in March and April 2020, Schaff and her team quickly reconceived a follow-up study already in the works to accommodate patients who were unable to continue their inpatient treatment because of the pandemic. They opened the study to patients who had isolated CNS lymphoma and previously tolerated high-dose methotrexate. The study enrolled four patients who received a total of 10 methotrexate treatments (3.5 g/m2) in the outpatient setting with hydration. Patients came back 24 hours later for 2,000 units of glucarpidase and additional hydration. None of the patients required hospitalization, and in each case, methotrexate levels dropped to less than 100 nmol/L 48 hours after the dose. Two patients experienced grade 1 elevation of aspartate aminotransferase/ alanine aminotransferase levels over three treatments, and one had a grade 2 creatinine increase that was remedied with additional hydration. Patients really appreciated the outpatient option, Schaff said. “Every patient who received this treatment opted to continue the outpatient treatment as long as feasible.”

Some Centers Likely To Face Logistical Hurdles “It’s very interesting and exciting to see what researchers and clinicians are doing to try to move patients from an inpatient setting to an outpatient setting in a way that’s safe,” said Lisa Holle, PharmD, BCOP, an associate clinical professor at the University of Connecticut School of Pharmacy, in Storrs. However, moving these treatments to an outpatient setting likely will involve surmounting some logistical hurdles, Holle said. Many smaller institutions don’t have the laboratory capacity to process their own methotrexate, she noted. In addition, a new treatment like this could require additional training for infusion center staff, and the costs and cost-effectiveness of the treatment also need to be determined, she added. For now, the MSKCC researchers are continuing to study the safety and efficacy of this approach. They are treating

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26 Clinical

Pharmacy Practice News • May 2021

Anticoagulation

New Guidance for Managing DOAC-Related Bleeding A

new resource from the Anticoagulation Forum provides guidance on bleeding related to direct oral anticoagulants (DOACs), highlighting areas where pharmacists and other clinicians can promote stewardship of these agents and develop systematic approaches to facilitate ordering, delivery, administration and management of reversal agents. The resource “provides distilled, evidence-based guidance on appropriately identifying patients [who] might need reversal, and how to effectively manage those patients depending on which anticoagulant they take,” said

36% to 48%. Withholding anticoagulant reversal in DOAC-associated ICH leads to a 1.5-fold increased risk for death and poor outcomes (Front Neurol 2020;11:760), he noted. Thus, Kaatz stressed, patients should not leave the hospital after a bleeding event without a plan in place to restart anticoagulation through medication or other options, such as a Watchman device for stroke prevention.

Stopping a Bleeding Event The Anticoagulation Forum m resource can be used to inform m

standard supportive care and resuscitative measures always should be applied. Besides holding anticoagulation, consider mechanical intervention to stop bleeding events, the use of topical hemostatic agents, and replacing losses through transfusions or supplemental oxygen. The document divides its bottom-line recommendations into four actions: do, do not do, consider, or proceed with caution (Table). Regardless of the situation, Kaatz aatz advised clinicians to be cautious with h these reversal strategies because there are no comparison trials th

hospital, “so you can slowly escalate the intensity and get a repeat scan to ensure tolerability.” But she said that’s not always possible, especially for patients who have short hospital stays. Restarting therapy also is a good time for reeducation of patients, noted Kelly Rudd, PharmD, BCPS, the director of network pharmacy operations for Bassett Healthcare Network, a health system in New York. “Often patients may not be fully com compliant or [are] doing things or taking additional over-the-counter prodov ucts that may have u

Table. Bottom-Line Recommended Actions Do

Do Not

Consider

Be Cautious About

• Determine timing of the last anticoagulant dose. Depending on this, there may not be a lot of drug left circulating, so reversal may not be needed • Reverse life-threatening or uncontrolled bleeding with andexanet alfa (Andexxa, Alexion), if available, in patients taking apixaban or rivaroxaban (Xarelto, Janssen) and with idarucizumab (Praxbind, Boehringer Ingelheim), if available, in patients taking dabigatran • Form an anticoagulation restart plan or at least a stroke prevention plan

• Give FFP for DOAC reversal • Delay administration of reversal agents for life-threatening bleeding while awaiting lab results

• Reversing life-threatening or uncontrolled bleeding with PCC or activated PCC if a specific reversal agent is unavailable • Activated charcoal to absorb any anticoagulant drug taken within the previous 2 to 4 hours • Hemodialysis for dabigatran removal if the drug was taken recently and idarucizumab is unavailable • Lab measurements of DOACs if you can get them rapidly

• Potential thromboembolic risks with reversal • Reversal agent redosing due to limited safety and efficacy data

DOAC, direct oral anticoagulant; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate D S Source: Anticoagulation Forum.

Allison Burnett, PharmD, CACP, an antithrombosis stewardship pharmacist at the University of New Mexico Health Sciences Center, in Albuquerque, and the president-elect of the Anticoagulation Forum, a group of anticoagulant service providers in North America. Although DOACs are associated with improved safety compared with vitamin K antagonists, 2.1% to 3.6% of patients who took these agents in phase 3 clinical trials experienced major bleeding (Blood 2014;124[15]:2450-2458; Lancet 2014;383[9921]:955-962), noted Scott Kaatz, DO, MSc, one of the authors of the guidance document, during a webinar sponsored by the Anticoagulation Forum. The rate of major bleeding in atrial fibrillation/venous thromboembolism trials is about 2.0 per 100 patient-years (Blood 2019;133[5]:425-435), with the distribution being predominantly gastrointestinal bleeding versus intracranial hemorrhage (ICH), said Kaatz, a senior staff hospitalist at Henry Ford Health System, in Detroit. Pointing out the importance of 30-day mortality rates in DOAC-associated hemorrhages, Kaatz said between 9% and 20% of patients who bleed on anticoagulant therapy die within 30 days ((Eur Heart J 2015;36[20]:12641272). With intracranial hemorrhage (ICH), that percentage increases to

systematic approaches, such as DOAC reversal protocols to manage bleeding events, Burnett said. As agents are used, she added, the document recommends tracking and documenting efficacy and any adverse events. The guidance lists reversal strategies for dabigatran, rivaroxaban (Xarelto, Janssen), apixaban and edoxaban (Savaysa, Daiichi Sankyo), including timing and other considerations. It also discusses the role of laboratory tests to measure “clinically significant” DOAC levels that may contribute to bleeding. Such tests include assays to determine the concentration of DOAC in plasma, such as diluted thrombin time for dabigatran, and assays that can identify whether a clinically significant amount of drug is present, such as the DOAC Dipstick (DOASENSE), said guidance co-author Adam Cuker, MD, an associate professor of medicine and of pathology and laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia. But Cuker emphasized the importance of monitoring and treating the patient if and when it becomes indicated. “If isn’tt going to come back the lab result isn right away and the patient is having serious bleeding, don’t wait before making a decision whether to use a reversal agent.” In the setting of bleeding with hemodynamic compromise, Kaatz said,

in this setting. Be aware of thee potential thromboembolic risk isk with reversal, and be cautiouss about reversal agent redosing due to limited safety and efficacy data.

