Pharmacy Practice News - July 2021 by McMahon Group



The Best-Read Pharmacist’s News Source

pharmacypracticenews.com

Genotyping Not Yet Appreciated As ChemoRx Tool

CLINICAL

Ketamine comes to the rescue in ICU ......

COVID-19 today: Rx lessons learned .......... 6 New genitourinary cancer advances ..........

TECHNOLOGY

Reforming medication management via health IT innovation ...

harmacogenetic testing for DPYD and UGT1A1 gene variants could cost-effectively prevent severe chemotherapy-related toxicity, but there are barriers to its uptake, two research teams reported at the 2021 Gastrointestinal Cancers Symposium. “Pharmacogenetic, or PGx, variants in the DPYD and UGT1A1 genes are known to be associated with fluoropyrimidine and irinotecan toxicity, respectively. PGx testing prior to starting chemotherapy has been proposed as a way to safely guide the dosing of these drugs, but this strategy is rarely used in routine care,” said Kelsey S. Lau-Min, MD, a fellow in hematology/oncology at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia. “We found that clinicians expressed favorable attitudes toward PGx testing but cited multiple barriers to

POLICY

Raising the SBAR for safer cleanrooms during COVID-19 ..........

Continued on page 12

SPECIALTY PHARMACY

7 habits of effective COVID-19 managers ...

REVIEW ARTICLE

Opioids, cold chain among revamped areas

What’s New In Accreditation For Specialty

Safe to Touch Guidelines: A Plan for Implementation See page 26.

xecutives from two leading specialty pharmacy accreditation organizations shared the latest information on new and reorganized standards and credentials, along with advice for specialty pharmacies on managing the accreditation process, during the ASHP 2021 virtual Specialty Pharmacy Conference. In 2019, ASHP began revising its Telehealth Pharmacy Practice (TPP) Continued on page 24

Volume 48 • Number 7 • July 2021



Safety, efficacy, high cost questioned

Experts Confused by FDA Alzheimer’s Drug Approval

s news of the FDA’s decision to approve aducanumab for Alzheimer’s disease under its accelerated approval pathway spread, critics were just as rapid in expressing their astonishment that the agency could have given its nod to a drug with such spotty clinical trial data. Coupled with major concerns about cost, including Continued on page 29

Education gaps, payor discrepancies addressed

Pharmacists Show Their Skill In Easing Biosimilar Switches M anaging biosimilar adoption and utilization has become almost a specialty in itself for many health-system pharmacists, experts told attendees at the ASHP 2021 virtual Specialty Pharmacy Conference. “There are multiple challenges, including regulatory issues, unique formulary management considerations, forecasting coverage and reimbursement, and education of providers, which are very different when it comes to biosimilars compared with small-molecule product or originator biologics,” said Isha Rana, PharmD, a pharmacy administrative

MAD-ID Roundup Antibiotic stewardship, C. diff, penicillin allergy and more. See pages 10–11.

specialist in formulary management and drug information at Houston Methodist, who presented at the ASHP meeting. Even something as apparently straightforward as FDA approval is much more complicated with biosimilars, Dr. Rana told Pharmacy Practice News. When an innovator product is approved by the FDA, the company is then typically free to bring it to market for the approved indications. But for biosimilars there’s another hurdle, or set of hurdles: the courts. Continued on page 17

WITH A REVOLUTIONARY 10-MINUTE HAZARDOUS DRUG TESTING SYSTEM. At BD, healthcare worker safety is an utmost priority. The same is true of developing new technologies to help you quickly identify and address hazardous drug contamination. The BD ® HD Check system gives you a new breakthrough technology that lets you easily monitor and identify surface contamination in less than 10 minutes *, not the days or weeks that conventional testing technologies require. The result? A fast, new way to stay on top of contamination monitoring and adherence to your healthcare worker safety policies—for a difference your team will appreciate. Discover the confidence of test results in minutes, not weeks. Discover the new BD.

Identify surface contamination in LESS THAN 10 MINUTES* Now detecting cyclophosphamide, doxorubicin and methotrexate

Learn how to better protect your team at bd.com/bdhdcheck *For select hazardous drugs. BD and the BD Logo are trademarks of Becton, Dickinson and Company or its affiliates. © 2020 BD. All rights reserved. BD-5049 (1/20)

Up Front

Pharmacy Practice News • July 2021

Liked/

Trending

Digital

Retweeted

@PharmPracNews

The top 5 articles On Pharmacy PracticeNews.com

Kienle’s 10 New Building Blocks of Compounding Safety

Top 10 Errors Related To COVID-19 Vaccination

Drug Diversion on Radar Of the Joint Commission

Why Is It Difficult to Discontinue Use of Some Antidepressants?

Steps to an ‘A’ Grade In Sterile Compounding June 2021

New Multimedia Feature!

PPN on Instagram! Pharmacy Practice News is now on Instagram. Check us out here and hit follow! https://www.instagram.com/ pharmpracnews/

In the inaugural “One Burning Question” video, Keith Streckenbach asks Herschell Hitchcock, an expert on health care engineering, one burning question: If my cleanroom looks clean, why doesn’t it pass muster? If you have one burning question you’d like answered, send it to Keith at keith@ pharmacystars.com.

To receive breaking news, as well as announcements and links to all of our multimedia content, be sure to sign up for our twiceweekly e-newsletter at www. pharmacypracticenews.com/ Registration

EDITORIAL BOARD

ART/PRODUCTION STAFF Michele McMahon Velle, MAX Graphics/Creative Director

ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

Frank Tagarello, Senior Art Director/Managing Director MAX Graphics

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

Volume 48 • Number 7 • July 2021 • pharmacypracticenews.com

Indu Lew, PharmD, Livingston, NJ

James O’Neill, Senior Systems Manager Marty Barbieri, Associate Director of Production

AMBULATORY CARE Meghan D. Swarthout, PharmD, MBA, BCPS, Sallston, MD ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL

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

EDITORIAL STAFF

Leona Smith, Production Associate

David Bronstein, Editorial Director davidb@mcmahonmed.com

Rob Sinclair, Circulation Manager

Marie Rosenthal, MS, Senior Editor mrosenthal@mcmahonmed.com

Van Velle, President, Partner

McMAHON PUBLISHING

Vanessa Kumpf, PharmD, BCNSP, Nashville, TN

David S. Craig, PharmD, BCPS, Tampa, FL

ONCOLOGY Cindy O’Bryant, PharmD, Aurora, CO

Robert L. Barkin, MBA, PharmD, Chicago, IL CARDIOLOGY C. Michael White, PharmD, Storrs, CT

Lisa Holle, PharmD, Farmington, CT

Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Partners

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Ali McBride, PharmD, MS, BCPS, Phoenix, AZ

CNS/PSYCHIATRY Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE Cathy Rosenbaum, PharmD, Cincinnati, OH CRITICAL CARE Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Sara S. Kim, PharmD, BCOP, New York, NY

Kevin Horty, Don Pizzi, Adam Marcus, Contributing Editors

ORGAN TRANSPLANT PHARMACY Eric Tichy, PharmD, BCPS, New Haven, CT

James Prudden, Group Editorial Director

PEDIATRICS Gretchen Brummel, PharmD, BCPS, Hudson, OH

Ray and Rosanne McMahon, Co-founders

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

Elizabeth Zhong, Senior Copy Editor Kristin Jannacone, Copy Editor

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

SALES

REIMBURSEMENT Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

David Kaplan, Group Publication Director dkaplan@mcmahonmed.com

SPECIALTY PHARMACY JoAnn Stubbings, BSPharm, MHCA, Chicago, IL

Sarah Rezvani, Account Manager srezvani@mcmahonmed.com

Elaine Strauss, PharmD, MS, Atlanta, GA

STERILE COMPOUNDING Kristina N. Bryowsky, PharmD, MBA, BCPS, Fenton, MO

Joe Malichio, Director, Medical Education jmalichio@mcmahonmed.com

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

TECHNOLOGY Thomas Van Hassel, RPh, Yuma, AZ

Craig Wilson, Sales Associate, Classified Advertising cwilson@mcmahonmed.com

INFECTIOUS DISEASES Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH David P. Nicolau, PharmD, Hartford, CT Jason Pogue, PharmD, Detroit, MI LEADERSHIP Ernest R. Anderson Jr., MS, RPh, Boston, MA

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 receive the publication, you must add your professional address or make your address change directly with Pharmacy Practice News Circulation Dept., 545 W. 45th St.,

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

8th Floor, New York, NY 10036. You can also fax your request to (815) 366–8297, or send it via email, circulation@mcmahonmed.com. If you are not a hospital pharmacist but would like to receive Pharmacy Practice News, please send a check for $70.00 (U.S.) or $90.00 (outside U.S.) for a year’s subscription payable to Pharmacy Practice News to McMahon Publishing, 545 West 45th St., 8th Floor,

Copyright © 2021 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to 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.

New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. Individual issues are $9.00 (U.S.) or $12.00 (outside U.S.). Founded in 1972, McMahon Publishing is a family-owned medical publisher of clinical newspapers and specialty periodicals, and creates continuing medical education programs and custom publications.

4 Clinical

Pharmacy Practice News • July 2021

Critical Care

Ketamine a Reasonable Rescue Sedative in ICU C

ontinuous infusion (CI) ketamine is a reasonable alternative for ICU patients failing to respond to traditional sedative and analgesic regimens, a study has concluded. When patients refractory to other sedative agents are switched to CI ketamine, there is an increase in the proportion of time spent within goal pain and sedation ranges and a reduction in the use of other sedatives, according to pharmacists at medical centers and university hospitals across the country who undertook this large multicenter, retrospective observational study. “There’s a lack of literature out there that guides us on what to do” when using CI ketamine in the ICU, according to Christine M. Groth, PharmD, BCCCP, the lead author and a clinical pharmacy coordinator for adult critical care and emergency medicine at the University of Rochester Medical Center, in New York. The pharmacists conducted the study to gain a better understanding of how to use ketamine in the ICU, she said. The researchers looked at pain and sedation scores, delirium screenings, and opioid and sedative requirements in the 24 hours before ketamine initiation, comparing that with the first 24 hours of a ketamine infusion and the 25 to 48 hours after an infusion, Dr. Groth said. The researchers evaluated 390 adult ICU patients at 25 institutions who received CI ketamine between January 2014 and December 2017. Their average age was 52 years; 61% were men; and they were mostly medical, surgical and trauma patients. Eighty percent received mechanical ventilation, with 34% requiring vasopressors. Of the 390 patients, 357 (91.5%) received ketamine for pain and sedation. During the 24 hours before CI ketamine, the first 24 hours after CI, and the 25 to 48 hours of CI, pain scores were recorded for 285 (85%), 293 (87%) and 178 (90%) patients, respectively. The researchers saw a significant increase in median time spent within a goal pain score range after CI ketamine initiation, with increases of 68.9% (66.7%-72.6%) in the pre–24-hour group, 78.6% (74.3%82.5%) in the first post–24-hour group, and 80.3% (74.6%-84.3%) in the 25- to 48-hour group (P<0.001). Sedation scores were recorded in 278 (80%), 304 (87%) and 182 (88%) patients in the 24 hours before, the first 24 hours during, and the 25 to 48 hours of CI ketamine, respectively. “There was a significant increase in median time spent within goal sedation score range after ketamine initiation (24 hours prior: 57.1% [52.5%-60.0%], first 24 hours:

‘They may be worth the risk if by providing better control of pain and agitation we are able to shorten time on the ventilator and in the ICU.’ —Christine M. Groth, PharmD, BCCCP

64.1% [60.7%-67.2%], 25-48 hours: 68.9% [65.5%-79.5%]; P<0.001),” the researchers said.

Passing the Delirium Test A delirium screening was done in the 24-hour time frames for 110 (45%), 115 (46%) and 59 (41%) patients, respectively. The researchers found no difference in median time spent with delirium among these patients after ketamine initiation (24 hours before, 43.0% [17.0%-47.0%]; first 24 hours, 39.5% [27.0%-43.8%]; 25 to 48 hours, 0% [0%-43.7%]; P=0.233). In addition to a significant improvement in the percentage of time patients spent in goal pain and sedation ranges, the study found the addition of CI ketamine had no effect on the incidence of delirium. However, Dr. Groth told Pharmacy Practice News that may be because, as the study found, delirium screenings were underperformed. “In recent years, ketamine has had increasing use as an adjunctive agent for sedation and pain control, but data supporting its use as a continuous infusion in the ICU and defining appropriate dosing is lacking,” said Lars-Kristofer N. Peterson, MD, an attending physician and assistant professor in the Departments of Medicine and Emergency Medicine at Cooper University Hospital and Cooper Medical School of Rowan University, in Camden, N.J. Dr. Peterson was not part of the study. “This important study by Groth and colleagues identifies a number of hypothesis-generating findings, including improved time within pain goals without

an increase in delirium,” Dr. Peterson said. “Should these findings be replicated, ketamine could serve as an alternative to dexmedetomidine or propofol as a first-line agent for management of pain and agitation in the ICU.” Given the relatively neutral hemodynamic profile of ketamine compared with dexmedetomidine and propofol, “there are critical care situations where a clinician may prefer its use over more traditional medications,” Dr. Peterson said. “This study is a significant first step to determining how ketamine is best used in the critically ill and injured.”

Worth the Risks? Clifford M. Gevirtz, MD, an anesthesiologist affiliated with Phelps Memorial Hospital Center, in Sleepy Hollow, N.Y., gave a broader and more critical view of ketamine. “While I agree that ketamine is an excellent analgesic and may have a role in ICU sedation, I would draw the opposite conclusion as to its utility,” he said. “Increased secretions translate into increased need for suctioning, which you don’t see with propofol, benzodiazepines or dexmedetomidine. Emergence delirium has long been associated with ketamine and is not an issue with the other common sedative agents. The 5% reported incidence is in line with historical averages. In ICU patients, delirium may have several other causes and might lead to further unnecessary testing.” Dr. Gevirtz added that long-term ketamine use has been associated with cystitis and advised a “healthy amount of caution” before using it.

“I understand the concerns addressed, but all drugs have the potential for harm, and we have to weigh the risks and benefits,” Dr. Groth said. “I don’t feel our study answers the true risk versus benefit of ketamine, but some of the concerns addressed may be worth the risk if we are able to keep patients more calm and awake with better pain control.” Dr. Groth agreed that increased secretions and the need for anticholinergics are concerns, but “they may be worth the risk if by providing better control of pain and agitation we are able to shorten time on the ventilator and in the ICU.” Additionally, it is unknown how ketamine compares with benzodiazepines regarding delirium, she said. “There are several studies of ketamine for various indications that continued for several days with no reports of cystitis,” Dr. Groth said, adding that the reports she saw were a result of long-term recreational abuse of ketamine. “We definitely need more data to know the true risk,” she agreed. Ketamine was continued for a median of 1.6 days in their study, which is consistent with other reports on the use of ketamine for analgosedation in the ICU; Dr. Groth said she doubts whether this was a true concern. The study was a STAR research presentation at the Society of Critical Care Medicine’s 2020 Critical Care Congress in Orlando, Fla. (abstract 48). —Tom Rosenthal Drs. Groth, Peterson and Gevirtz reported no relevant financial disclosures.

Investing

More in America to Serve You Better

As a leading supplier of U.S. sterile injectable medicines, Fresenius Kabi is focused on delivering the support our customers need today and, just as important, preparing for what may come next. Over the last several years, we have been doing More in America to help us serve customers and patients better. We’ve invested nearly $1 billion in U.S. manufacturing facilities – in Illinois, New York and North Carolina – and in new pharmaceutical distribution centers throughout the U.S. This network expansion can help us more rapidly adapt to shifting customer needs – right here in the United States. To learn more about how Fresenius Kabi is doing MORE IN AMERICA, go to www.fresenius-kabi.com/us/company/more-in-america.com

6 Clinical

Pharmacy Practice News • July 2021

COVID-19 Pandemic

COVID-19 Management Today: Lessons Learned

ince epidemiologists reported the first case of COVID-19 in the United States in January 2020, there have been several clinical lessons learned. That’s certainly the case in ICUs, where critical care pharmacists are on the front lines of treating the most severe cases. John W. Devlin, PharmD, a critical care specialist at Brigham and Women’s Hospital, in Boston, agreed there is a clear difference in how COVID-19 was

managed in the early months of the pandemic versus now. Back in March and April 2020, there were no treatments with proven value, except for supportive care and ventilation. People were coming in by the thousands in some places, with alarmingly low oxygen saturations. Ventilator support was offered aggressively and early, he noted. In addition, hospitals were well beyond capacity. The COVID-19 census in one

New York hospital in April 2020 was around 2,000 patients. As of late June 2021, in contrast, the total number of daily COVID-19 cases in all New York City hospitals was approximately 200 (on.ny.gov/3wzu5ur). There also was a lot of fear, Dr. Devlin explained, which led to greatly reduced interaction between ICU staff and patients. Hospitals were overrun, and staff were brought in from other areas

because there just were not enough bodies to handle the crisis. Even the best OR nurse may have challenges in delivering exemplary patient care in an ICU where they have never practiced, particularly in a pandemic, Dr. Devlin noted (Crit Care Explor 2020;2[6]:e0149).

Abandoning the Bundle Under normal circumstances, most hospitals practice the ABCDEF bundle

(awakening and breathing coordination, delirium monitoring/management and early exercise/mobility), which is an evidence-based, interprofessional strategy to minimize the use of sedatives, reduce the duration of mechanical ventilation and lower the risk for delirium in the ICU (Crit Care Clin 2017;33[2]:225-243). The bundle often went by the wayside due to a surge in ICU cases, personal protective equipment shortages, the use of non-ICU clinical staff to provide care, and a lack of knowledge about COVID-19 transmission and aerosolization. Today, thanks to new knowledge about strategies for managing severe hypoxemia in COVID-19 patients before intubation and mechanical ventilation are considered, along with the important roles of dexamethasone and other pharmacologic interventions, health care providers have proven approaches to shorten the time spent in the ICU, and to reduce post– intensive care syndrome and other postICU sequelae, Dr. Devlin said. “What was happening in the spring is everybody was immediately like, ‘Oh my God, their oxygen’s where? We need to ventilate them right away.’ Now, we’re waiting and doing other things to try to optimize their oxygenation before we intubate,” Dr. Devlin said. “What we see a lot now is these patients with horrible numbers are still actually stable enough” to just receive nasal cannula oxygen. Susan M. Mashni, PharmD, of the Icahn School of Medicine at Mount Sinai, in New York City, decribed a similar experience. “When we first encountered COVID-19, patients were intubated early in the course of their disease,” she said. “We were trying to respond

Clinical

Pharmacy Practice News • July 2021

COVID-19 Pandemic to something that was happening very quickly, but was not part of normal medical treatment.” Intubated patients needed extremely high doses of anxiolytics and sedatives, she added. “If we had to paralyze the patient, then we had to use really high doses of paralytics.” Dr. Mashni and her colleagues now are using fewer paralytics, avoiding deep sedation more often, getting back to pre– COVID-19 mobility efforts and introducing family members back to the bedside. Consistent use of the ABCDEF bundle is again an essential part of ICU care.

overwhelming feeling of fatigue, and just the inability to really sit down and keep on a task for a long period.” Although there is no cure for post– COVID-19 syndrome, there are medications that can be prescribed to help alleviate some of the symptoms.