Restarting Anticoagulation In a panel discussion during the webinar, Kaatz, Cuker and other authors of the guidance document noted that clinicians commonly ask when it is safe to restart anticoagulation therapy after treatment of a bleeding event. “The anticoagulation indication did not go away, so we need to do something about that,” said Ronni Nemeth, PharmD, CACP, DPLA, the manager of the anticoagulation clinics at Confluence Health, a health system in Washington. “We defer to specialists, especially for ICH. We find out why bleeds happen, do some diagnostic testing and imaging, hopefully stop the bleeding, and then restart therapy.” For most indications, such as gastrointestinal bleeding, a two-week waiting period is appropriate before restarting, the panelists said. However, for very large ICHs, some clinicians wait up to four to six weeks, said Megan Barra, PharmD, cliniBCPS, BCCCP, a neurocritical care clini cal pharmacy specialist with Massachusetts General Hospital, in Boston. She said it is helpful to restart anticoagulation when a patient is in the

ccontributed to [the bleeding],” Rudd said. Panelists addressed whetheer size of the ICH should dictate tat treatment. Large intracerebral hemorrhages are the ones with the highest risk for hematoma expansion, Barra said, and for which anticoagulant reversal might not be enough to improve functional outcome and mortality rates. However, expansion also can occur with small hemorrhages and could have a large impact on long-term functional outcomes, she said, stressing that it needs “to be an individualized approach.” —Karen Blum The guidance document project was supported by Alexion. Kaatz reported relationships with Bristol Myers Squibb, Janssen, Novartis, Osmosis, Pfizer and Portola/Alexion. Cuker reported relationships with Alexion, Novartis, Novo Nordisk, Pfizer, Sanofi, Spark Therapeutics and Synergy. The other speakers reported no relevant financial disclosures.

The Anticoagulation Forum produces 12 rapid resource guides. For more information, go to https://acforum-excellence.org/ Resource-Center/index.php.

Clinical

Pharmacy Practice News • May 2021

Cardiology

Polypill Reduces Cardiovascular Risk Global implications, but less likely to affect U.S. patients

aily use of a polypill composed of a statin, a beta-blocker, an angiotensin-converting enzyme inhibitor and hydrochlorothiazide reduced the incidence of cardiovascular disease (CVD) in TIPS-3 (International Polycap Study-3).

hypotension or dizziness, than placebo (2.7% vs. 1.1%), but nonadherence to the polypill and placebo was similar: 19% at two years, 32% at four years and 43% at the end of the study. The polypill resulted in a 21% reduc-

‘In the U.S., this polycap would likely not provide the same benefits as using the best drugs for each individual patient and titrating the drugs to effect.’

CV Risk Reduction Polypill

—C. Michael White, PharmD

>21%

C. Michael White, PharmD, the department head and a distinguished professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs, agreed that the TIPS-3 findings have “important implications for developing countries where their access to medications, ability to fully monitor for cardiac risk factors and to titrate therapies to goals is reduced.”

Polypill + aspirin

>31%

In the trial, investigators randomly assigned 5,713 patients in a 1:1 fashion to receive either a daily capsule composed of simvastatin (40 mg), atenolol (100 mg), ramipril (10 mg) and hydrochlorothiazide (2 mg) or placebo, then further randomized them in a 2×2 fashion to receive daily aspirin (75 mg) or placebo. The trial included patients who had an intermediate risk for CVD (>1% per year) but no vascular disease. Men ages 50 years and older and women 55 years and older with an INTERHEART Risk Score (IHRS) of at least 10, and men and women older than 65 years with an IHRS of at least 5, were included in the trial. The majority of the patients were from India and the Philippines. The patients had an average age of 53.9 years; 53% were women. After a follow-up of 4.6 years, the polypill was associated with a 21% reduced incidence of the primary outcome of cardiovascular death, myocardial infarction, stroke, heart failure, cardiac arrest or revascularization (4.4% vs. 5.5%; hazard ratio [HR], 0.79; 95% CI, 0.63-1.00; P=0.05). The combination of polypill and aspirin also was associated with a reduced incidence of the primary outcome relative to placebo (4.1% vs. 5.8%; HR, 0.69; 95% CI, 0.50-0.97; P=0.031). The polypill resulted in a higher incidence of side effects, including

expect to see,” said Bhatt, the executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, in Boston. “So, I think there’s really merit in this approach.”

But “in the U.S., this polycap would likely not provide the same benefits as using the best drugs for each individual patient and titrating the drugs to effect. For instance, they used atenolol once daily, which is not the most effective way to use that beta-blocker, and simvastatin instead of the more potent atorvastatin,” White told Pharmacy Practice News. Beyond that, combining aspirin with the polypill “led to greater reductions in

tion in CVD, and the polypill and aspirin together resulted in a 31% reduction in CVD, according to the results of the study, which were presented at the American Heart Association (AHA) Scientific Sessions 2020 and published in The New England Journal of Medicine (2021;384[3]:216-218). The researchers noted that the benefits of the polypill and aspirin combined are greater (approximately 40%) in patients who did not discontinue treatment for nonmedical reasons and underscored that aspirin “contributes importantly” to these benefits.

‘Enormous’ Potential Public Health Benefits “If half of eligible people use a polypill with aspirin,” the authors estimated, 3 million to 5 million CVD events could be “avoided each year globally.” During an American College of Cardiology podcast highlighting top papers presented at the AHA meeting, Deepak L. Bhatt, MD, MPH, called TIPS-3 “a terrific study,” noting that “for certain health care systems, in certain regions of the world, it could make an enormous difference.” The reductions in risk seen in the study population “are believable because if you’re treating multiple risk factors at once, that’s sort of the effect sizes you’d

cardiovascular risk than the drugs alone,” White said, which “adds to the confusion surrounding the role of aspirin for primary prevention.” —Sarah Tilyou The TIPS-3 investigators reported financial relationships with Cadila Pharmaceuticals and the Wellcome Trust. White and Bhatt reported no relevant financial disclosures.

28 Policy

Pharmacy Practice News • May 2021

Finance

340B Restrictions continued from page 1

The manufacturer restrictions “began with Eli Lilly and have expanded to five other drug companies that have either stopped offering 340B discounts through community and retail contract pharmacies, or have placed restrictions on providing those discounts,” said Ted Slafsky, the former CEO of 340B Health, a membership organization representing nonprofit hospitals participating in the 340B drug pricing program. (The other manufacturers are AstraZeneca, Merck, Novartis, Sanofi and United Therapeutics.)

dozens of patients with diabetes who have either had to pay much more or change to potentially less effective regimens from other manufacturers that do not have these restrictions. The patients are very upset and feel like they are at the mercy of the manufacturers.” “We’ve been talking with groups representing people with type 1 diabetes, and their patients are telling us that they saw dramatic price increases on their insulin beginning at the end of last year,” said Peggy Tighe, JD, a prin-

‘In some instances, we do pass on dollarfor-dollar [340B] savings to the patients in a direct manner, but even when we don’t, we use those savings to … expand care to our vulnerable patients and to all patients in an equitable way.’ —Jessica Galens, PharmD As noted, one of the biggest areas affected is diabetes care because all three manufacturers of insulin are no longer providing 340B discounts at contract pharmacies. “Our hospitals’ Community Benefit Program allows us as a 340B-covered entity to pass 340B pricing directly on to eligible patients, who can get the drug at their pharmacy at the 340B price,” said Jahred Washington, PharmD, the 340B program coordinator at UCSF Medical Center, in San Francisco. “But because of this pricing being removed at the contract pharmacy level, we have had

cipal at Powers, Pyles, Sutter and Verville and legislative counsel to the Ryan White Clinics for 340B Access. Meanwhile, she noted that Eli Lilly’s announcement that its U.S. fourth-quarter revenue for 2020 increased 31%, to $4.598 billion, attributed some of that increase to “lower utilization in the 340B segment,” primarily for two diabetes medications, dulaglutide (Trulicity) and insulin lispro (Humalog). “You’re making millions off the backs of people not getting a targeted discount anymore, and you’re proud of that?” Tighe asked.

Washington and other pharmacy leaders from UCSF have met with the manufacturers, and the companies “held their ground,” he said. “They believe that what they are doing is equitable, and they do not believe that they need to participate with the 340B pricing program at contract pharmacies.” “Their take is that the 340B program has grown out of proportion and has gone unchecked, and that the savings don’t actually go to the patients,” UCSF Medical Center’s Galens said. “But the intent of the 340B program is very clear:

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to provide savings to covered entities that are providing care to these patients. In some instances, we do pass on dollar-fordollar savings to the patients in a direct manner, but even when we don’t, we use those savings to be able to expand care to our vulnerable patients and to all patients in an equitable way.” Tarsis Lopez, a spokesperson for Eli Lilly, disputed the 340B-covered entities’ claims. “Unfortunately, there continues to be a lot of misinformation circulating about 340B and some of the details have obfuscated the truth,” Lopez told Pharmacy Practice News. “The 340B program, which was meant to help underserved and low-income populations, has become a major source of profit to forprofit pharmacies, which obtain insulins at deep discounts and then sell them to patients at egregious markups,” Lopez said. “If a patient doesn’t receive 340B pricing, Lilly offers multiple affordability solutions through the Lilly Diabetes Solution Center so that anyone, regardless of their insurance status, can purchase their monthly insulin prescription for $35. Further, we also offer solutions that address numerous circumstances—such as donations to charities where people struggling financially can get their insulin for free.” Lopez added that although “the statute does not require manufacturers to offer 340B discounts to contract pharmacies, Lilly nevertheless will voluntarily sell to a contract pharmacy when its covered entity either does not have an in-house pharmacy or that contract pharmacy is wholly owned by the entity. We have crafted our policy to explicitly provide 340B pennypriced insulin to any contract pharmacy

Policy

Pharmacy Practice News • May 2021

Finance In 2017, tax-exempt hospitals participating in the 340B drug discount program provided

$64.3 billion in total benefits to their communities.a Source: American Hospital Association. a The most recent year for which this information is available.

that passes the discounts on to patients at cost—which is 15 cents for a 5-pack of 3-mL pens of Lilly’s most prescribed insulin and would cost most patients less than $1 for their monthly prescription.” Washington responded by noting that Lilly “will allow the covered entity to have one contract pharmacy with 340B pricing. Is it reasonable to expect all patients of a covered entity to use a single pharmacy? And their insulin policy sounds great at face value, but is difficult to operationalize. If Lilly wanted to provide this medication for less than $1, they would offer coupon cards to patients directly and wouldn’t make covered entities jump through hoops to gain access.”

Federal Efforts to Thwart Restrictions Fail As the debate over the 340B program continues, efforts to rein in the manufacturers’ 340B restrictions by the Department of Health and Human Services (HHS) and the Health Resources and Services Administration (HRSA) have so far been unsuccessful. Last December, HHS finalized the long-awaited 340B Administrative Dispute Resolution (ADR) rule setting up a process for challenging the restrictions. Then, on Dec. 30, 2020, the agency issued an advisory opinion that held the restrictions to be unlawful. “We conclude that to the extent contract pharmacies are acting as agents of a covered entity, a drug manufacturer in the 340B Program is obligated to deliver its covered outpatient drugs to those contract pharmacies and to charge the covered entity no more than the 340B ceiling price for those drugs,” wrote then–HHS