Prescribe With Care These treatments need careful consideration, noted Allison Navis, MD, an assistant professor in the Division of Neuro-Infectious Diseases at the Icahn School of Medicine, who also spoke

at the IDSA briefing. For instance, if a person is suffering from depression and post-traumatic stress disorder and can’t sleep, a drug that might be sedating might be considered, but it might not be appropriate for someone who reports depression and fatigue. This is where a pharmacist could play an important role on the team, ensuring that the medications subscribed by various specialists work together to improve the situation, Dr. Mashni said. Some of the best medicine is to listen to patients and understand what they are going

through as they try to put their lives back together, she stressed. “We need to take this seriously,” said Rajesh T. Gandhi, MD, the director of HIV clinical services at Massachusetts General Hospital, in Boston. “Many millions of people have been infected. Many will resolve on their own, but not all of them will, and we need to help them.” —Marie Rosenthal The sources reported no relevant financial disclosures.

Long-Haulers There also have been valuable lessons learned about COVID-19 “long-haulers,” patients who continue to experience myriad sequelae long after the acute phase of disease. Researchers from Wuhan, China, have found that 76% of patients still experienced some symptoms at the six-month follow-up after discharge (Lancet 2021;397[10270]:220-232). For many patients, preexisting conditions make them much more susceptible to a prolonged COVID-19 course. “We’re seeing a lot of people, for instance, with diabetes, with obesity, with hypertension, which predisposes them to having more severe infections with COVID-19,” said Kathleen Bell, MD, chair of the Department of Physical Medicine and Rehabilitation at The University of Texas Southwestern Medical Center, in Dallas. Those chronic conditions often worsen in the presence of COVID-19 disease, Dr. Bell added. Patients with hypertension, for example, might develop chronic microvascular disease in the brain. Those with diabetes could experience chronic neuropathy in their extremities, she explained at a press briefing sponsored by the Infectious Diseases Society of America. The disease itself can cause “all sorts of problems with inflammatory responses in the brain, around the heart, around the muscles, etc.,” she said. Dr. Mashni has seen this syndrome play out in her own institution. “We’ve had patients struggle with lung function, and with the ability to walk distances or having the ability to just have day-to-day functionality,” she said. “And, of course, [there’s] the post-COVID brain fog that people talk about, with neurologic difficulties in their inability to concentrate,

Same 20% Benzocaine, NEW LOW PRICE. Compare with Hurricaine One®

To order Allevacaine®, contact your Distributor. Allevacaine® Unit Dose 20% Benzocaine NDC 10223-0700-1

A new Standard of Value

• 20% Benzocaine–same active ingredient as Hurricaine One® • Single-unit dosing virtually eliminates cross contamination • Utilizes Bar Code Medication Administration (BCMA) Hurricaine One® is a registered trademark of Beutlich® Pharmaceuticals LLC

8 Clinical

Pharmacy Practice News • July 2021

Cardiology

IV Ferric Agent a Potent Addition to HF Therapy A

dd in g I V ferric carboxymaltose to traditional standard therapy can improve outcomes for patients with heart failure (HF) with reduced ejection fraction and iron deficiency, according to results from the AFFIRMAHF trial. In patients with iron deficiency and a left ventricular ejection fraction of less than 50% who were stabilized after an episode of acute HF, treatment with ferric carboxymaltose (Injectafer, American Regent) was safe and reduced the risk for heart failure hospitalization. However, it had no apparent effect on the risk for cardiovascular death. In the AFFIRM-AHF study, investigators randomly assigned 1,132 patients to receive ferric carboxymaltose or placebo. (At least one post-randomization value was available for 558 patients in the carboxymaltose group and 550 placebo controls.) After a median follow-up of 52 weeks, the primary end point of total HF hospitalizations and cardiovascular death occurred in 52.5% of the ferric carboxymaltose group and 67.6% of the placebo group (rate ratio [RR], 0.79; 95% CI, 0.62-1.01; P=0.059). Secondary outcomes included cardiovascular deaths and HF hospitalizations. Cardiovascular death did not differ significantly between the two groups (ferric carboxymaltose group, 14% [77/558]; placebo group, 14% [78/550]; hazard ratio [HR], 0.96; 95% CI, 0.701.32; P=0.81). In contrast, there was a significant reduction in total HF hospitalizations in the ferric carboxymaltose

group (217 vs. 294 in the placebo group; RR, 0.74; 95% CI, 0.58-0.94; P=0.013). Another end point, a composite of first HF hospitalization or cardiovascular death, also showed significant improvement in the ferric carboxymaltose group, occurring in 32% of patients (n=181), versus 38% (n=209) in the placebo group (HR, 0.80; 95% CI, 0.66-0·98; P=0.030). In addition, fewer days were lost due to HF hospitalization and cardiovascular death for patients receiving ferric carboxymaltose compared with placebo controls (369 vs. 548 days per 100 patient-years; RR, 0.67; 95% CI, 0.47-0.97; P=0.035). Serious adverse events occurred in 250 patients in the ferric carboxymaltose group (45%) and 282 patients in the placebo group (51%).

Preventing Hospitalizations ‘Vitally Important’ “While they did not significantly reduce the primary end point of heart failure rehospitalizations or cardiovascular death, they did significantly reduce rehospitalizations (48.9% vs. 53.5%; P=0.013),” said C. Michael White, PharmD, the department head and a distinguished professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs. “Preventing these rehospitalizations is vitally important to the well-being of patients and for the financial health

of the hospitals that do not get reimbursed for patients rehospitalized within 30 days of discharge,” Dr. White told Pharmacy Practice News. The AFFIRM-AHF data were presented at the American Heart Association (AHA) Scientific Sessions 2020 and published in Lancet (2020;396[10266]:1895-1904). Commenting on the study during an American College of Cardiology podcast highlighting top papers presented at the AHA meeting, Deepak L. Bhatt, MD, MPH, said he considered the study to be positive. “One can quibble about different P values—whether they were significant or not. The overall trial came close but didn’t quite hit. But this trial, like many … was a casualty of the COVID pandemic,” said Dr. Bhatt,

the executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center and a professor of medicine at Harvard Medical School, both in Boston. “So, I think you’ve got to give them a little bit of grace period there, in terms of the P values and so forth. I think it’s a hypothesis that made sense, and, as far as I’m concerned, they did validate it. So, in patients that have marked anemia, I would say it would have been a good idea probably to correct that for a variety of reasons, but certainly if they’ve got heart failure … with reduced ejection fraction, go ahead and treat that low blood count.” —Sarah Tilyou Drs. White and Bhatt reported no relevant financial disclosures.

Novel Agent for HF Shows Mixed Results in Large Trial

he novel selective cardiac myosin activator omecamtiv mecarbil reduced a composite of a heart failure (HF) event or death from cardiovascular (CV) causes among patients with HF and a reduced ejection fraction (HFrEF) in the placebo-controlled phase 3 GALACTIC-HF trial. However, there was no significant difference in the secondary outcome of death from CV causes, which led Amgen and Servier to terminate their collaboration with Cytokinetics to develop the drug (bit.ly/3cIvyXm). Cytokinetics still plans in the “next year or so” to file for FDA approval for the drug (bit.ly/35sfo0i), which was granted fast track designation in May 2020 (bit.ly/3zqu2D7). In the trial, 4,120 patients were assigned to receive omecamtiv mecarbil (pharmacokinetic-guided doses of 25, 37.5 or 50 mg twice daily) and 4,112 to receive placebo. The primary outcome was a composite of a first HF event

(hospitalization or urgent visit for HF) or death from CV causes. After a median of 21.8 months, the omecamtiv mecarbil group had significantly fewer primary outcome events compared with the placebo group (37.0% vs. 39.1%; hazard ratio [HR], 0.92; 95% CI, 0.86-0.99; P=0.03). There was no significant difference between the two groups in the secondary outcome of death from CV causes (19.6% in the omecamtiv mecarbil group vs. 19.4% in the placebo group; HR, 1.01; 95% CI, 0.92-1.11; P=0.86). There also was no significant difference between groups in another secondary outcome, the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score (N Engl J Med 2021;384[2]:105-116). Omecamtiv mecarbil was discontinued in 847 patients (20.6%), and placebo was discontinued in 897 patients (21.9%). An adverse event was the reason for discontinuation in 371 patients (9.0%) in

the omecamtiv mecarbil group and 382 (9.3%) patients in the placebo group. The investigators acknowledged that the trial had some limitations, including the exclusion of patients older than 85 years and those with “a clinically unstable condition.” In addition, noting that only 7% and 21% of patients in the trial were Black and women, respectively, they wrote, “The underrepresentation of racial groups and women in clinical trials is a continuing concern.”

Questions Remain William Baker, PharmD, an associate professor in the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy, in Storrs, said omecamtiv mecarbil “offers a new mechanism of action for HF patients with HFrEF.” The large GALACTIC-HF trial “showed that, when given on top of solid background therapy, the composite of cardiovascular death or a HF event

was significantly lower with omecamtiv mecarbil. However, there was no evidence of a benefit on CV death alone, all-cause mortality or quality of life. Most of the benefit was in reductions in hospitalizations. Subgroup analyses suggested some benefit in those with especially low left ventricular ejection fraction LVEF.” As of now, Dr. Baker added, “the role of omecamtiv mecarbil remains unclear. We know patients should get a RAAS [renin– angiotensin–aldosterone system] blocker (likely an ARNI [angiotensin receptor/ neprilysin inhibitor]), a beta-blocker, an MRA (mineralocorticoid receptor antagonist), and an SGLT-2 [sodium-glucose cotransporter protein 2] inhibitor. In whom omecamtiv mecarbil may be beneficial remains unknown and requires further study.” —Sarah Tilyou Dr. Baker reported no relevant financial disclosures.

Cost Saving Time Saving Waste Saving Life Saving

ADVANCED

Universal, Needle-Free Admixture System for Immediate Use IV Administration To learn more visit:

West and the diamond logo and By your side for a healthier world, are trademarks or registered trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions. Vial2Bag AdvancedTM and Blue Vial Adapter are trademarks and registered trademarks of West Pharma. Services IL, Ltd., a subsidiary of West Pharmaceutical Services, Inc. Copyright © 2020 West Pharmaceutical Services, Inc. #11438 • 1020

10 Clinical

Pharmacy Practice News • July 2021

Infectious Disease

Penicillin Allergy Interventions Improve Preferred Antibiotic Use

bout 10% of all patients in the United States have a penicillin allergy listed in their medical records. But in more than 90% of patients, that label is wrong—in many cases, either because a viral rash was mistaken for a penicillin allergy when the person was a child, or because earlier acute penicillin reactions have declined and disappeared over time (JAMA 2017;318[1]:82-83). Patients labeled with penicillin allergies often receive non-preferred antibiotics, such as fluoroquinolones, clindamycin or vancomycin, when they are admitted to the hospital. This practice leads to increased broad-spectrum antibiotic use and higher rates of multidrug-resistant infections. At the 2021 annual MAD-ID (Making a Difference in Infectious Diseases) virtual meeting, two abstracts presented by researchers from the Moses H. Cone Memorial Hospital, in Greensboro, N.C., and Lee Health, in Fort Myers, Fla., demonstrated the effectiveness of penicillin allergy assessment interventions in improving antibiotic use among these patients. In the first study, pharmacists at Moses Cone prospectively evaluated 48 patients admitted to the hospital with an infection between September 2020 and February 2021 for pharmacist-led penicillin allergy de-labeling, using one of three strategies: • an amoxicillin challenge under direct observation for low-risk patients (those presenting with gastrointestinal symptoms, pruritus without rash, family history of allergy, unknown reactions occurring >10 years previously); • penicillin skin testing followed by an amoxicillin challenge if skin testing was negative for moderate-risk patients (urticaria or other pruritic rashes, non-anaphylactic immunoglobulin E reactions); or • allergy/immunology referral or desensitization for patients with a positive penicillin skin test or a high-risk history, such as anaphylaxis, recurrent penicillin reactions or hypersensitivities to multiple beta-lactams. The investigators then compared those patients with a retrospective cohort of 50 patients admitted from January 2019 to January 2020 who had a documented penicillin allergy. Of the 48 patients enrolled in the study, 98% had their allergy de-labeled and 56% had their antibiotic therapy optimized by the intervention. Only one patient developed a delayed rash reaction and was relabeled as penicillin-allergic.

Hospital readmission rates due to infection and total cost of therapy were ere significantly lower in the prospective arm. In the e retrospective group, 19 patients (38%) were rehospitalized hospitalized within 30 days; 11 of these cases were attributed to recurrent or worsening infection. In the prospective group, only seven patients ents (15%) met the criteria for 30-day readmission, just three of whom were re determined to be due to recurrent urrent or worsening infection (P<0.001). “By utilizing preferred antibiotics, we estimated that average e drug cost savings was $192 per patient in the prospective group,” said d lead researcher Tyler Baumeister, PharmD, a PGY-2 infectious diseases ses pharmacy resident at Moses C Cone. one Although the prospective group had a longer overall antibiotic duration than the retrospective arm (9.9 ±12.1 vs. 6.3±3.6 days), the prospective group was able to use preferred antibiotics 77% of the time, while the retrospective group had been unable to use preferred antibiotics. “Pharmacist-driven allergy reconciliation is a feasible patient care initiative that can significantly improve antibiotic use, decrease antibiotics costs, reduce antibiotic adverse events and possibly decrease readmission rates in hospitalized patients,” Dr. Burmeister said.

The Lee Health Approach At Lee Health, a pharmacist-led penicillin allergy assessment initiative was implemented beginning in July 2019, including pharmacist education and a standardized interview note template in the electronic health record (EHR). The interview template included questions such as the following: • What was the name of the agent that caused the event? • When did the reaction occur? • What was the course of the reaction? • How was the reaction treated? • Can you name other antibiotics you remember having taken and tolerated?

After a chart review for allergy history and the patient/caregiver allergy interview, pharmacists document their findings in the clinical note and update the EHR, then discuss notable findings and deescalation recommendations, if any, with the patient’s provider.

In a retrospective chart review of 100 patients with documented penicillin allergies who underwent the allergy assessment initiative after admission to one of Lee Health’s four adult acute care hospitals between March 2019 and October 2020, more than one-fourth of the cohort (28%) was successfully transitioned to a preferred betalactam antibiotic after the interview. In total, 46% of patients’ regimens were deescalated. “While not all patients could be transitioned to a preferred beta-lactam due to a true allergy, the average cost savings was $76 per allergy interview, largely attributable to aztreonam avoidance,” said presenting author Elisabeth Chandler, PharmD, BCIDP, a pharmacy clinical specialist in infectious diseases. The cost savings in the entire patient cohort was more than $7,000. “Penicillin allergy interviews can not only assist in transition to preferred beta-lactams, but they can prompt in-depth review of need for broad-spectrum antimicrobial therapy leading to more deescalations or discontinuation of unneeded empiric antibiotics,” Dr. Chandler said. —Gina Shaw

The sources reported no relevant financial disclosures.

Stewardship Programs Can Improve ABx Use in Cancer Patients

ecause of the complexity of their cases, immunocompromised patients such as individuals with cancer often have been excluded from antimicrobial stewardship programs (ASPs) and studies. But the limited amount of research available suggests that such programs can effectively reduce antibiotic consumption and improve outcomes (Ann Pharmacother 2020;54[6]:594-610). Building on the findings, investigators from Henry Ford Health System and Wayne State University, in Detroit, examined whether its own cancer patients could benefit from ASPs. The investigators found that nearly half of non-neutropenic oncology patients at their institution had at least one opportunity to improve their antibiotic regimen. The cross-sectional cohort study, presented at the 2021 annual MADID (Making a Difference in Infectious

Diseases) virtual meeting (poster A67), included 200 adult patients who were admitted to the oncology unit at Henry Ford and received an antimicrobial agent between Aug. 1, 2018, and Aug. 30, 2019. A total of 84 (42%) patients had at least one opportunity for antibiotic optimization. Among this group, the most common area for improvement was empiric coverage discordance, which occurred in 62 patients (73.8%). Moreover, urinary tract and intraabdominal infections had inappropriate antibiotic coverage among 41.9% (13/31) and 41.2% (14/34) of patients, respectively. In the vast majority of these cases (57/62, 91.9%), the antibiotic spectrum was too broad, reported Corey J. Medler, PharmD, an infectious diseases/antimicrobial stewardship pharmacy fellow at Henry Ford. Other intervention opportunities included no deescalation when

possible (29 patients, 34.5%), no IV-tooral switch at discharge (six patients, 7.1%) and dual anaerobic coverage (four patients, 4.8%). (Some patients had more than one ASP intervention.) “Immunocompromised patients present a challenging and complex

scenario for stewardship, but still can provide an opportunity to improve antibiotic use and patient outcomes,” Dr. Medler said. “Opportunities for improvement include assessing allergy history, optimizing empiric antibiotic coverage, avoiding dual anaerobic coverage, deescalation based on microbiology cultures and susceptibilities, and switching from IV to oral therapies.” —Gina Shaw The sources reported no relevant financial disclosures.

Clinical

Pharmacy Practice News • July 2021

Infectious Disease

C. difficile Infection Linked to Recurrent Hospitalizations

lostridioides difficile infections (CDIs) continue to impose a serious financial burden on the nation’s health systems, according to a study presented at the 2021 annual MAD-ID (Making a Difference in Infectious Diseases) virtual meeting (poster A01). Reducing CDI, and particularly recurrent CDI (rCDI), may enable hospitals to significantly reduce these added costs and their attendant stresses on operations. “Our study attempted to quantify the burden of CDI and rCDI on the hospital systems in the U.S.,” said Meg Franklin, PharmD, PhD, the president of Franklin Pharmaceutical Consulting, in Rock Hill, S.C. “CDI is the most common cause of health care–associated infections in U.S. hospitals, and is the leading cause of health care–associated diarrhea, leading to approximately 30,000 deaths each year in the United States.” Nearly 500,000 patients tested

positive for CDI in 2017, and up to 35% of patients who develop CDI will also develop rCDI. Both CDI and rCDI are associated with substantial added health care costs, driven largely by an increase in hospitalizations. The retrospective analysis used Medicare Part A claims analyzed through the Definitive Healthcare platform over an 18-month period, from January 2018 through June 2019. Hospital admissions involving CDI among patients ages 65 years and older were identified using International Classification of Diseases, Tenth Revision,

codes, and readmissions were defined as all-cause hospital admission within 30 days of the initial CDI or rCDI admission. Of the 47,115 CDI-related hospital admissions, 64.9% were female, 88.2% white, with a median age of 78 years. Recurrent CDI was the principal diagnosis in 20% of patients. For patients with rCDI, the hospital stay was longer (six vs. 5.5 days), and both charges and payments per claim were higher than for non-rCDI admissions (charges, $45,049 vs. $41,141; payments, $9,811 vs. $9,166).