General Counsel Robert Charrow. Despite this opinion, as well as bipartisan letters from nearly 250 members of the House of Representatives and 28 senators, the manufacturers refused to yield. Eli Lilly, AstraZeneca and Sanofi filed complaints challenging the advisory opinion and ADR rule in Indiana, Delaware and New Jersey district courts, respectively. This year, on March 30, the U.S. District Court for the Southern District of Indiana granted Lilly’s request for an injunction against the ADR, noting that HHS and HRSA had not reopened a required comment period before issuing the ADR rule. “[The] agency’s message regarding the ongoing rulemaking related to the ADR Rule was ambiguous, confusing, duplicitous and misleading—the antithesis of fair notice under the APA [Administrative Procedure Act],” Judge Sarah Evans Barker wrote. So what’s next? It’s unclear whether HHS and HRSA will appeal the ruling, or reissue the ADR with a notice and comment period. In the meantime, experts say it’s unlikely that the six manufacturers that have placed contract pharmacy restrictions on 340B-covered entities will reverse their positions. HHS Secretary Xavier Becerra has yet to take any specific action on the 340B contract pharmacy restrictions in his new role, but as California’s attorney general, he spearheaded a bipartisan coalition of attorneys general who urged HHS to require drug manufacturers to provide the 340B discounts to contract pharmacies. “While Americans grapple with COVID-19, it is critical that we protect access to affordable care,” Becerra said in a statement (bit.ly/3seRFK1). “Discounts afforded under the 340B Drug Pricing Program are more critical now than ever. They ensure that low-income and uninsured patients have access to affordable medication as they deal with the substantial impact of [COVID-19]. We call on HHS to hold these non-compliant drug manufacturers accountable and provide immediate relief for health care centers and the Americans they serve.” Becerra’s stance is good news for covered entities, but it doesn’t mean an overnight resolution, noted Slafsky, who is now the publisher and CEO of 340B Report, a news service that focuses specifically on the 340B program. “It’s very likely that the court cases will have to play out. However, in the meantime, no additional manufacturers have moved toward restricting access, and I think if some of these advocacy efforts had not occurred, others would possibly have felt emboldened to restrict 340B discounts.” Even if the manufacturers are forced to reverse course, many of the losses experienced by covered entities and their patients will be impossible to recoup. “These restrictions have already been in place for more than six months, and even

if this were to be reversed, manufacturers don’t let you do a credit rebill for such a long time frame,” said Kristin Smith, a senior vice president for the Hospital & Health System Services Division at Visante, Inc. “We’re outside the window where [a credit] would even be feasible.”

Ryan White Clinics Vulnerable Ryan White 340B providers, such as the Damien Center, in Albany, N.Y., have been particularly hard hit. The center provides housing, food, mental health counseling and access to support services—including 340B drug discounts—for their clients, people living with HIV and AIDS. “We can purchase the medications our patients are refilling for them, and then capture the savings between the 340B discount and what the insurance companies pay in order to expand and create services for people who are underserved, which is what the federal law was intended to do,” said Perry Junjulas, the executive director. The center lost $80,000 in savings over just a three-month period as a result of manufacturers not honoring 340B pricing, Junjulas told Pharmacy Practice News. “Our overall budget is only $3 million, so that’s enormous to us,” he said. “Those are funds that we

were planning to spend on meals, housing, mental health counseling, transportation and medication adherence services. We’ve had to cut staff and reduce the amount of services we can provide. I can’t even tell you what this agency is going to look like in a year. I can tell you what the need will be, though: There will still be people walking up to my door, homeless and hungry and in need. That’s going to continue.” “We’re doing all we can to guide our patients through this very difficult health care environment,” UCSF Medical Center’s Washingon said. “We have a coordinator who does the legwork to help them find alternative therapies and set up appointments with providers to get their regimen changed. We will continue to care for our patients; we will not let them suffer. If we have to pay for their medications, we will do so, because it’s not about the money—it’s about the patients and their needs.” —Gina Shaw Tighe reported that she represents 340B providers/groups participating as covered entities in the 340B program and 340B service providers with whom they work. The remaining sources reported no relevant financial disclosures other than stated employment.

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30 Policy

Sterile Compounding

The Cost Equation for CSTDs

Serving managed care health-system and specialty pharmacy decision makers Brought to you by the same people who publish

Pharmacy Practice News • May 2021

an a hospital make a sound economic evaluation when it comes to purchasing a closed system drugtransfer device (CSTD)? A group of Canadian researchers say no. They claim the literature addressing the economic impact of CSTDs is sparse, and the evidence in the handful of studies that do tackle the issue lacks robustness (Eur J Hosp Pharm 2020;27[6]:361-366). But is there a potential for a comprehensive cost-effectiveness analysis of a disposable device that’s essential for preparing and administering hazardous drugs? Such data could be a major benefit to hospitals making the case to their C-suites for investing in the devices, which can cost hundreds of thousands of dollars per year for a high-volume cancer treatment center. Patricia C. Kienle, RPh, MPA, BCSCP, the director of accreditation and medication safety at Cardinal Health, told Pharmacy Practice News that the answer is yes. Furthermore, it is imperative to do so, she said, because “cost is the biggest barrier to adopting CSTDs.” But cost, Kienle said, should only be one piece of an equation that she termed the “big triad” of decision-making factors, which also include safety and efficacy. It’s the same trio that pharmacists use to assess formulary drugs, she noted. Safety may be the easiest aspect to evaluate. Despite what the Canadian researchers found in their review, Kienle said, “there are plenty of studies in the literature that say these devices absolutely work to protect personnel against contamination of chemotherapy when used correctly” (J Oncol Pharm Pract 2019;25[5]:1160-1166). Setting standards for assessing efficacy may be more challenging. After nearly four years of waiting, the National Institute for Occupational Safety and Health (NIOSH) still has not published the final unified testing protocol that could help hospitals decide which of the CSTDs they have under consideration—either the mechanical barrier types or the air-cleaning models—are most effective in preventing hazardous drug escape and personnel exposure. Then there’s the economics portion of decision making. Kienle ticked off three key determinants in weighing whether a purchase makes sense financially: the

price of the device itself; the available reimbursement; and the cost of antineoplastic drugs—a big-budget item that some health systems have tried to moderate by using CSTDs to optimize the value of single-dose drug vials through beyond-use dating (BUD). Unlike Europe and Canada, she said, in the United States device cost “is largely driven by which group purchasing organization the hospital uses. And sadly,” she added, “the decision is often made solely by materials management looking at which one is cheapest, without involving pharmacy and nursing to see which one works best in their organization. That’s a problem from a cost perspective.” As for reimbursement, Kienle noted that the CSTD economic study mentioned above was done by Canadian researchers and published in a European journal, but the way health systems get paid in this country is far different from Europe or Canada. Moreover, most health systems do rate safety and efficacy above cost when assessing CSTDs.

‘Safety, Quality and Accuracy’ At Cone Health, in Winston-Salem, N.C . , f o r exa m p l e, A n d re Ha r v i n , PharmD, the director of Pharmacy, Oncology Services, told Pharmacy Practice News that although cost was a consideration in deciding on a CSTD upgrade, “it was never from a ‘hey, this is going to save us money’ perspective.” “It’s a big pill to swallow,” Harvin conceded, referring to the cost of CSTDs, “but what we look at is the potential for preventing exposure to our technicians and nursing staff and reducing spills around the hood.” Last year in the midst of the COVID-19 pandemic, Harvin said, “we did look at the relative cost per component to find ways we could save money.” But the savings, he added, were “nothing earthshattering.” He drew a parallel between the benefits of CSTDs and Cone Health’s automated robotic compounding technology. The latter, he said, “is a multimilliondollar system that is not only a robot, but also provides gravimetrics for anything drawn up by hand.” He added: “That’s a hard return on investment to talk about. We justify it by safety and reducing low-level exposure for technicians.

Policy

Pharmacy Practice News • May 2021

‘I never get the argument of why you have to bring an ROI to the table for some of these [technologies]. Either you invest in quality and safety, or you don’t.’ —Andre Harvin, PharmD It’s safety, it’s quality, it’s accuracy that we’re really looking for.” The same standard applies to CSTDs, he said. “I never get the argument of why you have to bring an ROI to the table for some of these [technologies],” Harvin added. “Either you invest in quality and safety, or you don’t.”

compounding patient-specific doses.” But the challenge, he said, is performing the BUD stability studies required for every drug and concentration. “I would like to be able to do that here at WVU Medicine for a lot of our monoclonal antibodies because of their high cost,” he said.

Sterile Compounding He cited four examples of “drugs we were interested in pursuing”: polatuzumab vedotin-piiq (Polivy, Genentech), nivolumab (Opdivo, Bristol Myers Squibb), trastuzumab (Herceptin, Genentech) paclitaxel protein-bound (Abraxane, Bristol Myers Squibb), and applicable biosimilars. “The issue we’re running into is that they are large-molecule drugs; [it’s] not as easy as doing stability studies for regular molecule drugs like chemo,” Walker said. “The molecules are so large they require more sophisticated technology,

and that is very expensive and very difficult to do for a health system. So, that’s the main barrier of being able to show the financial value of using CSTDs for the new agents that make up the large percentage of the drug spend at oncology centers nationwide.” —Bruce Buckley Kienle is a member of the USP Compounding Expert Committee, but her comments in this article are her own and not those of USP or Cardinal Health, her employer. Harvin and Walker reported no relevant financial disclosures.

Free CME/CE now available! 1.0 AMA PRA Category 1 Credit™ 1.0 contact hour (0.10 CEU) of the ACPE 1.0 contact hour of the AANP (which includes 0.10 hour of pharmacology) A pharmacist uses a proposed NIOSH vapor containment testing protocol to evaluate the facility’s CSTD equipment.

Drug Vial Optimization The use of CSTDs for drug vial optimization (DVO) could help to offset part of the devices’ acquisition costs. But the practice remains controversial. It requires elaborate safety testing to prove the drugs remain stable and uncontaminated as a result of CSTD use. The tests are complex and remain beyond the reach of most hospitals. Kienle said accrediting organizations have been citing hospitals throughout the country for using the devices to extend vial BUD unless they have performed the required tests. Kienle said: “I really want this extended BUD to work, and I’ve been saying this for years. I want to save drug and I want to save money. But I wouldn’t do it at the expense of not knowing the safety to the patient.” Dmitry Walker, PharmD, the assistant director of Oncology, Infusion and Investigational Drug Services at West Virginia University (WVU) Medicine, in Morgantown, said the use of CSTDs for DVO would “give hospitals the potential to extend dating and realize cost savings by reducing the amount of wasted drug that is left over in each vial after

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32 Policy

Pharmacy Practice News • May 2021

Review Article

Source: ICU Medical Inc.

Lean Thinking For CSTDs FRED MASSOOMI, PHARMD, RPH, BCSCP, FASHP SETH EISENBERG, RN, OCN, BMTCN JIM JORGENSON, RPH, MS, FASHP St. Paul, Minnesota Visante Inc.

ean management principles have been used effectively in manufacturing scenarios for decades, particularly in Japan. More recently, the use of Lean concepts in health care1 has caught the

interest of regulators, who suggest that the discipline be a guide for training pharmacists who

are involved in pharmacy compounding procedures. One of those procedures—the use of closed system drug transfer devices (CSTDs)—may well be an under-recognized area for Lean applications. The first step is to understand the basics of Lean management principles. Lean thinking begins by driving out waste so that all work adds value and serves customers’ needs. Identifying value-added and non–value-added steps in every process is the beginning of the Lean initiative. More specifically, Lean thinking comprises five principles: 1) defining value, 2) mapping the value stream, 3) creating flow, 4) using a pull system and 5) pursuing perfection.2 Too often in our everyday work in health care, we don’t really think about these principles as we make decisions about technology or design work processes. Often, consideration for things such as value stream mapping only happens once something has broken and needs repair. But the application of Lean principles should be a consideration on the “front end” of technology selection and process design and should periodically be reevaluated for all key processes. By dismissing Lean principles, health systems lose the opportunity to benefit from its tool kit of efficiencies, consistency, safety and waste reduction. Also lost is the opportunity to improve complex processes while delivering substantial gains to the bottom line.3 Given those benefits, it’s not surprising that the use of Lean concepts in health care has caught the interest of the Massachusetts Board of Registration in Pharmacy, which has published “An Introduction and Guide to the Practices and Implementation of Lean Concepts in a Pharmacy Setting.” The document notes that “sterile compounding, complex non-sterile compounding, and institutional sterile compounding pharmacies shall ensure their employees are trained in lean concepts before renewing their pharmacy license.”4

Making the Initial Assessment Since the introduction of the first CSTD to the U.S. market in 1998, many new CSTDs have emerged, providing organizations with a variety of options that best fit their compounding and drug administration processes (Table). Preferred features of a CSTD, based on general Lean principles, would include intuitive connections, pre-bonded

components to limit the number of attachment/ disconnection steps, pre-purging displacement air into the system, wetting potential of filters, and locking mechanisms that clearly indicate complete connection. In addition, systems also should limit the pressure required to engage and disengage the components, thus reducing the risk for repetitive stress injuries. The risk for repetitive motion injuries is a concerning yet underappreciated issue with drug compounding.5 Each device is very unique in the number of components, component options, mechanism of protection, integration with existing systems and costs, and, thus, should be assessed individually as a system versus generically categorizing the devices as a “CSTD.” The overall effect

of integrating any device into medication safety systems must consider each end user’s use of the device(s), standard operating procedures, primary engineering controls, infusion pumps, disposal, staff perception of safety, number of components and overall costs. Another factor to consider is the FDA’s clearance code for CSTDs, “ONB.” The code is applied to devices that have indications for use with antineoplastic and other hazardous drugs. Regardless of their technology, all devices cleared by the FDA under the ONB code are considered CSTDs.