The investigators found that CDIrelated 30-day readmissions accounted for 15.9% of all CDI hospitalizations. The in-hospital mortality rate among readmissions was 5.1%—more than twice that among initial CDI admissions. “This data quantifies the burden to hospital networks as a result of patients with CDI and rCDI,” Dr. Franklin said. “Future research directed at developing a safe, effective and standardized microbiome-based therapeutic, and providing a reduction in recurrence, will be instrumental in the prevention of readmissions and potentially improving patient mortality.” —Ethan Covey Dr. Franklin reported employment at Franklin Pharmaceutical Consulting, LLC, and provided consulting services to Ferring Pharmaceuticals.

Pharmacist Evaluation Improves Appropriate ABx Prescribing At Hospital Discharge

harmacist review of patients’ antimicrobial prescriptions at the time of hospital discharge can significantly decrease inappropriate prescribing, a new study has found. In 2016, the Infectious Diseases Society of America published guidelines to stipulate recommendations for the implementation of antibiotic stewardship programs (ASPs) within health care settings (Clin Infect Dis 2016;62[10]:e51-e77). “Although many of the recommendations within the guidelines are directed toward the inpatient setting, studies have demonstrated a majority of antibiotic regimens are completed upon discharge,” said Amneh Fares, PharmD, a PGY-1 pharmacy resident at Memorial Regional Hospital, in Hollywood, Fla., who presented the results (poster A32) at the 2021 annual MAD-ID (Making a Difference in Infectious Disease) virtual meeting. “Antibiotics prescribed at discharge have frequent opportunities for improvement primarily due to broad spectrums of activity or excessive durations,” Dr. Fares said. “Assessment of antimicrobials at discharge presents a significant opportunity to utilize antimicrobial stewardship and complement the transition-of-care process.” In August 2020, Memorial Regional Hospital implemented a pilot program of pharmacist evaluation of discharge antibiotic regimens. Dr. Fares, then in her infectious disease rotation, would conduct periodic daily reviews of patients being discharged on antimicrobials, assess each regimen for appropriateness,

Do you receive your FREE subscription?

and consult with supervising infectious disease pharmacists if she deemed any to be inappropriate. “Based on their expertise, we would then make a recommendation to the prescribing physician,” she said. After the pilot project, Dr. Fares and her colleagues conducted a retrospective chart analysis. A total of 168 charts from adult patients discharged on oral antibiotics between Aug. 3 and Aug. 28, 2020, were reviewed; 101 intervention patients had received pharmacist evaluation of their discharge prescription, while 67 control group patients had not. Overall, 91% of the intervention patients were discharged on an appropriate antimicrobial regimen, compared with 68.7% of the control group (P<0.000445). The team implemented 29

interventions, 20 of which were accepted by prescribers. There was no difference in hospital readmissions within 30 days, nor in emergency department visits within 72 hours of discharge due to a reoccurrence of the index infection(s) between patients who received pharmacist-led intervention and patients who did not. Memorial Regional Hospital is reviewing staffing options for expanding its ASP to include discharge antibiotics. “The pilot helped us realize what a significant impact this can have,” Dr. Fares said. —By Gina Shaw

The sources reported no relevant financial disclosures.

Keep it coming! Go to PharmacyPracticeNews.com/ RenewSubscription to renew or start your subscription.

NOW AVAILABLE: FREE HOME DELIVERY!

12 Clinical

Pharmacy Practice News • July 2021

Oncology

Genotyping Roadblocks continued from page 1

using this testing to guide chemotherapy dosing in patients with gastrointestinal cancers,” Dr. Lau-Min said. Such testing, however, would be costeffective, concluded Gabriel Brooks, MD, MPH, and his colleagues from the Norris Cotton Cancer Center at Dartmouth, in Lebanon, N.H. For stage 3 colon cancer patients treated with adjuvant fluoropyrimidines, they found the

incremental cost of DPYD genotyping to be low, at $106 per patient, with an incremental cost-effectiveness ratio (ICER) of $37,000 per quality-adjusted life-year (QALY).

Clinicians’ Attitudes Dr. Lau-Min and her colleagues sought to better understand clinicians’ attitudes toward preemptive

PGx-guided chemotherapy dosing, identify barriers to uptake and determine how best to implement preemptive PGx testing in clinical practice. They analyzed interviews with 25 clinicians, including 16 medical oncologists and nine oncology pharmacists at hospitals within Penn Medicine (abstract 54). Of the clinicians, 60% reported feeling comfortable or very comfortable with interpreting PGx test results, and they were “deeply aware of the gravity of administering chemotherapy” to patients at risk, she said. “As one clinician said, ‘I appreciate the toxicity and I fear it, but I also have to give chemo.’” The clinicians expressed generally favorable attitudes toward testing—and some had used it reactively in patients with prior events—but many cited barriers to testing (Table) and hesitated to use it preemptively due to a perceived lack of evidence for this practice. They cited a lack of consensus chemotherapy dosing recommendations in response to PGx test results and concerns about decreases in efficacy with lower doses, especially in patients treated with curative intent. “These findings supported the conclusion that additional clinical effectiveness studies are needed before preemptive PGx-guided chemotherapy dosing can effectively be adopted in routine practice,” Dr. Lau-Min said.

Oncology Pharmacist’s Take J. Kevin Hicks, PharmD, PhD, a precision medicine specialist at H. Lee Moffitt Cancer Center, in Tampa, Fla., said evidence supports the routine use of DPYD genotyping as a tool for more safely dosing chemotherapy. “Although lack of clinical effectiveness is often cited as a reason for not preemptively integrating DPYD-guided fluoropyrimidine prescribing into patient care, Dr. Henricks and colleagues demonstrated that prospective DPYD genotyping is feasible in routine practice and can improve patient safety,” Dr. Hicks said, referring to a study of more than 1,100 patients published in Lancet Oncology (2018;19[11]:1459-1467). Hendricks et al found that “DPYD genotype-based dose reductions improved the safety of fluoropyrimidine treatment,” and suggested that “DPYD genotype-guided individualised dosing should be a new standard of care” for patients given this commonly used agent, Dr. Hicks noted. He added that the Clinical Pharmacogenetics Implementation Consortium provides evidence-based recommendations for DPYD-guided fluoropyrimidine

Clinical

Pharmacy Practice News • July 2021

Oncology

Table. Potential Barriers to Pharmacogenomic Testing A low prevalence of actionable PGx variants Long PGx test turnaround times Testing costs and lack of insurance coverage Burdensome integration of PGx testing into clinical workflows An inability to interpret results PGx, pharmacogenomics

prescribing (Clin Pharmacol Ther 2018;103[2]:210-216). To facilitate unobtrusive integration of PGx testing into clinical practice, health systems can use their electronic health record (EHR) systems. “Leveraging the electronic health record to disseminate important genetic information is a proven way of creating workflow efficiencies to support pharmacogenetics implementation,” Dr. Hicks said. Through the EHR, he noted, clinicians can order PGx tests for eligible patients through a computerized entry process, with direct interfacing with testing labs, discrete reporting of variants and clinical decision support.

DPYD Genotyping Cost-Effective Such testing has been shown to be costeffective in European care delivery settings, but Dr. Brooks and his colleagues at the Norris Cotton Cancer Center at Dartmouth wanted to see if that also was true in U.S. practice settings. They conducted a cost-effectiveness analysis from the U.S. perspective, creating a Markov model to simulate the use of genotyping versus no screening over a six-month period with a five-year horizon, in stage 3 colon cancer patients (abstract 55). DPYD variant carriers were modeled to receive reduced-dose chemotherapy, with outcomes including no toxicity, severe toxicity, treatment-related death, post-treatment survival and death. Their model assumed a 2.2% probability that patients carried a deleterious DPYD variant (representative of the U.S. population), a cost of $174 for testing (based on the Medicare fee schedule), and a 3% discounting of future costs. Numerous cost parameters (such as cost of hospitalization for toxicity) were derived from U.S. sources. As noted, compared with no screening, DPYD genotyping cost $106 per patient and yielded an incremental benefit of 0.0028 QALYs and an ICER of $37,300 per QALY. Although the average benefit of screening was small, at 0.0028 QALYs, “this is consistent with a small number of patients who experience large benefits,” Dr. Brooks said, “such as [prevention of ] death during adjuvant treatment.”

Dr. Brooks further noted that the $37,000 ICER is lower than the threshold of $100,000 benchmark for cost-effective interventions or technologies in health care. “Therefore, our study suggests that DPYD deficiency screening with genotyping is cost-effective.” He

added that one-way sensitivity analysis showed the ICER exceeded $100,000 per QALY when the frequency of the variants was less than 1.2% and specificity of genotyping was less than 98.9%. The test remained cost-effective up to a cost of $200. —Caroline Helwick and Sarah Tilyou Dr. Brooks reported financial relationships with CareCentrix and Merck. Drs. Lau-Min and Hicks reported no relevant financial disclosures.

NOW AVAILABLE

The First and Only Antiemetic Approved for Rescue Treatment of PONV Despite Prophylaxis • Barhemsys is a selective dopamine-2 and dopamine-3 receptor antagonist, TKKJWNSL F UMFWRFHTQTLNHFQ TUYNTS \NYM IJRTSXYWFYJI XFKJY^ FSI JK‫ ܪ‬HFH^ at the doses approved for PONV management1 • Barhemsys 10 mg was more effective than placebo at treating PONV in patients who failed prophylaxis: 42% vs 29% achieved the primary endpoint of complete response; P=0.0031,2,* • In patients who failed prophylaxis, 70% (160/230) of patients met the criteria for complete response at 2 hours after receiving a 10 mg dose of Barhemsys compared with 49% (116/235) of placebo-treated patients (secondary endpoint)2,* • The most common adverse reaction reported for Barhemsys 10 mg (N=418) and at a higher rate than placebo (N=416) was infusion site pain (6% vs 4%)1,†

Scan for additional information or visit Barhemsys.com

Indications

Packaging and vial shown are not actual size.

Barhemsys is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist indicated in adults for: • prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class • treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis

Select Important Safety Information Contraindication: 'FWMJRX^X NX್HTSYWFNSINHFYJI್NS UFYNJSYX \NYM PST\S MÛJWXJSXNYN[NY^ YT FRNXZQUWNIJ ್ QT Prolongation: Barhemsys causes dose- and concentration-dependent prolongation of the QT interval. The recommended dosage NX ್RL್TW ್RL FX F XNSLQJ NSYWF[JSTZX .; ITXJ NSKZXJI T[JW YT RNSZYJX &[TNI 'FWMJRX^X NS UFYNJSYX \NYM HTSLJSNYFQ QTSL 69 X^SIWTRJ FSI NS UFYNJSYX YFPNSL IWTUJWNITQ *QJHYWTHFWINTLWFR *(, RTSNYTWNSL NX WJHTRRJSIJI NS UFYNJSYX \NYM UWJ J]NXYNSL FWWM^YMRNFX HFWINFH HTSIZHYNTS INXTWIJWX JQJHYWTQ^YJ FGSTWRFQNYNJX J L MÛTPFQJRNF TW MÛTRFLSJXJRNF HTSLJXYN[J MJFWY KFNQZWJ FSI NS UFYNJSYX YFPNSL TYMJW RJINHNSFQ UWTIZHYX J L TSIFSXJYWTS ್TW \NYM TYMJW RJINHFQ HTSINYNTSX್PST\S YT UWTQTSL YMJ 69 NSYJW[FQ Please see Brief Summary of Prescribing Information for Barhemsys on next page. *Barhemsys was evaluated as rescue treatment of PONV in a randomized, double-blind, multicenter trial in adult patients who had undergone elective ambulatory TW NSUFYNJSY XZWLJW^ ZSIJW LJSJWFQ NSMFQFYNTSFQ FSJXYMJXNF FSI KFNQJI UWNTW FSYNJRJYNH UWTUM^QF]NX 9MJ UWNRFW^ JK‫ ܪ‬HFH^ JSIUTNSY \FX HTRUQJYJ WJXUTSXJ IJ‫ ܪ‬SJI FX FGXJSHJ TK FS^ JUNXTIJ TK JRJXNX [TRNYNSL TW WJYHMNSL TW ZXJ TK WJXHZJ RJINHFYNTS \NYMNS YMJ ‫ ܪ‬WXY MTZWX FKYJW YWJFYRJSY J]HQZINSL JRJXNX NS YMJ ‫ ܪ‬WXY RNSZYJX Ѫ7JUTWYJI NS Մ TK FIZQY UFYNJSYX YWJFYJI \NYM 'FWMJRX^X RL FSI FY F MNLMJW WFYJ YMFS UQFHJGT KWTR YMJ 543; YWJFYRJSY FSI WJXHZJ YWJFYRJSY YWNFQX PONV=Postoperative nausea and vomiting. 1. 'FWMJRX^X @UFHPFLJ NSXJWYB .SINFSFUTQNX .3 &HFHNF 5MFWRF .SH 2. -FGNG &8 JY FQ Anesthesiology. 2019;130:203-212.

14 Clinical

Pharmacy Practice News • July 2021

Oncology

New Agents Making a Mark Against Genitourinary Cancers New treatment options for bladder, renal and prostate cancers can help extend survival rates without significant toxicity, according to several studies presented at the virtual 2021 Genitourinary Cancers Symposium. Nivolumab Extends DiseaseFree Survival in Advanced Bladder Cancer Patients treated with adjuvant nivolumab after surgery for advanced high-risk muscle-invasive urothelial

Delivers when it matters most

cancer (MIUC) had improved survival rates compared with patients given placebo in the phase 3 CheckMate 274 trial (abstract 391). “Nivolumab is the first systemic immunotherapy to demonstrate a clinically

meaningful improvement in outcomes when administered as adjuvant therapy to patients with muscle-invasive urothelial carcinoma,” said presenter Dean F. Bajorin, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York City. The results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with highrisk MIUC after radical surgery, he said.

™

Brief Summary of Prescribing Information for Barhemsys® (amisulpride) Injection See package insert for full Prescribing Information Indications: Barhemsys is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist indicated in adults for: • prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class • treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis Dosage & Administration: The recommended adult dosage of Barhemsys: • Prevention of PONV, either alone or in combination with another antiemetic: 5 mg as a single intravenous dose infused over 1 to 2 minutes at the time of induction of anesthesia. • Treatment of PONV: 10 mg as a single intravenous dose infused over 1 to 2 minutes in the event of nausea and/or vomiting after a surgical procedure. Protect from light. Barhemsys is subject to photodegradation. Administer Barhemsys within 12 hours of removal of the vial from the protective carton. See full prescribing information for preparation and administration instructions. Dosage Forms and Strength: Injection: 5 mg/2 mL (2.5 mg/mL) or 10 mg/4 mL (2.5 mg/mL) as a clear, colorless sterile solution in a single-dose vial. Contraindication: Barhemsys is contraindicated in patients with known hypersensitivity to amisulpride. QT Prolongation: Barhemsys causes dose- and concentration-dependent prolongation of the QT interval. The recommended dosage is 5 mg or 10 mg as a single intravenous (IV) dose infused over 1 to 2 minutes. Avoid Barhemsys in patients with congenital long QT syndrome and in patients taking droperidol. Electrocardiogram (ECG) monitoring is recommended in patients with pre-existing arrhythmias/cardiac conduction disorders, electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, and in patients taking other medicinal products (e.g., ondansetron) or with other medical conditions known to prolong the QT interval. Adverse Reactions: Common adverse reactions reported in ≥ 2% of adult patients who received Barhemsys 5 mg (N=748) and at a higher rate than placebo (N=741) in clinical trials for the prevention of PONV were: chills (4% vs. 3%), hypokalemia (4% vs. 2%), procedural hypotension (3% vs. 2%), and abdominal distention (2% vs. 1%). Serum prolactin concentrations were measured in one prophylaxis study where 5% (9/176) of Barhemsys-treated patients had increased blood prolactin reported as an adverse reaction compared with 1% (1/166) of placebo-treated patients. The most common adverse reaction, reported in ≥ 2% of adult patients who received Barhemsys 10 mg (N=418) and at a higher rate than placebo (N=416), in clinical trials for the treatment of PONV was infusion site pain (6% vs. 4%). Drug Interactions: • Barhemsys causes dose- and concentration-dependent QT prolongation. To avoid potential additive effects, avoid use of Barhemsys in patients taking droperidol. • ECG monitoring is recommended in patients taking other drugs known to prolong the QT interval (e.g., ondansetron). • Reciprocal antagonism of effects occurs between dopamine agonists (e.g., levodopa) and Barhemsys. Avoid using levodopa with Barhemsys. Postmarketing Experience: The following adverse reactions have been identified during postapproval chronic oral use of amisulpride outside of the United States (Barhemsys is not approved for oral dosing or chronic use). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and Lymphatic System Disorders: agranulocytosis; Cardiac Disorders: bradycardia, torsades de pointes, ventricular tachycardia, prolonged QT by electrocardiogram; General Disorders: neuroleptic malignant syndrome; Immune System Disorders: angioedema, hypersensitivity, urticaria; Hepatic Disorders: increased hepatic enzymes; Nervous System Disorders: agitation, anxiety, dystonia, extrapyramidal disorder, seizure; Psychiatric Disorders: confusional state, insomnia, somnolence; Vascular Disorders: hypotension. Use in Specific Populations: Pregnancy—Risk Summary: Available data with amisulpride use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, there were no adverse developmental effects observed with oral administration of amisulpride in rats and rabbits during the period of organogenesis at exposures about 43 and 645 times, respectively, the exposure delivered by the highest recommended human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data—Animal Data: Reproduction studies of amisulpride were conducted in pregnant rats administered oral doses up to 160 mg/kg/day (43 times the exposure based on area under the curve (AUC) at the highest recommended dose of 10 mg) throughout the period of organogenesis. No adverse embryo-fetal developmental effects were observed at any dose level. Maternal animals exhibited a dose-related decrease in overall mean body weight gain. In rabbits administered amisulpride throughout the period of organogenesis, oral doses up to 210 mg/kg/day (645 times the exposure based on AUC at the highest recommended dose of 10 mg) had no adverse developmental effects on the fetus. Maternal animals exhibited reduced mean body weight gain at doses of 100 and 210 mg/kg/day and reduced food intake was observed at 210 mg/kg/day. The pre- and post-natal developmental effects of amisulpride were assessed in rats administered oral doses of 60, 100 or 160 mg/kg/day during the periods of organogenesis and lactation. At 160 mg/kg/day (43 times the exposure based on AUC at the highest recommended dose of 10 mg), maternal animals exhibited a reduction in mean body weight gain and decrease in food intake during lactation. Amisulpride had no effect on maternal pregnancy parameters, litter survival or pup growth, development or maturation at any dose tested. Lactation—Risk Summary: Based on case reports in published literature, amisulpride is present in human milk at concentrations that are 11- to 20-fold higher than human plasma in patients taking multiple oral doses of amisulpride (200 to 400 mg/day). The estimated infant daily dose ranged from 5% to 11% of the maternal dose. There are ways to minimize drug exposure to a breastfed infant (see Clinical Considerations). There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production. The pharmacological action of amisulpride, a dopamine-2 (D 2) receptor antagonist, may result in an increase in serum prolactin levels, which may lead to a reversible increase in maternal milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Barhemsys and any potential adverse effects on the breastfed child from Barhemsys or from the underlying maternal condition. Clinical Considerations: A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after Barhemsys administration to minimize drug exposure to a breastfed infant. Females and Males of Reproductive Potential—Infertility: In animal fertility studies, administration of repeated doses of amisulpride over a 10-day period to female rats resulted in infertility that was reversible. Pediatric Use—Safety and effectiveness in pediatric patients have not been established. Geriatric Use—No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment—Avoid Barhemsys in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2). The pharmacokinetics of amisulpride in patients with severe renal impairment have not been adequately studied in clinical trials. Amisulpride is known to be substantially excreted by the kidneys, and patients with severe renal impairment may have increased systemic exposure and an increased risk of adverse reactions. No dosage adjustment is necessary in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2). Overdosage: Doses of oral amisulpride (Barhemsys is not approved for oral dosing) above 1200 mg/day have been associated with adverse reactions related to dopamine-2 (D2) antagonism, in particular: • cardiovascular adverse reactions (e.g., prolongation of the QT interval, torsades de pointes, bradycardia and hypotension). • neuropsychiatric adverse reactions (e.g., sedation, coma, seizures, and dystonic and extrapyramidal reactions). There is no specific antidote for amisulpride overdose. Management includes cardiac monitoring and treatment of severe extrapyramidal symptoms. Since amisulpride is weakly dialyzed, hemodialysis should not be used to eliminate the drug. How Supplied/Storage and Handling: Barhemsys is supplied as follows: • NDC 71390-125-20: Package of 10 cartons. Each carton (NDC 71390-125-21) contains one single-dose vial of Barhemsys (amisulpride) injection, 5 mg in 2 mL (2.5 mg/mL). • NDC 71390-125-50: Package of 10 cartons. Each carton (NDC 71390-125-51) contains one single-dose vial of Barhemsys (amisulpride) injection, 10 mg in 4 mL (2.5 mg/mL). Store vials at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Patient Counseling Information: QT Prolongation—Instruct patients to contact their healthcare provider immediately if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode. Drug Interactions—Advise patients to report to their healthcare provider if they are taking drugs which prolong the QT interval. Lactation—Women may consider reducing infant exposure through pumping and discarding breastmilk for 48 hours after Barhemsys administration. BAR HCP BS 10/2020