Lean Attributes of CSTDs Within updated USP Chapter <800> standards6 and nursing and pharmacy guidelines, the

Table. Closed System Drug Transfer Devices Device

Manufacturer

FDA Cleared

BD PhaSeal

Becton Dickinson and Company

1998

Spiros

ICU Medical Inc

2005

ChemFort or OnGuard with Tevadaptor

Simolivia Healthcare Ltd. B. Braun (U.S. Distributor) TEVA Medical Ltd (manufacturer)

2006

ChemoClave

ICU Medical Inc

2006

Equashield

Equashield LLC

2008

ChemoLock

ICU Medical Inc

2013

EquaShield II

Equashield LLC

2014

Halo

Corvida Medical Inc

2015

Arisure

Baxter International Inc

2017

BD PhaSeal Optima

Becton Dickinson and Company

2018

NeoShield

JMS North America

2018

ProSeal

Epic Medical Pte. Ltd

2020

Source: Visante.

Policy 33

Pharmacy Practice News • May 2021

Review Article introduction of CSTDs was mandated for antineoplastic drug administration and recommended for compounding of hazardous drugs. In deciding which CSTD to deploy and how to effectively integrate a CSTD into compounding and administration processes, it is useful to think about these processes in the context of the five Lean principles.

outside of hazardous drugs handling, where the noted Lean advantages can be applied to all sterile compounding, and the application of the devices to minimize potential medication waste through drug vial optimization programs.7 As the individual devices continue to evolve and the demand for sterile compounding continues to increase, CSTDs can serve as tools for growth.

1. Defining Value Value at the simplest level is the quality delivered plus the customer satisfaction at a defined cost. It is imperative for a new technology such as a CSTD to meet the actual needs of the users. To select the optimal product and integrate that most Figure. Almost all CSTD manufacturers effectively and efficiently into pharmacy make options that allow connecting and nursing practices, end-users have to integrated CSTD tubing with the IV bag. clearly understand what they want and the price they can afford. For a CSTD, this When these direct spikes (shown above) are used in compounding, they eliminate the need to prime tubing can be challenging because the technolin the biological safety cabinet. ogy has two main user groups in nursing and pharmacy, both of which come with different needs and elements driving satisfaction. The primary value proposition drug vaporous sprays, lapses in aseptic technique for both health care professionals in regard to and Luer line disconnections and spills, which can choosing a CSTD is protection—for their patients lead to delays in therapy and loss of revenue. and for themselves. Compounding and adminisFurther aiding flow, almost all CSTD manufactering medications require diligence in balancing turers make options that allow connecting intetimeliness and expected attributes while ensurgrated CSTD tubing with the IV bag. When these ing safety from needlesticks and exposure to direct spikes are used in compounding, they elimhazardous drugs. inate the need to prime tubing in the biological safety cabinet. This not only frees up pharmacy 2. Mapping the Value Stream or technician time but also removes large, bulky In value stream or process mapping, the goal items from the sterile compounding area. Examis to use the customer’s defined value as the ples of direct spikes can be seen in the Figure. desired end point and then to identify and map 4. Establishing Pull all the activities in the processes that contribute to these values. Activities that do not add value Inventory is considered one of the biggest to the end user would be identified as waste. The wastes in any production system. The goal of a waste can be further delineated into two catepull-based system is to limit inventory and workgories: non-value added but necessary and nonin-process items while ensuring that the requivalue added and unnecessary. The first category site materials and information are available for a should be reduced as much as possible, and the smooth workflow. The uniqueness of each CSTD second category is just pure waste and should be brings a significant variation in the number of eliminated to the maximum extent possible. components required for use. It is important to By reducing and eliminating unnecessary understand each component of CSTD systems to processes or steps in compounding and admindetermine which components are required for a istration, including the steps for CSTD applisite’s medication management processes. Value cation, users can improve the likelihood that stream mapping is a valuable tool to visualize the they are getting exactly what they want while number of steps requiring CSTD components and reducing their costs. In compounding, eliminatwhich components are required. If you do not have ing the concern for possible needlesticks, overall required components, this will result in delays, pressurized drug vials resulting in spills/sprays, frustrations and safety issues. The importance of and lapses in aseptic technique due to individnursing and pharmacy defining the specific CSTD ual variations with the use of traditional comcomponents and putting them together helps to pounding tools (ie, syringe in combination with understand what works for a particular site. a needle) are non-valued waste that may be 5. Pursuing Perfection eliminated by a CSTD. Waste is prevented or minimized through the 3. Creating Flow achievement of the first four Lean steps. The fifth After reducing wastes from the value stream, step of pursuing perfection makes Lean thinkthe next consideration is to ensure that the flow ing a continuous process improvement endeavor. of the remaining implementation steps runs Pharmacy and nursing should actively promote smoothly, without interruptions or delays. From and encourage continuous learning. As such, they the moment a CSTD is integrated from the vial, always should look to find ways to use CSTDs to it is in a system of “flow” from compounding, to make the process of hazardous drug compounddelivery, to administration and, finally, to disposing and administration safer, more efficient and al. Health systems that employ CSTDs minimize more cost-effective. angst by not having to worry about needlesticks, Future application of CSTDs includes use

Standard Work Another hallmark of Lean management is eliminating variations in practice that can lead to increased waste and decreased quality and safety. CSTD components are designed to be modular and integrated in such a way as to standardize a specified method of drug compounding and drug administration. In addition, a well-designed CSTD provides a safe method for flushing tubing after the drug has been administered.8 Since nurses do not have the benefit of working in the same type of contained, controlled environment associated with compounding, the proper use of CSTDs helps to prevent widespread environmental contamination in the patient care areas. In addition, the more intuitive a system is to use, the easier it is to lessen variances in compounding and to facilitate effective training. The device that integrates into pharmacy and nursing practices with perceived protection from both disciplines is the ideal CSTD. Other Lean attributes to consider are devices with the least number of components, packaging, steps for user-to-device interfacing, steps for device-todevice interfacing and drug transfer. These attributes should be fully vetted and validated at each site to ensure the advertised benefits of a specific CSTD meet the expectations of the staff using the devices. Ultimately, a CSTD should meet the efficiency needs of pharmacy and nursing with the benefits of saving time, controlling costs, minimizing line items and training.

References 1.