Barhemsys® is a registered trademark of Acacia Pharma Limited. © 2021 Acacia Pharma Inc. All rights reserved. PP-BAR-1863 04/2021 Acacia Pharma Limited and Acacia Pharma Inc. are wholly owned subsidiaries of Acacia Pharma Group Plc.

Dr. Bajorin and his co-investigators randomly assigned 709 patients with high-risk MIUC, with primary tumor sites including bladder, ureter or renal pelvis, to receive nivolumab ( O p d i v o, B r i s t o l Myers Squibb) or placebo in a 1:1 fashion after radical surg e r y. N i v o l u m a b wa s a d m i n i s t e re d at a dosage of 240 mg every two weeks for up to one year. Patients were allowed but not required to have received neoadjuvant cisplatin. Primary outcomes of interest were disease-free survival in all randomized patients and in the subgroup of patients with tumor programmed death ligand-1 (PD-L1) expression of at least 1%. Of the 353 patients in the nivolumab group, 140 had PD-L1 levels of at least 1%; of the 356 in the placebo group, 142 had PD-L1 expression of at least 1%. Over a median follow-up of approximately 20 months, median disease-free survival was significantly longer for patients receiving nivolumab compared with those receiving placebo (21 vs. 11 months; hazard ratio [HR], 0.70; 95% CI, 0.54-0.89; P<0.001). A similar effect was observed in the population with PD-L1 levels of at least 1% (HR, 0.53; 95% CI, 0.34-0.84; P<0.001). The findings support the use of nivolumab monotherapy “as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery, regardless of PD-L1 status and prior neoadjuvant therapy,” according to the investigators.

EV-301 Increases PFS In Bladder Cancer The antibody drug conjugate enfortumab vedotin significantly increased progression-free survival (PFS) of patients with locally advanced or metastatic urothelial cancer in the EV-301 phase 3 clinical trial (abstract 393). The trial, conducted in 19 countries, included 608 adults with locally advanced or metastatic urothelial cancer who were treated previously with platinum-based chemotherapy and a PD-L1 inhibitor. Presenting the findings at the symposium, lead investigator Tom Powles, MD, said the risk for death was 30% lower among those treated with enfortumab vedotin-ejfv (Padcev, Astellas/Seattle Genetics) than those given chemotherapy. At interim analysis, overall survival (OS) was 12.88 months with enfortumab

Clinical

Pharmacy Practice News • July 2021

Oncology vedotin and 8.97 months with chemotherapy (HR, 0.70; 95% CI, 0.56-0.89; P=0.00142). Median PFS was 5.6 months with enfortumab vedotin versus 3.7 months with chemotherapy (HR, 0.62; 95% CI, 0.510.75; P<0.00001). The investigator-assessed overall response rate was 40.6% with enfortumab vedotin and 17.9% with chemotherapy treatment (P<0.001). Adverse effects were manageable and overall similar to chemotherapy, according to the investigators.

P<0.001) and delayed development of castration resistance, defined as time from randomization to radiographic disease progression, prostate-specific antigen progression or symptomatic skeletal event, whichever occurred first (HR, 0.34; P<0.001). The safety profile of apalutamide with longer follow-up and in the crossover group was consistent with previous reports. The cumulative incidence of any grade treatment-emergent falls, fractures and fatigue was similar between the two groups.

The final analysis of TITAN, with almost four years of median followup and nearly 40% of patients in the placebo group crossing over to receive apalutamide, demonstrates the continued benefit of the addition of apalutamide to ADT for a broad population of patients with metastatic castrationsensitive prostate cancer, according to the investigators.

Cabozantinib Prolongs PFS In Renal Cancer Cabozantinib significantly prolonged

PFS relative to sunitinib in the SWOG 1500 phase 2 study of patients with metastatic papillary renal cell carcinoma (abstract 270). In the study, investigators enrolled 152 patients with metastatic papillary renal cell carcinoma across 65 centers throughout the United States and Canada, randomly assigning them to receive sunitinib (Sutent, Pfizer), cabozantinib (Cabometyx, Exelixis), crizotinib (Xalkori, Pfizer) or savolitinib (AstraZeneca). All drug doses see GENITOURINARY, page 16

TITAN Final Analysis Supports Addition of Apalutamide to Androgen Deprivation Therapy Adding apalutamide to androgen deprivation therapy (ADT) improves OS for a broad population of patients with metastatic castration-sensitive prostate cancer, according to results from the phase 3 TITAN trial (abstract 11). Investigators enrolled 1,052 patients in this randomized, placebo-controlled, double-blind international trial and randomized them in a 1:1 fashion to receive either apalutamide (Erleada, Janssen) or placebo in addition to standard ADT. The dual primary end points were radiographic PFS and OS. A variety of preplanned secondary and exploratory end points also were assessed. In the primary analysis reported in 2019 after a median follow-up of 22.7 months, both radiographic PFS and OS met statistical significance. When the TITAN study was unblinded at that time, on the recommendation of the independent data monitoring committee, 39.5% of patients in the placebo group who had not progressed crossed over to receive open-label apalutamide, according to presenter Kim Chi, MD, a medical oncologist at BC Cancer and Vancouver Prostate Centre, in British Columbia. The final event-driven OS analysis, conducted at a median follow-up of 44 months and after 405 events had occurred, showed the risk for death with apalutamide was reduced by 35% (HR, 0.65; P<0.0001). The median treatment duration in the apalutamide group was 39.3 months, nearly double the median treatment duration of 20.2 months in the placebo group. Among patients who crossed over from placebo to apalutamide, the median treatment duration on apalutamide was 15.4 months. Treatment with apalutamide also significantly prolonged second PFS on next subsequent therapy (HR, 0.66;

THE MORE YOU DETECT THE BETTER YOU PROTECT Improve care for more patients with ePlex® Blood Culture Identification Panels, the only BCID panels that can detect >95% of organisms that cause sepsis Sepsis is a common complication of COVID-19 and rapid diagnosis is key to effective treatment. ePlex BCID Panels rapidly detect more of the organisms that cause sepsis. Armed with this critical information, you can prescribe the right treatment within hours – rather than days – improving patient care. The ePlex BCID Panels can identify >95% of the pathogens that cause sepsis. Combine this with order-to-report integration and templated comments and you’re ready to fast-track treatment intervention, enabling earlier escalation for resistant organisms or de-escalation of empirical antimicrobials.

To learn more, scan or visit GenMarkDX.com/DetectMore

16 Clinical

Pharmacy Practice News • July 2021

Oncology

GENITOURINARY continued from page 15

were administered orally: sunitinib 50 mg, delivered on the conventional four-week-on, two-week-off schedule, with dose reductions to 37.5 and 25 mg allowed; cabozantinib 60 mg daily, with reductions to 40 and 20 mg allowed; crizotinib 250 mg twice daily, with reductions to 200 mg twice daily and 250 mg once daily permitted; and savolitinib 600 mg daily, with reductions to 400 mg daily and then 200 mg

daily allowed. Patients were randomized equally to each of the study arms. The primary end point was PFS with secondary end points of OS, response rate and adverse events. The savolitinib and crizotinib study arms were terminated prematurely in a futility analysis. Neither showed benefit in PFS relative to sunitinib. Cabozantinib significantly prolonged PFS relative to sunitinib (HR, 0.6; 95% CI, 0.37-0.97; P=0.019). Cabozantinib also was associated with a significantly increased response rate relative to

sunitinib (23% vs. 4%). Cabozantinib resulted in a “statistically significant and clinically meaningful prolongation” of patients’ PFS rate, reported lead investigator Sumanta K. Pal, MD, the co-director of the kidney cancer program at City of Hope Comprehensive Cancer Center in Duarte, Calif., and his co-investigators, suggesting that cabozantinib should be considered a new “reference standard” for systemic therapy in patients with metastatic papillary renal cell carcinoma.

We’ve Got You

Covered

FULL LINE OF USP <797> & <800> COMPLIANT PRODUCTS

Pharmacy/Cleanroom/Chemo Gloves available at Acute Care Pharmaceuticals

» » » » »

Cleaners & Disinfectants Sterile & Non-Sterile Wipers Disposable Cleanroom Apparel Enviromental Controls Cleanroom Supplies

In Stock & Available at AmerisourceBergen Cardinal McKesson Medline SPEAK DIRECTLY WITH A PRODUCT EXPERT 888.909.7700 | pharma-choice.com info@acutecareonline.com Poway, CA

» » » »

Sterile & Non-sterile Available in multiple sizes Chemo tested Various brands in-stock

Featured: Pharma-GloveTM » AVAILABLE IN TWO DIFFERENT » » » » » »

PACKAGING CONFIGURATIONS

AMBIDEXTEROUS LATEX FREE, POWDER FREE 12” CUFF ISO CLASS 5 RATED STERILE USP <797> & <800> COMPLIANT

*Pharma-GloveTM

Encouraging and Promising Findings The range of studies presented at the 2021 Genitourinary Cancers Symposium was greatly encouraging for providers, Stacey Lisi, PharmD, BCOP, a clinical pharmacist in GU Oncology at Duke Cancer Center, in Durham, N.C., told Pharmacy Practice News. “These are very difficult diseases to treat, and these results are very promising for GU oncology patients.” The phase 3 CheckMate 274 trial of adjuvant nivolumab is encouraging because it’s the first immunotherapy study in the setting of advanced highrisk MIUC with positive results, Dr. Lisi said. Noting that there are other, ongoing trials of immunotherapy in this setting, she said the findings “set the stage” for patients to have additional options. “The quality of life was tolerable, with the usual expected side effects,” Dr. Lisi said. “The risk of recurrence is significant for this patient population, so an improvement in disease-free survival is exciting, although we’ll need to wait a little bit longer to see the overall survival data,” she added. Data from the EV-301 clinical trial are encouraging because in the metastatic bladder cancer setting there are few treatment options, especially for patients who cannot tolerate chemotherapy, Dr. Lisi said. Enfortumab vedotin offers a survival advantage. “This is an exciting, new type of therapy. It’s the first antibody drug conjugate available in this space,” she said. “These patients now have a very different option with positive results.” Initial analyses from the TITAN study two years ago showed positive results at about 22 months follow-up, but the data presented this year are the final analyses at the 44-month follow-up. The data confirm the benefit OS benefit of apalutamide, which Dr. Lisi said already was known as a promising option for patients with metastatic castration-sensitive prostate cancer. She called the SWOG 1500 phase 2 study “significant because papillary renal cell carcinoma is not a common type of renal cell cancer, so to accrue patients specifically with this type of histology is great.” The trial is further advantageous because it allows dose reductions for patients who cannot tolerate 60 mg, to 40 or 20 mg, daily, she added. “Moving forward, cabozantinib will likely be considered the standard therapy in future trials,” Dr. Dr. Lisi predicted. “The disease is difficult to treat, and it’s encouraging to know there is a treatment that prolongs progression-free survival for this specific patient population.” —Sharon Donovan The sources reported no relevant financial disclosures.

COMPANY

Clinical

Pharmacy Practice News • July 2021

Formulary

Biosimilars Specialty continued from page 1

“Of approximately 30 biosimilars approved by the FDA since 2015, at least eight cannot enter the market for anywhere between two and nine years because of patent litigation and exclusivity,” Dr. Rana said. In May 2021, the U.S. Supreme Court denied a petition from Sandoz to review a July 2020 decision from the Federal Circuit on its Sandoz biosimilar etanercept-szzs (Erelzi) for reference medicine etanercept (Enbrel, Amgen). “The lower court had upheld Amgen’s patent exclusivity for several more years. So despite there being several approved products already, we likely won’t have an etanercept biosimilar available until 2029. There’s a huge regulatory and legal side to this that has impeded biosimilar uptake.” Moreover, a report from the House Committee on Oversight and Reform, issued in May 2021, noted that AbbVie has obtained or applied for more than 250 patents on its adalimumab (Humira) to block competition from lower-priced biosimilars, with the last of these patents not set to expire until 2037. “According to an internal analysis obtained by the committee, earlier biosimilar entry would have forced a reduction in the price of Humira that would have saved the U.S. health care system at least $19 billion from 2016 to 2023,” the report stated (bit.ly/2TlCvqk).

Payor Preferences a Challenge After a new biosimilar actually enters the market, hospitals must manage discrepant preferred product status between a payor and hospital formulary. “As hospitals and their P&T [pharmacy and therapeutics] committees look to streamline inventories and preferred products, this is becoming more and more of an issue,” Dr. Rana said. “If there is only one reference product on the market, there’s typically a pretty well-defined medical policy for coverage. But with multiple biosimilars for a single reference product, you might have one large payor saying products X and Y are preferred, while another says A and B are preferred. That makes it harder for us as a health system to streamline [workflow to encourage] use of a single preferred product, which is ideal from an inventory management, medication safety and information technology perspective. And the payors might change their medical policies for preferred products on a regular basis, making things even more complicated.” Differences in FDA-approved indications for biosimilars as opposed to their reference products add another wrinkle for pharmacists to manage. Although some reference products and biosimilars are approved for all of the same

indications, there are notable variations for others. Consider rituximab (Rituxan, Genentech/Biogen) as one example. The originator product has an orphan drug designation until 2025 for a rare autoimmune disorder, pemphigus vulgaris, while its biosimilar competitors do not. One biosimilar, rituximab-abbs (Truxima, Celltrion), shares the originator’s indication in rheumatoid arthritis, while rituximab-pvvr (Ruxience, Pfizer) and rituximab-arrx (Riabni, Amgen) are not approved for that indication.

for use in epithelial ovarian, fallopian tube and primary peritoneal cancer. That’s an indication previously held only by Avastin, and only recently approved for Zirabev. Overall, however, explicit guidance is rare on the use of biosimilars for non–FDA-approved indications. Sometimes the only way to find out is by closely auditing reimbursement after using an agent on the first patient.”

Championing Infliximab-dyyb Adoption In addition to keeping up with and managing all these complicating factors, hospital pharmacists often take on the responsibility of championing

BMC Biosimilar Successes 97% of eligible IBD patients successfully transitioned to infliximab-dyyb

90% remained in remission $500,000 saved annually BMC, Boston Medical Center; IBD, inflammatory bowel disease Source: J Manag Care Spec Pharm. 2020;26(4):410-416.