Going Lean in Health Care. IHI Innovation Series white paper. Institute for Healthcare Improvement; 2005.

2. Womack JP, Jones DT, Roos D. The Machine That Changed the World. Free Press; 2007. 3. Shaw G. The ‘Gemba walk’ and its role in compounding quality assurance. Pharmacy Practice News. June 25, 2020. Accessed March 16, 2021. bit.ly/3tsYxV0 4. The Commonwealth of Massachusetts; Executive Office of Health and Human Services; Department of Public Health; Bureau of Health Professional Licensure; Massachusetts Board of Registration in Pharmacy; Policy No. 2016013: An Introduction and Guide to the Practices and Implementation of Lean Concepts in a Pharmacy Setting. August 2016. Accessed March 13, 2021. bit.ly/3luAl1F 5. Abbot L, Johnson T. Minimizing pain resulting from the repetitive nature of aseptic dispensing. Hospital Pharmacist. March 2002. 6. USP General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings. Accessed April 6, 2021. www.usp.org/ compounding/general-chapter-hazardous-drugs-handlinghealthcare 7. Buckley B, Buckley J. Is drug vial optimization set to expire? Pharmacy Practice News. June 8, 2018. Accessed March 17, 2021. bit.ly/3qUg9aI 8. Polovich M, Olsen M. ONS Safe Handling of Hazardous Drugs. 3rd ed. Oncology Nursing Society; 2018.

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Pharmacy Practice News • May 2021

Finance

White Bagging Slammed continued from page 1

the medical benefit to the pharmacy benefit, barring the hospital from purchasing the drug itself and requiring that a prescription be sent to a payor-designated specialty pharmacy for fulfillment and shipment to the hospital. “A primary motivator for payors to adopt white bagging is that they can dictate who the purchaser of the drug is, mandating that the drugs come from a specific source—often a plan-affiliated specialty pharmacy that is not associated with the health system,” explained Kyle Robb, PharmD, a state policy and advocacy associate with ASHP, during a webinar on the topic. “They believe white bagging gives them more control in negotiating the pricing, reimbursement and distribution channels for these drugs.” White bagging has been around for years, but hospital and health-system pharmacies have reported an increase in the practice recently, with many of the white-bagging restrictions now being a mandatory component of the drug’s dispensing. The practice “is growing at astronomical rates of double digits per year,” Robb said. “More than 10% of the annual spend year-over-year is being shifted from the medical benefit to the pharmacy benefit for many of these drugs.” “White bagging takes formulary development and health system-specific policies and procedures around safety and completely disrupts this,” said David Chen, BSPharm, the assistant vice president for pharmacy leadership and planning at ASHP. “This process adds at least 10 extra steps for each patient unique for that payor, and this is happening with multiple payors. It runs counter to all Lean and patient safety models to reduce risk and ensure the best outcomes.” In addition to potential treatment delays and other difficulties for patients in accessing their medications, Chen noted that white bagging disrupts the ordering process and potentially introduces errors. “With the complexity of these treatments, a complete drug therapy plan is often built into our electronic health records, and this disrupts that. It also can require duplicate ordering and management [processes] because this is technically a patient’s own medication.” A representative of the FDA told Pharmacy Practice News that the agency “is aware of payor-mandated white bagging activities and is looking further into these and other models that may impact patient safety and supply chain security.” Chen said ASHP and its members are concerned that payor-mandated white bagging models are being described as cost-saving measures, but in reality are increasing the total cost of care and risks to patients due to significant added cost

to coordinate care, a negative impact on managing transitions of care, and medication waste resulting from misdirected and inappropriately dispensed white-bagged medications from payor-designated pharmacies. He added that cases of the detrimental effects of payor-mandated white bagging policies are mounting nationwide.

had delays in care because the specialty pharmacy didn’t have their drugs here on time. We do not have those delays when we order the drugs in advance through our wholesaler.” Hollabaugh estimated that the patients, three of whom are taking omalizumab (Xolair, Genentech/ Novartis) for asthma, one who is taking belimumab (Benlysta, GlaxoSmithKline) for lupus, and one who is taking rituximab (Rituxan, Genentech/Biogen) for

“[White bagging] adds at least 10 extra steps for each patient unique for that payor, and this is happening with multiple payors. It runs counter to all Lean and patient safety models to reduce risk and ensure the best outcomes.” —David Chen, BSPharm

‘We’ve offered multiple options for our [Blue Cross Blue Shield] in-network providers based on their feedback, including one that allows them to continue a “buy and bill” approach.’ —Natalie Tate, PharmD “ASHP is receiving case studies daily, ranging from a premature baby requiring palivizumab [Synagis, Sobi] for prevention of RSV [respiratory syncytial virus] that took over 13 days to resolve, patients who had their MS [multiple sclerosis] and RA [rheumatoid arthritis] treatment delayed by more than two months due to complications with the payor-designated specialty pharmacy, and medications being sent to the provider multiple days after the treatment dose was due.”

Cost Savings Questioned At Citizens Memorial Hospital and Health Care Foundation (CMH), in Bolivar, Mo., a rural health care network that provides care to the residents of eight counties in southwestern Missouri, 17 patients are currently affected by white bagging requirements. “They have a lot of frustration with the process,” said Mariah Hollabaugh, PharmD, the system pharmacy director. “At least five of those patients have had to be rescheduled and

RA, have experienced average treatment delays of one to two weeks due to white bagging. “When you are talking about conditions that flare up if there is a delay in a monthly medication, and you have the window for treatment delayed by up to 50%, that definitely affects their health,” she said. One patient, who receives IV iron for chronic anemia, hasn’t just had her treatment delayed—she hasn’t been able to get it at all since January. “We have the drug, but we aren’t allowed to supply it,” Hollabaugh said. “Their specialty pharmacy hasn’t been able to ship it to us for some reason, while we can get it from our wholesaler and could give it to her tomorrow. At some point, if we continue to be unable to get this drug through their specialty pharmacy, she will probably have to travel somewhere else to get her infusion. But that will mean more inconvenience for her; if we aren’t able to offer someone an infusion here, most of our patients have

to travel between 40 and 90 minutes one way to Springfield.” Smaller hospitals and health systems, such as CMH, are particularly affected by white bagging requirements because of their limited negotiating power. Truman Medical Centers/University Health in Kansas City, two hours northwest of Bolivar, also has faced pressure to accede to these arrangements. “It’s become more frequent over the last few months,” said Joel Hennenfent, PharmD, the chief pharmacy officer. “But our pharmacy team has successfully worked with finance to let the payors know that our policies do not allow that practice and our medical staff does not support it from a safety perspective. We then have to work at negotiating the contract to change the terminology to stipulate that we do not accept medications from outside our inhouse pharmacy for safety reasons.” But CMH is an 86-bed rural health care system and Truman is a 298-bed medical center with twice the patient revenue. “When you’re talking about a handful of patients per payor at our institution, they aren’t going to listen to us when we say no,” Hollabaugh said. “Their stance is that you have to use their pharmacy and there’s no wiggle room. Then, once the delayed product finally gets here, sometimes we get three months of doses because they overshipped to ‘rectify’ the situation from earlier. So, now we have storage issues as well as workflow problems. Our system is designed to charge for medications that we supply, so interrupting that and changing the coding adds to our process. We always have to maintain a list of patients for whom we have to undo our documentation, coding and billing. That doesn’t even touch on the thousands in lost revenue for not being able to bill on those medications, when we barely break even every year.”