“These differences in approvals sometimes stem from patent settlements between two companies in court,” Dr. Rana said. “Of course, it can be challenging to explain on the clinical side that a product is not approved for a particular indication not necessarily for lack of clinical equivalence, but because of regulatory issues instead.” Depending on an institution’s region and resources, it also may have to develop expertise in forecasting Medicare coverage and reimbursement. “Commercial payors typically have a pre-authorization process, but Medicare does not, so it’s often a gray area as to whether the biosimilar will be approved for those ‘offlabel’ uses where FDA-approved indications differ,” Dr. Rana said. “Typically, they will rely either on a national coverage determination or a local coverage determination [LCD] by your local Medicare Administrative Contractor [MAC].” For example, Houston Methodist’s MAC is Novitas; its LCD discussing offlabel use for biologics states that the MAC relies on preapproved Centers for Medicare & Medicaid Services compendia, such as the National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium. “I’ve found this resource to be slightly different from the NCCN’s clinical practice guidelines,” Dr. Rana said. “For example, the guidelines state that any FDA-approved biosimilar is an appropriate substitute for bevacizumab [Avastin, Genentech], but the compendium has gone a step further to note that Zirabev [bevacizumab-bvzre, Pfizer] and Mvasi [bevacizumab-awwb, Amgen] have a class 2A recommendation

biosimilar adoption among the medical staff. That’s the approach taken by Shubha Bhat, PharmD, who was part of a Boston Medical Center (BMC) pharmacy team that participated in a biosimilar switch program and who now is a clinical pharmacy specialist in gastroenterology at Cleveland Clinic in Cleveland. To address concerns over biosimilars, BMC’s specialty pharmacy director met with physician leaders from the departments of dermatology, rheumatology, and adult and pediatric gastroenterology, explained Dr. Bhat, who also presented at the ASHP session. Because only the outpatient gastroenterology clinic had an embedded pharmacist and pharmacy technician at the time, Dr. Bhat took the lead in evaluation, education and implementation of infliximabdyyb (Inflectra, Pfizer). The pharmacy team compiled the clinical evidence from the United States and Europe, as well as consulting with providers in the United Kingdom, Denmark and Spain who were part of a European gastroenterology network to discuss their clinical and operational process experiences with switching to infliximab-dyyb. The pharmacy team also created patient education materials and contacted each patient directly by phone to discuss the transition as soon as the prior authorization was approved, and developed talking points for providers regarding financial implications of switching to a biosimilar for patients and the health system. In December 2017, the P&T Committee approved the addition of infliximab-dyyb onto the formulary and as the preferred

infliximab product. All new patients prescribed infliximab would be started on the biosimilar unless it was not covered by their insurance. “The challenge was how to transition those already on the originator,” Dr. Bhat said. “Certain patients were excluded because of insurance company denials; others were getting infusions at an outside site, and we did not want to interrupt that workflow. Then some patients were concerned about the clinical stability of their remission and did not want to switch, even after patient education.” Ultimately, 146 of 151 eligible patients (97%) transitioned to infliximab-dyyb between March 2018 and June 2019, with an estimated savings of $500,000 annually to the health system. No significant impact on clinical outcomes was observed in an analysis of 40 patients with inflammatory bowel disease who switched from infliximab to infliximab-dyyb, with 36 of those patients (90%) remaining in remission, two (5%) not in remission on infliximab attaining remission on infliximab-dyyb, and one (2%) in remission on infliximab reporting an increase in clinical symptoms on infliximabdyyb. However, in the latter patient, a colonoscopy did not indicate active Crohn’s disease (J Manag Care Spec Pharm 2020;26[4]:410-416). “We’re now at the point where providers are becoming more comfortable with biosimilars, so we have the potential for more conversions down the line,” Dr. Bhat said.

Educating Stakeholders Education of key stakeholder groups is critical, Dr. Rana agreed. “Before implementing any formal changes or going through our P&T process, I provided a presentation on the biosimilar approval pathway, regulatory considerations and terminology like interchangeability and extrapolation that are unique to the biosimilar space, to key players like our hematology/oncology team and our P&T Committee.” That education process began in January 2020, and the P&T Committee began a comprehensive review of biosimilars later that year. “We have now successfully taken every biosimilar class that has an available biosimilar through our P&T Committee. At this point, we receive targeted questions about each class, but no significant hesitation about biosimilar implementation in general. Overall, our provider group is very comfortable with the use of these products.” —Gina Shaw Dr. Bhat reported no relevant financial disclosures. Dr. Rana reported that she is the primary investigator for a research study funded by a grant from Pfizer and NCCN evaluating the impact of discordant preferred biosimilars between payors and hospitals.

NOW AP PROVE D F O R 72-HOUR POSTOPERATIVE PAIN RELI E F The First and Only Extended-Release Dual-Acting Local Anesthetic (DALA)1-4 ZYNRELEF redeﬁnes postoperative pain management by providing superior pain relief for up to 72 hours, with fewer patients experiencing severe pain, and reducing or eliminating the need for opioids in many patients following surgery versus standard-of-care bupivacaine HCl solution.1-4

SYNERGISTIC MECHANISM OF ACTION1,5,a

SUPERIOR 72-HOUR PAIN RELIEF1-3,b

OPIOID REDUCTION & ELIMINATION1-3,b

NEEDLE-FREE APPLICATION1

BROAD ACCESS PRICING & FAVORABLE REIMBURSEMENT

Synergistic increases in analgesia compared with meloxicam or bupivacaine alone shown in preclinical and Phase 2 studies.1,5 Clinical ﬁndings were demonstrated in Phase 3 trials for bunionectomy with osteotomy and open inguinal herniorrhaphy comparing ZYNRELEF to both placebo and bupivacaine HCl solution.1-3

EXPLORE THE DATA AT ZYNRELEF.COM/PHARMA

Indication

Contraindications

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.

ZYNRELEF is contraindicated in patients with known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDS have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing coronary artery bypass graft (CABG) surgery.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures. IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS • Nonsteroidal anti-inﬂammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/ or GI bleeding are at greater risk for serious GI events.

Warnings and Precautions Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after application of ZYNRELEF. When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours. Hepatotoxicity: If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient. Hypertension: Patients taking some antihypertensive medication may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. Heart Failure and Edema: Avoid use of ZYNRELEF in patients with severe heart failure unless beneﬁts are expected to outweigh risk of worsening heart failure. Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless beneﬁts are expected to outweigh risk of worsening renal failure. Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.

PP-HTX011-0213 | 06/21

Use in Speciﬁc Populations Methemoglobinemia: Cases have been reported with local anesthetic use. Serious Skin Reactions: NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): If symptoms are present, evaluate clinically. Fetal Toxicity: Due to the risk of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus with NSAIDS, limit use of ZYNRELEF between about 20 to 30 weeks gestation, and avoid use after about 30 weeks. Hematologic Toxicity: Monitor hemoglobin and hematocrit in patients with any signs or symptoms of anemia. Drug Interactions Drugs That Interfere with Hemostasis: Monitor patients for bleeding who are using ZYNRELEF with drugs that interfere with hemostasis (eg, warfarin, aspirin, SSRIs/SNRIs). ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ACE Inhibitors and ARBs: Use with ZYNRELEF in elderly, volumedepleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function. Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effect.

Infertility: NSAIDs are associated with reversible infertility. Consider avoidance of ZYNRELEF in women who have difficulties conceiving. Severe Hepatic Impairment: Only use if beneﬁts are expected to outweigh risks; monitor for signs of worsening liver function. Severe Renal Impairment: Not recommended. Adverse Reactions Most common adverse reactions (incidence *10%) in controlled clinical trials with ZYNRELEF are constipation, vomiting, and headache. Report side effects to Heron at 1-844-437-6611 or to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For additional information about ZYNRELEF, please refer to the Brief Summary of Prescribing Information on adjacent page. References: 1. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2021. 2. Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee G-C. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: Phase III results from the randomized EPOCH 1 study. Reg Anesth Pain Med. 2019;44(7):700-706. doi:10.1136/rapm-2019-100531. 3. Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the Phase 3 EPOCH 2 study. Hernia. 2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6. 4. Lachiewicz PF, Lee G-C, Pollak R, Leiman D, Hu J, Sah A. HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized Phase 2b trial. J Arthroplasty. 2020;35(10):2843-2851. doi:10.1016/j.arth.2020.05.044. 5. Ottoboni T, Quart B, Pawasauskas J, Dasta JF, Pollak RA, Viscusi ER. Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain. Reg Anesth Pain Med. 2020;45(2):117-123. doi:10.1136/rapm-2019-100714.

REDEFINE POSTOPERATIVE PAIN MANAGEMENT

ZYNRELEF™ (bupivacaine and meloxicam) extended-release solution, for soft tissue or periarticular instillation use BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events INDICATIONS AND USAGE ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty. Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures. DOSAGE AND ADMINISTRATION Important Dosage and Administration Information: ZYNRELEF is intended for single-dose administration only. Avoid intravascular administration of ZYNRELEF. ZYNRELEF should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurologic or cardiac toxicity. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. The safety of concomitant administration of ZYNRELEF and other NSAID medications has not been evaluated. If additional NSAID medication is indicated in the post-operative period, monitor patients for signs and symptoms of NSAID toxicity. ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit. See ZYNRELEF Instructions for Use included in the kit for complete administration instructions. ZYNRELEF is not indicated for the following routes of administration: epidural, intrathecal, intravascular or intra-articular, regional nerve blocks, pre-incisional, and pre-procedural locoregional anesthetic techniques. Administration Instructions: ZYNRELEF is applied without a needle into the surgical site using a Luer lock cone-shaped applicator attached to the syringe following final irrigation and suction of each layer and prior to suturing. Only apply ZYNRELEF to the tissue layers below the skin incision and not directly onto the subdermal layer or skin. Use only the amount necessary to coat the tissues, such that ZYNRELEF does not leak from the surgical wound after closure. Dosing Instructions: The recommended dose of ZYNRELEF (bupivacaine/meloxicam) is as follows: − Bunionectomy: up to 2.3 mL to deliver 60 mg/1.8 mg − Open inguinal herniorrhaphy: up to 10.5 mL to deliver 300 mg/9 mg − Total knee arthroplasty: up to 14 mL to deliver 400 mg/12 mg See full Prescribing Information for all important dosage and administration information, preparation instructions and compatibility considerations. CONTRAINDICATIONS ZYNRELEF is contraindicated in patients with known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing coronary artery bypass graft (CABG) surgery. WARNINGS AND PRECAUTIONS Cardiovascular (CV) Thrombotic Events with NSAID Use: To minimize the risk of CV thrombotic events, do not exceed the recommended dose. Monitor for serious CV events. Aspirin does not mitigate the risk of these thrombotic events. In patients with a recent MI, avoid the use of ZYNRELEF unless the benefits are expected to outweigh the risk, and if used, monitor patients for signs of cardiac ischemia. The risk of these events following single-dose local application of ZYNRELEF is uncertain. Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID Use: To minimize the risk of GI bleeding, do not exceed the recommended dose and avoid using more than one NSAID at a time. If additional NSAID medication is indicated in the post-operative period, monitor patients for signs and symptoms of NSAID-related GI adverse reactions. In high-risk patients, evaluate if the benefit outweighs the risk of bleeding, remain alert for GI ulcerations and bleeding, and promptly evaluate and treat suspected serious GI adverse events. In patients using concomitant low-dose aspirin, monitor for GI bleeding. Dose-Related Toxicity: The toxic effect of local anesthetics are additive. When using with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours. Monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity.

Risk of Use in Patients with Impaired Cardiovascular Function: Patients with impaired cardiovascular function may be less able to compensate for the prolongation of AV conduction. Monitor patients closely for blood pressure, heart rate, and ECG changes. Hepatotoxicity: Bupivacaine should be used cautiously in patients with hepatic disease because of their inability to metabolize local anesthetics normally. NSAIDs are associated with elevations of ALT or AST and rare, sometimes fatal cases of severe hepatic injury. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur, perform a clinical evaluation of the patient. The risk of these events following single-dose local application of ZYNRELEF is uncertain. Hypertension: NSAID use in patients taking ACE inhibitors, thiazide or loop diuretics may result in impaired blood pressure control. Monitor blood pressure. Heart Failure and Edema: NSAID use in patients with heart failure may increase the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed with NSAIDs. Avoid use in patients with severe heart failure unless the benefit outweighs the risk of worsening heart failure; if used, monitor for signs of worsening heart failure. The risk of these events following single-dose local application of ZYNRELEF is uncertain. Renal Toxicity: NSAIDs may cause a dose-dependent reduction in renal blood flow and overt renal decompensation. Additionally, the metabolites of meloxicam are excreted by the kidney which may hasten the progression of renal dysfunction in those with renal disease. Correct dehydration and hypovolemia prior to initiating ZYNRELEF. Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Anaphylactic Reactions: Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs. Chondrolysis with Intra-Articular Infusion: Intra-articular infusions of local anesthetics have been associated with chondrolysis. ZYNRELEF is not approved for intra-articular infusion. Methemoglobinemia: Local anesthetics have been associated with methemoglobinemia. Treat with supportive care, and if necessary, methylene blue, exchange transfusion, or hyperbaric oxygen. Exacerbation of Asthma Related to Aspirin Sensitivity: NSAIDs are contraindicated in patients with aspirin-sensitive asthma. When ZYNRELEF is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for exacerbation of asthma symptoms. Serious Skin Reactions: NSAIDs can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, which can be fatal. If symptoms present, evaluate clinically. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): NSAIDs may cause DRESS. If signs or symptoms are present, evaluate the patient immediately and treat as clinically indicated. Fetal Toxicity: NSAIDs may cause fetal renal dysfunction leading to oligohydramnios at about 20 weeks gestation and premature closure of the fetal ductus arteriosus at about 30 weeks gestation or later. Limit use between about 20 to 30 weeks gestation, and avoid use after about 30 weeks. Hematologic Toxicity: NSAIDs may cause anemia due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), SSRIs and SNRIs may increase this risk. Monitor these patients’ hemoglobin and hematocrit and for signs or symtoms of anemia. Masking of Inflammation and Fever: NSAIDs reduce inflammation, and possibly fever, which may diminish detection of infections. ADVERSE REACTIONS The safety of ZYNRELEF has been evaluated in a total of 1067 patients undergoing various surgical procedures across 7 randomized, double-blind, bupivacaine- and placebo-controlled studies designed to investigate ZYNRELEF to reduce postoperative pain for 72 hours and the need for opioid analgesics. Among 504 patients who received ZYNRELEF in single doses of 60 mg/ 1.8 mg to 400 mg/12 mg via instillation into the surgical site, the most common adverse reactions (incidence greater than or equal to 10%) following ZYNRELEF administration were constipation, vomiting, and headache. The most common adverse reactions (≥ 5% and higher than placebo) in the following 3 studies were: • Bunionectomy: 157 patients received ZYNRELEF 60 mg/1.8 mg and the most common adverse reactions were dizziness, incision site edema, headache, incision site erythema, bradycardia, impaired healing, and muscle twitching. With the exception of muscle twitching, these events were also higher for bupivacaine HCl compared to placebo. A total of four subjects had delayed bone healing (assessed by X-ray on days 28 and 42), with no clinically meaningful difference between treatment groups. Additional local inflammatory adverse events observed at a higher incidence for ZYNRELEF compared to placebo or bupivacaine HCl included incision site cellulitis, wound dehiscence and incision site infection. • Herniorrhaphy: 163 patients received ZYNRELEF 300 mg/9 mg and the most common adverse reactions were headache, bradycardia, dysgeusia, and skin odor abnormal. With the exception of skin odor abnormal, these events were also higher for bupivacaine HCl compared to placebo. • Total knee arthroplasty: 58 patients received ZYNRELEF 400 mg/12 mg and the most common reactions were nausea, constipation, vomiting, hypertension, pyrexia, leukocytosis, and pruritus. With the exception of hypertension, these events were also higher for bupivacaine HCl compared to placebo.

DRUG INTERACTIONS Bupivacaine Drug Interactions: Local anesthetics: In clinical studies, other local anesthetics (including ropivacaine and lidocaine) have been administered before, during, or after application of ZYNRELEF without evidence of local anesthetic systemic toxicity. Administration of ZYNRELEF with other formulations of local anesthetics (ie, bupivacaine liposome injectable suspension) has not been studied. Drugs associated with methemoglobinemia: Bupivicane may increase risk of methemoglobinemia when concurrently used with nitrates, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other methemoglobinemia-associated drugs. Meloxicam Drug Interactions: Drugs That Interfere with Hemostasis: Meloxicam use with anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Monitor patients with concomitant use of ZYNRELEF with anticoagulants, antiplatelet agents, SSRIs, and SNRIs for signs of bleeding. ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Meloxicam may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ACE Inhibitors and ARBs: Meloxicam use with ACE inhibitors and ARBs in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, adequately hydrate and monitor for signs of worsening renal function. Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy, including antihypertensive effect. Digoxin: NSAIDs increase the serum concentration and prolong the half-life of digoxin. Monitor serum digoxin levels. Lithium: NSAIDs elevate plasma lithium levels and reductions in renal lithium clearance. Monitor for signs of lithium toxicity. Methotrexate: NSAIDs use with methotrexate may increase risk for neutropenia, thrombocytopenia, and other methotrexate-associated toxicities. Monitor for signs of methotrexate toxicities. Cyclosporine: NSAIDs use with cyclosporine may increase nephrotoxicity. Monitor for signs of worsening renal function. Pemetrexed: Meloxicam used with pemetrexed may increase myelosuppression, renal, and GI toxicities. In patient with creatinine clearance 45 to 79 mL/min, monitor for pemetrexed-associated toxicities. OVERDOSE No data are available with regard to overdose of ZYNRELEF. Management of Local Anesthetic Overdose: At the first sign of change, oxygen should be administered. The first step for convulsions, underventilation, or apnea is immediate maintenance of a patent airway and assisted or controlled ventilation capable of immediate positive airway pressure. After assuring airway and ventilation, evaluate and establish adequate circulation as indicated. Drugs that treat convulsions may depress the circulation. If convulsions persist despite adequate respiration, and if the circulation permits, small increments of an ultra-short acting barbiturate or a benzodiazepine may be administered intravenously. Supportive treatment of circulatory depression may require intravenous fluids and, when appropriate, a vasopressor. 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, may be indicated after initial administration of oxygen by mask if maintenance of a patent airway is inadequate or if prolonged ventilatory support is indicated. CLINICAL PHARMACOLOGY ZYNRELEF contains bupivacaine, an amide local anesthetic, and meloxicam, an NSAID. The contribution of each active ingredient in ZYNRELEF has been studied in clinical studies in herniorrhaphy or bunionectomy, utilizing ZYNRELEF and formulations of meloxicam alone or bupivacaine alone in the ZYNRELEF vehicle. Meloxicam alone provided negligible local analgesia and bupivacaine alone provided greater analgesia compared with placebo through 24 hours post surgery, despite exposure to bupivacaine for approximately 72 hours. Compared with bupivacaine alone in both studies, ZYNRELEF demonstrated greater and longer analgesia through 24, 48, and 72 hours. The instillation of ZYNRELEF into the surgical site results in significant systemic plasma levels of bupivacaine and meloxicam through 96 hours. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy. PATIENT COUNSELING Inform patients of the risks and mitigations for: CV thrombotic events; GI bleeding, ulceration, and perforation, including the increased risk of GI toxicity with use of NSAIDs in the postoperative period; anaphylactic reactions; serious skin reactions, including DRESS; methemoglobinemia; fetal toxicity; and temporary loss of sensation near the surgical site. This information is not comprehensive. Visit www.zynrelef.com to obtain the full Prescribing Information, including Boxed Warning. © 2021 Heron Therapeutics, Inc. All rights reserved. ZYNRELEF™ is a trademark of Heron Therapeutics, Inc.