The Payors’ Defense Payors argue that white bagging is saving money for patients. “In 2020, we delivered $10.2 million in savings to Tennessee employers through our Advanced Specialty Benefit Management program,” said Natalie Tate, PharmD, the vice president of pharmacy management for Blue Cross Blue Shield of Tennessee. “Using our specialty pharmacy network, our members can save money right away. Someone whose employer participates in this program and has a high-deductible health plan would see their share of the cost for a specialty drug drop for each visit. If a member is taking [infliximab], for example, they could see their cost drop by around $400 per treatment.” Tate also said that, for her organization at least, white bagging is not a requirement but a choice. “We’ve offered multiple options for our in-network providers

Policy

Pharmacy Practice News • May 2021

Finance based on their feedback, including one that allows them to continue a ‘buy and bill’ approach. We started by offering a six-month continuity of care program— essentially a transition period during the first half of 2020. During that time, we expanded our specialty pharmacy network and gave providers the option to join it. We had at least one large hospital system and six infusion centers join the network. We’re also offering ‘dispensing provider agreements’ to in-network providers. That’s like a middle ground. Providers can continue to buy and bill for

Brief Summary (For full prescribing information refer to package insert) INDICATIONS AND USAGE EXPAREL is indicated for single-dose infiltration in patients aged 6 years and older to produce postsurgical local analgesia and in adults 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 amidecontaining 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 6 years old for infiltration • patients younger than 18 years old for interscalene brachial plexus nerve block • 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 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 in All Local Infiltration Clinical Studies in Pediatric Patients Aged 6 to Less Than 17 Years The safety of EXPAREL in 110 pediatric patients between the age of 6 and 17 years old undergoing various surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site. Patients were administered a weight-based dose of EXPAREL at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg). In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritus, and tachycardia. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration were bradycardia, muscle spasms, tachypnea, hypoesthesia oral, anemia postoperative, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment. Adverse Reactions Reported in Nerve Block Clinical Studies The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled 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.

specialty drugs, but at the same rates as our in-network specialty pharmacies. But they don’t have to actually become or set up a true specialty pharmacy.” Delays in treatment should not be a problem, Tate said. “The specialty pharmacies in our network can deliver drugs in under 24 hours and make sure they’re handled appropriately based on the drug’s requirements. Because they are delivering individual doses just in time for treatment, these specialty pharmacies should also be prepared to handle any type of recall situation

Postmarketing Experience 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 coadministration 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 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 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. Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior to administration. Water and Hypotonic Agents 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 Summary 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 embryofetal 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)

as they fulfill orders for our members.”

‘Site-of-Care Dependent’ There is no simple answer or solution to white bagging; “it’s completely site-ofcare dependent,” said pharmacy consultant Bonnie Kirschenbaum, BSc, MS, a member of the Pharmacy Practice News editorial advisory board. “Some hospitals will be radically opposed to it and want to keep their buy-and-bill model, because the loss of revenue looms very large. But there are other facilities that want to retain patients and avoid a devastating

from implantation through weaning (during pregnancy and lactation). Lactation Risk Summary 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 The safety and effectiveness of EXPAREL for single-dose infiltration to produce postsurgical local anesthesia have been established in pediatric patients aged 6 years and older. Use of EXPAREL for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 6 years and older. Safety and effectiveness have not been established in pediatric patients aged less than 6 years old for local infiltration or less than 18 years old for interscalene brachial plexus nerve block. 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 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 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 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.

cost of product themselves, and stave off financial toxicity for their patients. They will take a completely different attitude toward white bagging.” Ms. Kirschenbaum pointed to a recent AIS Health Daily industry poll, which asked readers’ views on white-bagging policies: 50% of respondents supported the practice, 43% opposed it, and 7% were neutral. —Gina Shaw The sources reported no relevant financial disclosures.

• 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 Local Analgesia via Infiltration Dosing in Adults 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. Local Analgesia via Infiltration Dosing in Pediatric Patients The recommended dose of EXPAREL for single-dose infiltration in pediatric patients, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), and is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery. Regional Analgesia via Interscalene Brachial Plexus Nerve Block Dosing in Adults 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

March 2021

ADVANCING POSTSURGICAL PAIN MANAGEMENT AND RECOVERY Powered by DepoFoam® technology to deliver precise pain control for the critical ﬁrst few days after surgery MORE THAN

8 MILLION ADULT PATIENTS HAVE RECEIVED EXPAREL SINCE 20121

LEARN MORE AT WWW.EXPAREL.COM

Indication EXPAREL® (bupivacaine liposome injectable suspension) is indicated for single-dose infiltration in patients aged 6 years and older to produce postsurgical local analgesia and in adults 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 in adults with an incidence greater than or equal to 10% following EXPAREL administration via infiltration were nausea, constipation, and vomiting; adverse reactions reported in adults with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation. Adverse reactions with an incidence greater than or equal to 10% following EXPAREL administration via infiltration in pediatric patients six to less than 17 years of age were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritis, and tachycardia. 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 populations: patients <6 years old for infiltration, patients younger than 18 years old for interscalene brachial plexus nerve block, and/or pregnant patients. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the 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 ©2021 Pacira BioSciences, Inc. Parsippany, NJ 07054 PP-EX-US-6517 03/21

blocks other than interscalene brachial plexus nerve block, or intravascular or intra-articular use. 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, please visit www.EXPAREL.com or call 1-855-793-9727. Reference: 1. Data on File. 6450. Parsippany, NJ: Pacira BioSciences, Inc.; January 2021.

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