Manufactured and marketed by: Heron Therapeutics, Inc., 4242 Campus Point Court, Suite 200, San Diego, CA, 92121, USA. PP-HTX011-0102 05/21

Clinical

Pharmacy Practice News • July 2021

Opinion

Clinical Pharmacists Save Time in an Emergency Vincent Peyko, PharmD, BCPS (AQ-ID) Clinical Pharmacy Specialist – Emergency Medicine Mercy Health – St. Elizabeth Boardman Hospital Boardman, Ohio

he emergency department (ED) presents many challenges related to the selection, dosing, administration, and monitoring of medications. The American College of Emergency Physicians considers the role of pharmacists in the ED critical to ensure efficient, safe, and effective medication use.1 Pharmacists should serve as well-integrated members of the ED multidisciplinary team and actively participate in patient care decisions to optimize pharmacotherapy for patients.1 Since pharmacists are unable to generate revenue by billing for their services in most states, quantifying cost avoidance is a common modality to demonstrate the monetary value of clinical pharmacy services.2 Although it is difficult to procure precise data on cost avoidance, published reports have demonstrated thousands to millions of dollars of cost savings and cost avoidance through pharmacy interventions in various health care settings.3-5 Specific to the ED, clinical pharmacy services have demonstrated cost avoidance of hundreds of thousands to millions of dollars and may increase survival to hospital admission.6,7 Although cost avoidance is a common way to demonstrate the value of clinical pharmacy services, value also has been demonstrated through the time pharmacists save physicians. The expanded role of clinical pharmacy in the ED has enabled clinical pharmacists to take on certain tasks that typically had been the responsibility of ED physicians. Grill et al evaluated the role of 4 clinical pharmacists in this setting and demonstrated total physician time saved of 69.8 hours over the course of their study, which equated to 75 minutes per 10-hour shift.8 Nationally, the average number of patients evaluated by physicians in the ED between 2011 and 2014 was 2.5 per hour.9 Many physicians are reimbursed based on the calculation of the relative value unit (RVU), an assigned value for each Current Procedural Terminology (CPT) code.10 Three components compose an initial RVU: work (55%), practice expense (42%), and professional liability insurance (3%). These 3 components are adjusted by the geographic practice cost indexes, which attempt to adjust for cost of living for different regions of the country. This total RVU is finally multiplied by an annually determined conversion factor. Emergency physician reimbursement is directly derived from RVU generation.10 RVU per patient will

vary by institution, but a report from 79 academic medical centers determined the average RVU to be 2.92 per patient.11 In 2019, the CMS payment per RVU was approximately $36.12 RVU and RVU compilation are discussed for 2 reasons: First, the generation of physician time saved, as demonstrated by Grill et al8, may seem to possess a degree of confounding. This is similar to the confounding often seen with reimbursement for physicians, as illustrated by RVU calculation.13 Second, physician time saved by clinical pharmacists directly affects physician RVUs. A physician who is able to see 1 more patient every 3 hours generates more RVUs. Considering the time-saved totals from Grill et al (ie, 75 minutes per 10-hour shift), physician-hours saved were 0.125 hours for every pharmacist hour worked.3 This equates to 1 physician-hour per 8-hour shift, 2.5 extra patients per 8-hour shift, and 7.75 RVUs per 8-hour shift. This yields a savings of 0.969 RVUs per hour. At $36 per RVU, that is approximately $279 per 8-hour shift. Grill et al describe staffing their ED 10 hours per day, 7 days per week, which is 3,640 hours per year. Their data demonstrate saving their physicians more than $127,000 per year. These results pose this question: Should clinical pharmacists or the hospitals that employ them be compensated by the physicians or physician groups contracted to provide care in EDs? Cost avoidance is the main reason hospitals have clinical pharmacists on staff. The therapeutic optimization and safety the ED pharmacist provides to the patient, the instruction and service the ED pharmacist provides to nursing, the direct drug cost savings to the pharmacy, and the recommendations and services—traditionally pharmacy services—provided to the physician all factor into cost avoidance. It’s why the cost avoidance numbers are so high and very difficult to quantify. For physicians, saved time means they get to see more patients and generate more RVUs, which means more direct pay to physician groups and physicians. This may indirectly benefit the hospital but is directly profitable to physicians. In the evaluation by Grill et al, the physician group staffing their ED gains an extra $127,000 per year that goes into their pockets entirely because the ED pharmacist is freeing them up to see more patients. The question now is whether physician groups contracted by hospitals should compensate hospitals

for the time and subsequent additional RVUs the pharmacists employed by that hospital enabled them to generate. How physician groups could appropriately compensate hospitals for ED clinical pharmacy services is another matter, as is whether or how hospitals would compensate clinical pharmacists for this additional revenue. But recognition of this untapped revenue stream for clinical pharmacists is the purpose of this article. The experience, acumen, and skill set of all ED clinical pharmacists is not equal and, thus, some ED clinical pharmacists will be able to achieve more cost avoidance and save ED physicians more time than others. Likewise, the reliance of physicians on pharmacists will vary. Some physicians rely heavily on clinical pharmacy assistance, whereas other physicians use clinical pharmacists significantly less. The experience of clinical pharmacists and ease of physicians working with the clinical pharmacists in their department will lead to variation in the time ED clinical pharmacists save physicians. Beyond this, could the idea of physician time saved be expanded outside of the ED? Pharmacists are consulted about antimicrobials, anticoagulants, pain management, and other medications, saving physicians time, and allowing them to see more patients. Although RVU generation outside of the ED may become more complicated in relation to physician reimbursement, this may be another avenue of compensation to explore.

Conclusion Pharmacists have consistently demonstrated cost savings through cost avoidance in a variety of health care settings.4-8 Patient satisfaction, outcomes of chronic diseases, prescribing practices, physician satisfaction, and risk for malpractice claims are all affected by physician time.13 More physician time also should translate to more patients evaluated, more RVUs, and, subsequently, more physician reimbursement. The ED clinical pharmacist may directly increase physician reimbursement. This reimbursement has a direct positive impact on the physician and/or physician group, without direct financial benefit for the pharmacist or hospital. As such, it certainly poses the question of whether ED clinical pharmacists or the hospitals that employ them should be compensated for the time and resulting financial benefit provided to the

physicians by their services. This, in turn, prompts the question of whether or not this is a new space for pharmacy service revenue generation at large.

References 1. American College of Emergency Physicians. Clinical pharmacy services in the emergency department. Revised January 2021. Accessed March 16, 2021. https://www.acep.org/patientcare/policy-statements/clinical-pharmacistservices-in-the-emergency-department/ 2. Hammond DA, Gurnani PK, Flannery AH, et al. Scoping review of interventions associated with cost avoidance able to be performed in the intensive care unit and emergency department. Pharmacotherapy. 2019;39(3):215-231. 3. Warden BA, Shapiro MD, Fazio S. The role of the clinical pharmacist in a preventive cardiology practice. Ann Pharmacother. 2019;53(12):1214-1219. 4. Munoz-Pichuante D, Villa-Zapata L. Benefit of incorporating clinical pharmacists in an adult intensive care unit: a cost-savings study. J Clin Pharm Ther. 2020;45(5):1127-1133. 5. Hammond DA, Flowers HJ, Meena N, et al. Cost avoidance associated with clinical pharmacist presence in medical intensive care unit. J Am Coll Clin Pharm. 2019;2(6):610-615. 6. McAllister MW, Chestnutt JG. Improved outcomes and cost savings associated with pharmacist presence in the emergency department. Hosp Pharm. 2017;52(6):433-437. 7.

Lada P, Delgado G Jr. Documentation of pharmacists’ interventions in an emergency department and associated cost avoidance. Am J Health Syst Pharm. 2007;64(1):63-68.

8. Grill J, Bryant C, Markel K, et al. A study of time saved by emergency medicine physicians through working with clinical pharmacists in the emergency department. Am J Emerg Med. 2019;37(9):1720-1722. 9. Augustine J. Emergency Department totaBenchmarking Alliance releases 2014 data on staffing, physician productivity. January 15, 2016. Accessed March 16, 2021. https://www. acepnow.com/article/emergency-departmentbenchmarking-alliance-releases-2014-data-onstaffing-physician-productivity/2/ 10. Proctor J. Gauging emergency physician productivity: are RVUs the answer? American College of Emergency Physicians. Accessed June 2020. https://www.acep.org/imports/ clinical-and-practice-management/resources/ reimbursement-imported/gauging-emergencyphysician-productivity-are-rvus-the-answer/ 11. Reznek M, Scheulen J, Harbertson C, et al. Contributions of academic emergency medicine programs to U.S. health care: summary of the AAAEM-AACEM benchmarking data. Acad Emerg Med. 2018;25:444-452. doi:10.1111/acem.13337. 12. Granovsky MA, McKenzie DA. 2019 Medicare physician fee schedule released. ACEPNow. December 17, 2018. Accessed March 16, 2021. https://www.acepnow.com/article/2019-medicare-physician-fee-schedule-released/ 13. Dugdale D, Epstein R, Pantilat SZ. Time and patient-physician relationship. J Gen Intern Med. 1999;14(suppl 1):S34-S40.

Dr Peyko reported no relevant financial disclosures.

22 Technology

Pharmacy Practice News • July 2021

Opinion

How Health IT Supports Medication Mgmt Reform Katherine Herring Capps GTMRx Institute Vienna, Virginia

s the Biden administration designs its strategy to reform health care policy, it must address the inherent need for medication management reform. It is time to embolden health care strategy by ensuring patients understand their medications and can collaborate with their physician along with a clinical

team leverages each member’s specialty and expertise to achieve optimized medication use. A thorough, data-driven record of the patient’s health and medical history, medications, and clinical and diagnostic findings serves as a guide to evaluating whether the individual’s goals of therapy have been met. Today this type of population identification, and individual patient evaluation, monitoring and medication correction is only happening on a very small scale, and not nearly broad enough to make a significant impact. Current health IT systems don’t easily allow access to all

Data indicate that improper medication therapy (misuse, underuse and overuse) can result in treatment failure, new medical problems or both. Each year, 275,000 avoidable deaths and $528.4 billion in health care costs result from suboptimal medication use (Ann Pharmacother 2018;52[9]:829-837). Studies show that by improving clinical outcomes and reducing hospital readmission rates, CMM reduces the strain on the health care system. Health IT enables CMM and fosters a health care process designed to consistently identify, manage and resolve medication therapy problems for patients

We need immediate delivery system, payment and policy transformation to streamline clinical trials and reduce the costs of bringing drugs to market while enabling successful, broad-scale adoption of integrated CMM services. Appropriate diagnosis and access to advanced diagnostics with companion/complementary and pharmacogenetics testing are essential to target the correct therapy. Success requires team-based, patient-centered care models that recognize appropriately skilled clinical

10 Steps to CMM

Identify patients who have not achieved clinical goals of therapy.

Understand the patient’s personal medication experience, history, preferences and beliefs.

Identify actual use patterns of all medications including OTCs, bioactive supplements and prescribed agents.

Assess each medication for appropriateness, effectiveness, safety (including drug interactions) and adherence.

Identify all drug therapy problems.

Develop a care plan addressing recommended steps, including therapeutic changes needed to achieve optimal outcomes.

Ensure patient agrees with and understands care plan.

Document all steps and current clinical status versus goals of therapy.

Follow-up evaluations are critical to determine effects of medication changes; reassess actual outcomes and recommend further therapeutic changes as needed.

CMM is a reiterative process! Care is coordinated with other team members and personalized goals of therapy are understood by all team members.

Source: GTMRx Institute.

pharmacist to ensure the medicines prescribed are right for them. With more than 10,000 drugs on the market, appropriate, effective, safe and precise use of medication and gene therapies is essential today more than ever. Complete and accurate clinical data, securely accessed through health information technology systems, at the point of care are pivotal to changing and reforming our medication use process. Clinical data must be actionable and accessible to every member of the care team—and that team must include a clinical pharmacist. Without a proper health IT solution in place, comprehensive medication management (CMM) will remain a limited-use concept rather than a practice that is broadly available to all Americans. CMM is defined as a team-based care solution, wherein the patient works with a physician and a team of other health care providers, including a clinical pharmacist (bit.ly/2QFMNk3). This interprofessional

team members or readily offer population insights and clinical data at the point of care that are required to get the medications right. To optimize medication use through CMM, the health care industry in both public and private sectors must adopt, implement and enforce data-sharing and reporting requirements. Making technology-enabled clinical data available at the point of care to the entire team allows providers to execute critical steps in the CMM process. The data help teams determine which patients have not achieved therapeutic goals and analyze actual use patterns for all medications (e.g., prescribed drugs, over-thecounter, supplements and biologics). This complete clinical data access provides patient care teams with information to assess medication for safe, effective and appropriate use. Whether it is diagnostic and lab results, pharmacogenomic testing results, clinical notes or patient status, all of the resulting data points are critical to making CMM successful.

across the continuum of care. This process then can be correlated with patients’ overriding changes in health status or health care utilization patterns, thus demonstrating CMM’s contribution and value to the nationwide health care system (J Am Coll Clin Pharm 2020;3[6]:1028-1037). To achieve medication management reform, there must be consensus among providers, payors, patients and policymakers. Our organization, the GTMRx Institute, developed a course of action titled “The GTMRx Blueprint for Change” (bit.ly/3vYk2iA). It is based upon five principles: A patient-centered, systematic and coordinated approach to medication use will vastly improve outcomes and reduce overall health care costs. We must align systems of care to integrate comprehensive medication management, engaging patients to ensure they are willing and able to take those medications that are indicated, effective and safe, to optimize outcomes.

pharmacists as medication experts who work in collaborative practice with physicians and other providers. We advocate that the Biden administration endorse this road map to deliver policy change focused on team-based health care to get the medications right. Our country is currently plagued by crisis upon crisis: COVID-19, opioid addiction and 27.2% of American adults living with multiple chronic health conditions (CDC Preventing Chronic Disease Research Brief. Vol. 17. Sept 17, 2020). Now is the ideal time for multidisciplinary collaboration and reform centered on CMM to optimize patient care. Ms. Capps is the co-founder and executive director of the GTMRx Institute.

What’s Your View? Send your comments to davidb@ mcmahonmed.com and we will share them with your colleagues.

Unit Dose Done Right Brightly Colored Labels Call Attention to Meds Requiring Special Handling

Unit Dos e Bar Cod , ing, Pharma c Nursing y & Supply Experts !

s Cold Seal s Tamper-Evident s Moisture Resistant s Ultraviolet Inhibitant s Reduces Cross Contamination s Ideal for Meds Covered by USP 800 s 6 and 12-month Beyond-Use Dating s 1-D and 2-D Bar Coding s Flexible Label and Report Formatting s Multiple Sizes and Shapes to Fit Your Meds & Storage Needs

Scan QR Code for more information and pricing.

Simple. Reliable.

800.523.8966

MediDose.com

24 Policy

Pharmacy Practice News • July 2021

Compliance

Accreditation Updates continued from page 1

standard, which has bcome relevant to many pharmacies over the past year. The new edition will be published “very soon,” said Lynnae Mahaney, BSPharm, MBA, ASHP’s senior director of pharmacy accreditation. “The revisions process [enabled] us to review the standard elements common to each of our standards and to use the same terminology in our core set of standard elements—the same

for each accreditation,” she said. “In addition, we now have six domains in the core standard elements. We did this by reorganizing standard elements into more welldefined areas of focus.” The changes are being coordinated by ASHP’s Pharmacy Accreditation Office of Global Resource Development and Consulting. As a result of the changes, three of ASHP’s primary accreditation

programs for pharmacies—Community and Outpatient Pharmacy (COPP), Specialty Pharmacy Practice (SPP) and TPP—will be organized around the same six standard domains: 1.0: Organizational Infrastructure 2.0: Financial Management 3.0: Medication Handling, Order Verification and Dispensing 4.0: Confidentiality, Privacy, and Security of Patient Information 5.0: Patient Care 6.0: Quality Improvement “This restructuring will make it much

easier for the clients who desire dual accreditations, such as SP and TPP or COPP and TPP,” Ms. Mahaney said. “Applicants will be able to view the common standard elements, the specific SPP standard elements, and the TPP-speecific elements all in one document, ment, and we can provide this in multiple iple views. It will make the process very efficient ficient and the cost of dual accreditations very ery attractive, whether the accreditationss are done concomitantly—which is most efficient from a resource and cost standpoint—or the pharmacy wants to add an accreditation at a later date.” Ms. Mahaney said the content, intent and expectations of the SP standard elements are staying the same, with only some minor changes in the language. “We will also provide a crosswalk from the 2019 SP standard version 3 to the 2021 reorganized standard to assist pharmacies going through reaccreditation.”

URAC Updates URAC also has revamped its specialty pharmacy accreditation program, with its most recent changes released in October 2019. “Now that we are a year and a half into it, this is the program everyone is accrediting and reaccrediting under, and there are some key areas of focus that are new to some people,” said Heather Bonome, PharmD, URAC’s pharmacy director. For example, the 2019 revision expanded URAC’s previous “cold chain” standard to more broadly address temperature management during distribution, requiring a validated process for all temperature ranges, including room-temperature medications. More validation also is required than with previous standards. “With the last round, we specified that these processes had to be tested, and while some organizations were doing a great job testing, others would just send one shipment,” Dr. Bonome said. “The new standards require multiple tests to representative geographic locations in cold and warm weather. The organizations can still establish their testing themselves, because every practice is different and every organization has a different geographical footprint. But because this element is new and the idea of roomtemperature medications being included wasn’t on these organizations’ radar, it can be a challenge, and focusing on it earlier rather than later is important.” The new standards also require clinical protocols to be specific to drug and therapy class. “Previously, it was acceptable to have one generic clinical protocol: ‘I’m going to contact every patient, ask how they’re doing and ask about side effects,’ Dr. Bonome said. “But that’s not what specialty pharmacy is about. We need to understand the specifics of these

Policy

Pharmacy Practice News • July 2021

Compliance URAC’s cold chain standards have been expanded to more broadly address temperature management during drug distribution, requiring a validated process for all temperature ranges, including room-temperature medications.

highly complex drugs in patients with highly complex diseases. So, although the protocols can have a similar structure, we now need to see evidence that interactions and interventions are designed to be drug- and/or class-specific.” Over the past three years, Dr. Bonome noted, URAC also has launched several new programs, including its Medicare Home Infusion Therapy Supplier Accreditation Program (a type of accreditation now required to qualify for bundled payment reimbursement by Medicare); its Rare Disease Pharmacy Center of Excellence Designation, which specialty pharmacies can add to their accreditations; and a Specialty Pharmacy Services Accreditation. “That accreditation is for organizations that provide services to affiliated dispensing partner pharmacies,” Dr. Bonome explained. “They partner with pharmacies that may not have the ability to build the infrastructure for all the clinical support, but can dispense and ship or provide to the patient. The specialty pharmacy services organizations provide outsourced offerings such as patient support programs, benefits and reimbursement services, regulatory and REMS [Risk Evaluation and Mitigation Strategies] requirements, distribution services, and data collection.”

their own credentialing process. “Payor and PBM credentialing requirements continue to increase,” Ms. Mahaney said. “We do see some PBMs going on site to some percentage of their pharmacies to do credentialing themselves.” These requirements can be a burden

for specialty pharmacies, Ms. Mahaney admitted. “It’s a lot,” she said. “Our approach to accreditation is that it is an ongoing, breathing, living philosophy and culture of quality, and we advise the organizations we work with to approach it the same way. If you have a culture that is focused on improvement, that sets you up well for any accreditation.” That’s why it is so critical “to update policies and procedures, share quality on an ongoing basis and keep projects upto-date,” Ms. Mahaney noted. Dr. Bonome agreed. “Don’t just

track metrics and submit them to us because we require it,” she said. “Use this information. This is your way to demonstrate that you do better at managing readmission rates, or maintaining adherence to medications, or deploying clinical interventions that avoid unnecessary interactions, better than anyone else.” —Gina Shaw The sources reported no relevant financial disclosures other than their stated employment.

Got a minute? That’s all we need.

Opioid Stewardship Another new program this year is URAC’s opioid stewardship designation, which is not limited to pharmacies. The program provides a framework for organizations to demonstrate their commitment to patients’ safe use of opioid medications. In addition, soon to come is a program called “Expanded Pharmacy Services,” which recognizes pharmacies that perform additional services such as medication therapy management, vaccine administration, health screenings, and collaborative practice programs. “This will not be exclusive to the specialty space, and probably will be more prevalent among community pharmacies as a way to differentiate themselves,” Dr. Bonome said. Besides requiring specialty pharmacies to achieve two or more accreditations from organizations such as URAC and ASHP, many payors and pharmacy benefit managers (PBMs) are now requiring

Sterile Contec Healthcare TB1-3300 Disinfectant Proven effective in 1 minute! ®

™

Contec Healthcare TB1-3300 Disinfectant has demonstrated effectiveness against viruses similar to COVID-19 on hard, nonporous surfaces. Therefore, TB1-3300 can be used against COVID-19 when used in accordance with the directions for use against Poliovirus type 1 and Feline Calicivirus on hard, nonporous surfaces. Refer to CDC website at https://www.cdc.gov/coronavirus/2019-nCoV/index.html for additional information.

26 Policy

Pharmacy Practice News • July 2021

Review Article

Practical Application of the Safe to Touch 2020 Consensus Conference on Hazardous Drug Surface Contamination:

Implementation Guidance For Health Care Institutions MICHAEL GABAY, PHARMD, JD, BCPS

DAVID KVANCZ

Clinical Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Senior Vice President, Strategic Client Relationships Visante, Inc St. Paul, Minnesota

n September 2020, the Safe to Touch Consensus Conference on Hazardous Drug Surface Contamination was convened, bringing together subject matter experts in the field of hazardous drugs (HDs) to develop consensus statements and

corresponding recommendations regarding surface contamination.1

During Safe to Touch, authoritative speakers virtually presented to a conference expert panel and an audience of approximately 25 reaction panel members on a variety of HD topics including the impact of HDs on health, the current regulatory and standards environment, and commercially available surface contamination monitoring systems.1 The full Safe to Touch conference agenda and an overview of the panelists and speakers may be accessed at safetotouch.uic.edu; Table 1 lists the overall objectives of the conference. Reaction panel members included pharmacists and nurses involved in clinical practice or administration in hospitals and health systems, infusion services, medication safety, regulatory affairs, and accreditation and professional organizations. Reaction panel members provided invaluable input that the expert panel used to develop a set of initial consensus statements after the formal conference. Subsequently, conference attendees were allowed to comment on these statements further in a virtual town hall. Overall, consensus was achieved through drafting recommendations, collecting verbal and written comments from conference attendees, and the expert panel revising until no additional substantive comments were provided.

Consensus Statements From the 2020 Safe to Touch Conference on HD Surface Contamination Eleven formal consensus statements were developed and agreed upon by the experts and attendees of the 2020 Safe to Touch Conference on Hazardous Drug Surface Contamination. These statements and abbreviated corresponding recommendations are listed below. The full summary report of the 2020 Safe to Touch Conference is published as a special feature in the American Journal of Health-System Pharmacy.1 1. Create an effective surface contamination monitoring plan to serve as a process validation tool and support a nonpunitive, fair, and just institutional culture. Ideally, the plans should emphasize patient and employee safety as a priority institutionally, assist in compliance with relevant regulatory and accreditation standards, reduce overall organizational risk, serve as a process validation tool, and demonstrate an institution’s values and promotion of a just culture. 2. Establish a surface contamination monitoring policy for every health care setting where HDs are handled. To ensure success, individualize the policies as needed and use an interdisciplinary approach that involves

affected stakeholders. 3. Reduce the occurrence of HD surface contamination. The reduction may require implementing administrative and engineering controls as well as other technologies that reduce the occurrence of HD surface contamination whenever possible. 4. Develop a comprehensive, setting-specific wipe sampling plan for ongoing HD surface contamination monitoring. The plan should be institution-specific and be used to determine baseline contamination, screen

for potential occupational exposures, and evaluate the efficiency of cleaning procedures. 5. Employ both qualitative and quantitative tests for ongoing surface contamination monitoring. Use qualitative tests for when rapid results are needed to determine the presence or absence of an HD, and quantitative tests to provide an actual amount of the detected HD. 6. Report surface contamination monitoring test results in a standardized format. Laboratories should report test results in a standard ng/cm2 format in order for comparisons with published values to be undertaken with ease, and should convey information within a surface contamination monitoring report in a consistent manner (eg, name of HD tested, description of the location of the sample, and so forth). 7. Mitigate HD spills and emphasize a commitment to decontamination.

Table 1. 2020 Safe to Touch Consensus Conference On HD Surface Contamination Objectives1,2 • To understand other healthcare disciplines’ standards and best practices for the handling of hazardous substances within their respective practices, which may have applicability to HD surface contamination monitoring. • To understand the current state of HD surface contamination monitoring within the medication use system for all dosage forms across all patient care sites. • To assess the capabilities, current utilization, benefits, and challenges of commercially available surface contamination monitoring technologies and systems. • To promulgate best practice recommendations for the monitoring of HD surface contamination. • To produce a conference consensus statement on the topic of HD surface contamination monitoring, suitable for publication in an appropriate peerreviewed journal. HD, hazardous drug

Policy 27

Pharmacy Practice News • July 2021

Review Article

Commit to ongoing decontamination of areas where HDs are handled, develop a plan for the potential prevention and cleanup of HD spills, and form a HD spill response team. 8. Implement safety practices related to preparation and administration of HDs. Clearly identify HDs that require safe-handling precautions and integrate HD statements into electronic medication workflow systems. 9. Conduct further research in the area of HD surface contamination. Continue to support and conduct research into topics related to HD surface contamination. 10. Collaborate to highlight the importance and increase the scope of ongoing HD surface contamination monitoring. Educate affected individuals and increase the scope of HD surface contamination monitoring across various settings through stakeholder collaboration. 11. Recognize barriers to implementation of an effective surface contamination monitoring program. Ascertain ways to overcome these barriers by considering that the costs of inaction may potentially exceed the institutional financial investment.

Practical Application of the Safe to Touch Consensus Statements for Health Care Institutions—Implementation Guidance The majority of the Safe to Touch consensus statements are directly applicable to health care institutions. It is essential that clinicians and administrators interpret and implement the statements and recommendations appropriately. The initial development of an institutional HD surface contamination monitoring

plan should include a rationale and background summarizing the numerous clinical studies over the past decades that demonstrate the widespread occurrence of HD surface contamination in health care institutions.3-8 The plan also should emphasize the importance of patient and employee safety with regard to HD exposure. Various federal agencies and professional organizations have developed best practices and guidelines on HD management that can serve as invaluable resources when developing the rationale and background of an HD surface contamination monitoring plan and/or policy (Table 2). An HD surface contamination monitoring policy should be tailored to the needs of the individual health care institution, recognizing that each institution may have several areas where the potential for HD surface contamination exists (eg, receiving, pharmacy, transport, patient care units/rooms, outpatient infusion centers, procedural areas, waste disposal areas). Policy development should be interdisciplinary, include various institutional stakeholders (eg, administration, environmental services, legal, medication safety, risk management, providers, patients), and driven by an experienced leader who is ultimately accountable for policy advancement and implementation. Key topics that should be detailed within a HD surface contamination monitoring policy include identification of all areas where the potential for HD surface contamination exists, individuals responsible for performing contamination monitoring in the identified areas, a discussion of initial and ongoing training, necessary personal protective equipment, interpretation of monitoring results and the process for reporting a positive test result, establishment of a cleaning protocol including staff notification, and when to retest if necessary. Health care institutions should implement administrative and engineering controls to reduce the occurrence of contamination. 9,15 Administrative controls rely on the worker handling HDs to adhere to practices intended to minimize exposure and include training on relevant policies and procedures (eg, new employee orientation, ongoing competency assessments), limiting access to areas containing HDs, limiting the time workers handle HDs, good housekeeping practices, handwashing, and monitoring of compliance with workplace practices. Engineering controls isolate the worker from the HD and include primary controls (biological safety cabinets, compounding

Table 2. Resources for HD Surface Contamination Monitoring Plan and/or Policy Development9-16 • CDC/NIOSH: Managing hazardous drug exposures: information for healthcare settings (2020; draft) • ASCO Safe handling of hazardous drugs: ASCO standards (2019) • ONS/HOPA Ensuring health care worker safety when handling hazardous drugs (2019) • ASHP Guidelines on handling hazardous drugs (2018) • ONS Safe handling of hazardous drugs (2017) • OSHA Technical Manual: Controlling occupational exposure to hazardous drugs (2016) • USP General Chapter <800> (2019) • NIOSH Alert: Preventing occupational exposure to antineoplastic and other hazardous drugs (2004) ASCO, American Society of Clinical Oncology; ASHP, American Society of Health-System Pharmacists; HOPA, Hematology/Oncology Pharmacy Association; NIOSH, National Institute for Occupational Safety and Health; ONS, Oncology Nursing Society; OSHA, Occupational Safety and Health Administration; USP, United States Pharmacopoeia

aseptic containment isolators), secondary controls (proper ventilation and negative-pressure rooms), and closed system drug-transfer devices (CSTDs). CSTDs mechanically prohibit the transfer of environmental contaminants into a system and the escape of HD or vapor out of a system.16 Results from various studies confirm the efficacy of CSTDs in reducing surface contamination with antineoplastic medications.17-19 Institutions also should implement other technologies that may reduce the occurrence of HD surface contamination, including robotic drug preparation, needleless systems, and unit-dose/ready-to-use HD preparations. The development of a wipe sampling plan for ongoing HD surface contamination monitoring also is essential. At minimum, surface wipe sampling should be conducted at baseline and at least every 6 months, with checking on a monthly basis or as necessary to assess institutional HD handling in various locations and the effectiveness of HD spill cleanup practices. Wipe sampling locations may include surfaces and floors in front of primary engineering controls in the pharmacy and various other areas in the pharmacy or nursing/patient care units including, but not limited to, door handles, computer keyboards and mice, drug administration areas, and bathrooms. A wipe sampling size of 400 to approximately 900 cm2 may be reasonable in most situations; however, the optimal size of the area to be wiped, or the optimal number of wipe samples to be performed, has not been established.20 Sampling should generally be conducted in the same locations over time to validate HD handling processes and reveal surface contamination

trends. Health care institutions should perform wipe sampling for HDs that are problematic with regard to preparation or administration and for the top 5 to 10 HDs by number of doses prepared, including robotically prepared doses. When considering which wipe sampling system to select, HDs of institutional concern should match those in the selected system, with the limit of detection and limit of quantitation reported by the laboratory for these agents. Institutions should use both qualitative and quantitative tests as part of their ongoing HD surface contamination monitoring plan in most situations. Currently, there is only 1 commercially available rapid qualitative system (BD HD Check), which offers 3 HDs that can be tested (cyclophosphamide, doxorubicin, and methotrexate). Vendors offer a variety of quantitative tests that provide an actual amount of the detected antineoplastic, hormone, or other HD. However, institutions should be aware that results from quantitative tests of surface contamination may not be received for weeks and there is no established standard for exposure limits. Ongoing decontamination of areas where HDs are handled is another important aspect of mitigating risks associated with HD surface contamination. Health care institutions should select appropriate decontamination agents for the type of HD contaminants, location, and surfaces to be cleaned.12,14 Additionally, creation of a plan for the potential prevention and cleanup of HD spills is vital; the 2018 American Society of Health-System Pharmacists Guideline on Handling Hazardous Drugs contains appendices on see SAFE TO TOUCH, page 28

Sign up @ SpecialtyPharmacyContinuum.com/ Registration Get the latest news from the most widely read specialty pharmacy publication in the United States, including multimedia and web-only content, delivered directly to your inbox!

28 Policy

Review Article

SAFE TO TOUCH continued from page 27

recommendations for a spill cleanup procedure and contents of a HD spill kit.12 These kits should be readily available in all areas where HDs are handled. Institutions also should consider the formation of an HD spill response team, particularly for largevolume spills. Finally, health care institutions can implement safety practices that will improve the preparation and handling of HDs, including creating a consistent approach for clearly identifying HDs that require safe-handling precautions and integrating HD statements into medication administration records and computerized physician order entry systems.

Conclusion The Safe to Touch 2020 Consensus Conference on Hazardous Drug Surface Contamination resulted in consensus statements and recommendations that health care institutions may use to successfully develop and implement plans and policies related to ongoing surface contamination monitoring. Although cost, competing priorities for available dollars, a lack of clear regulatory standards, and the fear of what a positive HD surface contamination result may mean for an institution remain barriers to implementation, organizations should consider the costs of inaction and the value that a robust monitoring program adds to patient safety and employee morale.

References 1.

Gabay M, Johnson P, Fanikos J, et al. Report on 2020 Safe to Touch consensus conference on hazardous drug surface contamination. Am J Health Syst Pharm. 2021 Mar 27:zxab134. doi:10.1093/ajhp/ zxab134

2. Sarna K. Best practices for monitoring hazardous drug surface contamination: A guidance for health care institutions. Pharmacy Practice News. 2020;47(7):26-29. 3. McDevitt JJ, Lees PS, McDiarmid MA. Exposure of hospital pharmacists and nurses to antineoplastic agents. J Occup Med. 1993;35(1):57-60. 4. Sessink PJ, Anzlon RB, Van den Broek PH, et al. Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharm Weekly Sci. 1992;14(1):16-22.

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

Pharmacy Practice News • July 2021

5. Sessink PJ, Van de Kerkhof MC, Anzlon RB, et al. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health. 1994;49(3):165-169. 6. Sessink PJ, Friemel NS, Anzlon RB, et al. Biological and environmental monitoring of occupational exposure of pharmaceutical plant workers to methotrexate. Int Arch Occup Environ Health. 1994;65(6):401-403.

7. Sessink PJ, Wittenhorst BC, Anzlon RB, et al. Exposure of pharmacy technicians to antineoplastic agents: reevaluation after additional protective measures. Arch Environ Health. 1997;52(3):240-244. 8. CDC. Environmental sampling, decontamination, protective equipment, robotics, closed system transfer devices, and work practice. Last reviewed: September 13, 2017. Accessed May 23, 2021. https://www.cdc.gov/niosh/topics/ hazdrug/sampling.html 9. Hodson L, Ovesen J, Couch J, et al. Managing hazardous drug exposures: information for healthcare settings. Department of Health and Human Services, CDC, National Institute for Occupational Safety and Health. May 1, 2020. Accessed May 23, 2021. https://www.cdc.gov/niosh/ docket/review/docket233c/pdfs/DRAFTManaging-Hazardous-Drug-Exposures_ Information-for-Healthcare-Settings.pdf 10. Celano P, Fausei CA, Kennedy EB, et al. Safe handling of hazardous drugs: ASCO standards. J Clin Oncol. 2019;37(7):598-609. 11. Oncology Nursing Society. Ensuring healthcare worker safety when handling hazardous drugs. Joint position statement from the Oncology Nursing Society and the Hematology/Oncology Pharmacy Association. August 2019. Accessed May 23, 2021. https://www.ons.org/ make-difference/ons-center-advocacyand-health-policy/position-statements/ ensuring-healthcare 12. Power LA, Coyne JW. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2018;75(24):1996-2031. 13. Polovich M, Olson MM, eds. Safe Handling of Hazardous Drugs. 3rd ed. Oncology Nursing Society; 2017. 14. U.S. Department of Labor. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. Accessed May 23, 2021. https://www.osha.gov/hazardous-drugs/ controlling-occex 15. United States Pharmacopeia. USP General Chapter <800>. Hazardous drugs – handling in healthcare settings. June 26, 2020. Accessed May 23, 2021. https://www. usp.org/compounding/general-chapterhazardous-drugs-handling-healthcare 16. Department of Health and Human Services. NIOSH alert. Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. September 2004. Accessed May 23, 2021. https://www.cdc.gov/niosh/docs/2004165/pdfs/2004-165.pdf 17. Simon N, Vasseur M, Pinturad M, et al. Effectiveness of a closed-system transfer device in reducing surface contamination in a new anti-neoplastic drug-compounding unit: a prospective, controlled, parallel study. PLoS One. 2016;11(7). doi:10.1371/ journal.pone.0159052 18. Sessink PJ, Connor TH, Jorgenson JA, et al. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. J Oncol Pharm Pract. 2011;17(1):39-48. 19. Sessink PJ, Trahan J, Coyne JW. Reduction in surface contamination with cyclophosphamide in 30 US hospital pharmacies following implementation of a closed-system drug transfer device. Hosp Pharm. 2013;48(3):204-212. 20. Connor TH. Overview of commercially available surface contamination monitoring technologies and systems. Presented at: Safe to Touch Consensus Conference on Hazardous Drug Surface Contamination. September 24, 2020.

Policy

Pharmacy Practice News • July 2021

FDA Watch

AD Approval Confusion continued from page 1

steep copays for patients and a projected billion-dollar annual price tag for Medicare, the approval promises to stir continued debate. “I think the FDA made a bad decision here. They do tremendous work and usually get things right, but unfortunately I think in this instance, this product was driven across the line by the magnitude of unmet need,” G. Caleb Alexander, MD, the co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins University School of Medicine, in Baltimore, told Pharmacy Practice News. “There is an enormous amount of desperation regarding Alzheimer’s, and that should propel funding and research, but not a weakening of our regulatory standards,” said Dr. Alexander, a member of the Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee that overwhelmingly voted against approving the medication. “The bottom line is that there is simply not convincing evidence that amyloid is a valid surrogate, and yet that’s what the FDA relied upon. We have a number of other studies that have demonstrated convincing reductions in amyloid with no corresponding improvements in cognition.” A majority of Dr. Alexander’s colleagues on the PCNS committee apparently shared his concerns. Eight panel members said no, one said yes and two said they were uncertain on the question of whether the two key clinical studies conducted by Biogen, EMERGE and ENGAGE, provided “strong evidence” that aducanumab is effective at treating Alzheimer’s. “The FDA going against the advice from their advisory board is a big deal,” said Lawrence Cohen, PharmD, a professor of pharmacotherapy (retired) at The University of North Texas System College of Pharmacy in Fort Worth, and a member of the Board of Pharmacy Specialties’ Geriatric Pharmacy Specialty Council. “Usually there has to be some obvious major reason, evidence that a treatment is truly life-changing (e.g, superior efficacy, significant adverse event risk, superior tolerability, prevention of disease progression). That does not appear to be what’s going on here. Approving a drug with only one slightly positive trial is unheard of. This really appears to be a divergence in practice from the FDA.” Indeed, less than a week after the approval was announced, three members of the PCNS advisory committee resigned: Mayo Clinic neurologist David Knopman, MD; Washington University neurologist Joel Perlmutter, MD; and Harvard professor of medicine Aaron Kesselheim, MD. In a letter

to the FDA, Dr. Kesselheim blast-ed the decision as “probably thee worst drug approval decision in recent U.S. history.” “The advisory committee members embers who decided to resign are people ple you really want to have on your advisory ry committees,” Dr. Cohen said. “You don’t ’t want them to be disappearing and not continuing to be engaged.” Biogen acknowledged its drug g was headed for troubled waters in a March 2019 press release, when it announced ounced that in an interim analysis, the EMERGE MERGE trial was “trending positive,” but ut the ENGAGE trial was “unlikely to meet its primary endpoints.” However, in n both trials, amyloid PET imaging showed howed dose-related reductions in beta-amyloid myloid plaque in the brain (Alzheimers Dement 2021;17[4]:696-701), the company noted. Several months later, Biogen announced that a new analysis, which included more patients, showed that those who received higher doses of aducanumab experienced a reduction in clinical decline in EMERGE. In FDA briefing documents, the company stated that patients treated with high-dose aducanumab showed 22% less clinical decline in their cognition at about 18 months than those who received a placebo. “Although the evidence from these trials regarding delay in functional and cognitive decline did not satisfy the criteria for traditional approval, in all studies in which it was evaluated, aducanumab consistently reduced the level of amyloid plaques in the brain in a dose- and time-dependent

‘‘[Aducanumab] ‘[ [Ad Aducan ucan uc anum anum umab ab] is ab] is not no ott for for or all all ll people peo eopl ple with witth wi wit h Alzheimer’s A Al lzh zhe eiime ime er’ r s disease. diise d seas ase. ase. e It It doesn’t does do essn n’’t reverse re ever vers ve rse se anything; anyt an ythi yt hing hi ng;; it doesn’t ng doe oesn sn’t sn ’tt improve imp mpro rove ro ve anything; any nyth thin th ing; in ng; it just reduces the decline in a small sliver of individuals with [mild cognitive impairment].’ —Douglas Scharre, MD fashion,” said Patrizia Cavazzoni, MD, the director of the FDA’s Center for Drug Evaluation and Research (CDER) in a press call on June 7. “A reduction in amyloid plaque is reasonably likely to predict clinical benefit in reducing the loss of brain function in patients with Alzheimer’s disease. This accelerated approval pathway provides earlier access to a potentially valuable drug when there is some residual uncertainty about the clinical benefits.”

A post-approval trial will be needed to verify that the drug provides the expected clinical benefit. “We believe that data support accelerated approval while holding the company accountable for conducting an additional study,” Dr. Cavazzoni said. “We acknowledge that it will take some time to conduct a confirmatory trial; however, the agency is very encouraged by the incredible progress being made in Alzheimer’s drug development.” see CONFUSION, page 30

Helping you deliver better medicine to more people. Leiters is an FDA registered and inspected 503B outsourcing provider of high-quality compounded sterile preparations and services including: Pre-ﬁlled syringes, IV bags and vials Opioid-free surgical pain services medications ON-Q* Pain Relief System ﬁll services Ophthalmology medications including FDA-compliant repackaged Avastin®

COMPOUNDING HEALTH™

Leiters.com | 800.292.6772

ON-Q* is a registered trademark of Avanos Medical, Inc., or its affiliates. Avastin® is a registered trademark of Genentech, Inc.

30 Policy

Pharmacy Practice News • July 2021

FDA Watch

CONFUSION continued from page 29

Is Beta-Amyloid a Good Bet? Responding to media questions, Peter Stein, MD, the director of CDER’s Office of New Drugs, acknowledged that previous drug development programs targeting beta-amyloid were unsuccessful. “Aduhelm is the seventh such program, and it showed a strong relationship between the extent of reduction in plaque and improvement in benefit,” he said. “It is important to recognize that there are

many types of antibodies used targeting different aspects of clearing amyloid plaque with different levels of effectiveness, and it is difficult to extrapolate from one candidate to another. With the other therapies, the extent of the reduction in beta-amyloid plaque may have been too small to yield clinical benefit.” The prescribing information for aducanumab includes a warning for amyloid-related imaging abnormalities (ARIA), which most commonly present as temporary swelling in areas of the brain that usually resolves over time

and often does not cause symptoms, although some people may have symptoms such as headache, confusion, dizziness, vision changes or nausea. “As with every drug, this drug does have risk; but with appropriate care, ARIA is detectable and manageable, and occurs infrequently,” Dr. Stein said. “We believe that Aduhelm is reasonably likely to have meaningful clinical benefit with regard to reducing the progression of cognitive loss, and that that potential outweighs the manageable risk of ARIA. We have heard clearly from patients

FUN E L L STAT F UN G IT ITE

A Single Sample Format (1J J3)-E-D-Glucan Detection Assay For Rapid Invasive Fungal Infection (IFI) Screening. Fungitell STAT ® is the first and only single sample format FDA-cleared and CE marked rapid in vitro diagnostic screening test for IFI (including Candida, Aspergillus and Pneumocystis) that detects (1J3)- E - D -Glucan in serum.

www.fungitell.com • 888.395.2221 MKT#20-043

that they are willing to accept some uncertainty to have access to a drug that could provide meaningful benefit in delaying the progression of this disease.” Leaders of the Alzheimer’s disease patient advocacy community responded enthusiastically to the approval. “It is a new day,” Harry Johns, the CEO of the Alzheimer’s Association, said in a statement. “This approval allows people living with Alzheimer’s more time to live better. For families, it means being able to hold on to their loved ones longer. It is about reinvigorating scientists and companies in the fight against this scourge of a disease. It is about hope.” Dr. Alexander suggested that the requirement for a confirmatory trial is a dubious scientific and regulatory strategy. “The CEO of Biogen has gone on record saying that the trial would be completed by 2030. Nine years is simply an unacceptably long time to wait for evidence that this product actually works,” he said. “Confirmatory trials often fall short, meaning that the way they are designed and the outcomes they examine aren’t always what is envisioned at the time a product is approved. They sometimes examine another surrogate or an intermediate clinical end point. The FDA has lost its most important leverage point, which is regulating market access, and the single best opportunity to figure out whether this product works.” Even a neurologist who participated in the aducanumab trials from their inception, Douglas Scharre, MD, the director of the Division of Cognitive Neurology at The Ohio State University Wexner Medical Center, in Columbus, expressed bafflement at the FDA’s decision—particularly its choice to approve the drug across the board for all stages of Alzheimer’s disease, despite the fact that it was studied only in patients with mild cognitive impairment (MCI) and mild dementia. “The criticisms of this decision are well justified and valid,” Dr. Scharre said. “The FDA is in a tight spot, but I don’t know why they made this decision. It may be because aducanumab did a fabulous job at getting rid of amyloid in the brain, which is what it’s designed to do. But the research studies only showed clinical benefit in subjects with MCI and very early Alzheimer’s dementia. In those cases, there was statistical significance that it was better than placebo. So the broad indication was very surprising.” Widespread use of aducanumab to treat Alzheimer’s disease across the board would “break the bank” for the health care system, Dr. Alexander said. “Even in a setting where there is only modest adoption of this product, the costs still may be catastrophic. The manufacturer has pegged a list price of $56,000,

Policy

Pharmacy Practice News • July 2021

FDA Watch

Managed Care’s Take

y late June, none of the major payors, including Medicare, had announced what their policies would be for covering aducanumab. But a selection of pharmacy benefit managers (PBMs) and other managed care stakeholders speculated on some initial steps that may be taken in the wake of the FDA’s controversial decision to approve the medication. Dea Belazi, the president and CEO of PBM Ascella Health, predicted that payors will restrict aducanumab coverage via traditional methods such as prior authorization and medical necessity requirements. “They may choose to require documentation that the drug is working, via cognitive testing and/or MRI evidence of amyloid clearance,” he said. “If this product had demonstrated utility, that would be different. But the fact is that the data just doesn’t show that. But even so, I can’t imagine CMS [Centers for Medicare & Medicaid Services] saying no and refusing to cover it. I imagine they’ll push this down for payors to deal with advocacy, patients, and physicians.” Prime Therapeutics, collectively owned by 19 Blue Cross and Blue Shield plans, subsidiaries or affiliates, did not indicate what any of those plans intended to do about aducanumab formulary placement, coverage or utilization management policies. But the payor has “concerns about the safety and efficacy of this product,” based in part on the FDA advisory committee’s critiques of the medication, noted April Kunze, PharmD, the senior director of clinical formulary development and trend management strategy. “Health plans will need to weigh the evidence against member requests,” she said. Given those concerns, “we were surprised with the price tag,” Dr. Kunze added. “ICER [Institute for Clinical and Economic Review] also noted that the drug is not priced to value. Given that Alzheimer’s occurs mostly within the Medicare population, this will have a significant impact on [drug spending] if all members who are eligible for the drug take it. The cost of the drug will be substantial, but outside of that, the cost of testing and monitoring for significant side effects will also impact payors.” Dr. Kunze cited two additional issues: the drug’s across-the-board approval, despite it being studied only in MCI (mild cognitive impairment) and mild Alzheimer’s dementia, and the approval coming without contraindications or warnings for people who use blood thinners, despite the fact that this group was excluded from the studies. “Due to the inconclusive effectiveness of aducanumab and the risk of amyloid-related imaging abnormalities, including both edema and hemosiderin deposition associated with treatment, it is very concerning that the drug was approved for a broad indication,” she said. “There is a very real potential that the risk could outweigh the benefit.” Jason Borschow, the founder and CEO of Abarca, a PBM with offices in San Juan, Puerto Rico and Aventura, Fla., agreed. “Even if this drug cost a quarter of what it has been priced at, you’d still have the issue of a lack of clinical evidence. If it isn’t effective, it doesn’t matter whether the drug costs $500 or $50,000, you shouldn’t take it. This is an example of why we believe so strongly in value-based agreements.” —G.S. The sources reported no relevant financial disclosures.

which is seven- to 25-fold greater than the value-based price of $2,500 to $8,300 assessed by ICER [Institute for Clinical and Economic Review].”

ICER Throws Cold Water On Biogen Pricing Indeed, ICER’s preliminary draft report on aducanumab, issued May 5, 2021, noted that only a hypothetical drug that halts Alzheimer’s entirely would merit a price like the one Biogen has set. In a response to the approval issued on June 7, 2021, ICER said: “Alzheimer’s disease has a tremendous impact on patients and loved ones, and no one can be insensitive to the hopes and the fears that are part of their daily lives. But no one should assume that approving a drug with such conflicting and uncertain evidence will necessarily help patients and families. On them now falls the decision of whether to use a treatment that may not work, that has modest effects at best, and that causes brain swelling and potential bleeding in approximately 30% of patients.”

The Kaiser Family Foundation (KFF) issued an analysis on June 11, finding that if just one-fourth of the nearly 2 million Medicare beneficiaries currently taking Alzheimer’s treatments covered by Medicare Part D were prescribed aducanumab, total Medicare spending for the drug would exceed $29 billion in a single year—“an amount that far exceeds spending on any other drug covered under Medicare Part B or Part D, based on 2019 spending,” the organization noted. “Alzheimer’s patients covered under Medicare Part B could also face high out-of-pocket costs for treatment with Aduhelm, both for the drug itself and for the cost of related medical services,” the KFF analysis noted. “For most Part B– covered drugs and services, Medicare pays 80% of the cost and beneficiaries are responsible for the remaining 20%. This means beneficiaries would face about $11,500 in coinsurance for one year of treatment, which represents nearly 40% of the $29,650 in median annual income per Medicare beneficiary in 2019.”

As for who gets aducanumab, “I can’t imagine Medicare will say yes, sure, we’ll [cover it] for everybody who has Alzheimer’s,” Dr. Scharre said. “I hope they don’t say that; it would be a big mistake. We don’t have health care dollars to waste like that. We want to treat just those patients who might benefit, which is those very early cases.” Dr. Alexander agreed. “I don’t understand why the FDA wouldn’t have constrained the label so that it’s better aligned with the evidence, such as it is.” Asked to comment on the FDA’s decision to approve aducanumab, a CMS spokesperson replied that the agency “is reviewing the decision and will have more information soon.”

A Call for More Transparency Dr. Scharre said the approval requires open communication from experts. “We have to [convey] that this drug is not for all people with Alzheimer’s disease. It doesn’t reverse anything; it doesn’t improve anything; it just reduces the decline in a small sliver of individuals with MCI.” Still, “hopefully, the approval will at least motivate patients to see their doctors earlier about mild cognitive issues they might otherwise have ignored.” Such calls for transparency seem to be

resonating with the FDA. In a June 22 letter, Dr. Cavazzoni acknowledged the “fierce public debate” the aducanumab approval triggered. But she characterized that debate as consisting of “one-sided views by a handful of commentators.” To better “inform public discourse,” the FDA announced in the letter that it was releasing a full set of review documents for the first time (bit.ly/3d5ehrw). “We are releasing the documents [to provide] interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni said. Dr. Cohen agreed that more transparency is needed. “But if I were still actively managing formularies, aducanumab would still be something you’d have to get prior authorization for and only after other treatments have been tried,” he said. “It shouldn’t be the first drug of choice.” —Gina Shaw Dr. Alexander reported no relevant disclosures beyond his PCNS Advisory Committee affiliation. Dr. Scharre reported that he was a member of the advisory board for Biogen and was a clinical investigator in the company’s trial. Dr. Cohen reported no relevant financial disclosures.

32 Policy

Pharmacy Practice News • July 2021

Sterile Compounding

Tool addresses unsanitary conditions, PPE shortages, other issues during pandemic

The SBAR Method for Cleanroom Compliance I

f the last several years of hurricanes and floods, changes in sterile compounding regulations and the COVID-19 pandemic have demonstrated anything, it’s that preparation and communication for planned or unplanned cleanroom closures or equipment shortages related to remodeling, inspection reports or natural disasters are essential. At the 2021 annual meeting of the National Home Infusion Association (NHIA), Gene Decaminada, BS Pharm, RPh, the pharmacy manager with MCP Home Infusion Pharmacy at Yale New Haven Health (YNHH) Services, in Connecticut, discussed some of these possible interruptions in the cleanroom process and methods for dealing with them in a clear and consistent way. “It is important to note that referring to the list of insanitary conditions involves potential safety concerns, not just an FDA citation,” he said. Common reasons for closures or interruptions include inspections from the State Board of Pharmacy and the FDA, Mr. Decaminada said. “I’ve been through many FDA inspections over the past few years, and they can be on-site for the better part of seven days or more. Other issues that can lead to process interruptions include cleanroom growth, such as actionable growth (i.e., mold and/or fungus) in your ISO [International Organization for Standardization] 5 areas; remodels and updates that require you to shut down your cleanroom or relocate your processes for days or weeks; and everything from harsh winters to power failures to floods. So it’s important to consider how these situations might change your cleanroom policies or practices with regard to patient safety and achieving a controlled environment.”

Unsanitary Conditions to Heed Mr. Decaminada cited a list of unsanitary conditions that could result in several FDA Form 483 citations, such as anything from missed microbial contamination under laminar flow hoods to moisture buildup from HVAC ductwork above the cleanroom, to processing beta-lactams and non–beta-lactams in the same laminar flow hood, to inadequate donning and doffing processes for personal protective equipment (PPE). “During site inspections, the FDA has also questioned proper smoke studies performed in laminar flow hoods by total parenteral nutrition compounders,” he said. “They want to see active compounding or mimicked dynamic compounding during smoke pattern testing. Make sure you are saving those videos for review with your cleanroom staff.”

Processes for conserving PPE, given pandemic-related shortages, must also be documented, Mr. Decaminada said. “You can’t just say you’re conserving PPE without building an addendum into your standard operating procedure [SOP]. If your SOP states to don a new gown every time someone exits the cleanroom and you’ve had to change to one gown per person per day for conservation purposes, you have to back up that SOP addendum in writing.” Other conservation measures he recommended include limiting the number of personnel engaged in compounding activities, staging supplies outside the compounding area to minimize trips into the cleanroom, and resanitizing sterile gloves after exiting ISO 5 areas.

Communication Is Key To communicate these changes to your cleanroom policies and PPE conservation plans if you have a busy pharmacy or multiple cleanrooms, Mr. Decaminada recommended a framing mechanism known as SBAR: Situation, Background, Assessment and Recommendation, which is endorsed by the Institute for Healthcare Improvement (IHI). “The SBAR communications method has been used successfully in many hospitals and health systems,” he said. “It’s an easy-to-remember method for structuring any conversation, but particularly critical ones requiring immediate attention and action. For example, we use SBAR at Yale New Haven Health for communicating any decisions about PPE conservation that has to come from pharmacy leadership to the cleanroom staff.” The SBAR technique, developed by Michael Leonard, MD, a physician leader for patient safety at Kaiser Permanente of Colorado, includes the following steps: Situation: a concise statement of the problem; Background: pertinent, brief information related to the situation and what has led up to it; Assessment: analysis and consideration of options; and Recommendation: action requested or recommended. The Department of Pharmacy at the University of Michigan, in Ann Arbor, has been using the SBAR method for several years, according to compounding compliance team manager Jamie Tharp, PharmD. “We employ it in both verbal communication and in writing. So many people can struggle with how to tell a story effectively and get off the beaten path. SBAR readies the listener to receive your assessment and recommendations.” The “background” segment of SBAR often can be the longest, Dr. Tharp said.

The University of Michigan’s SBAR Situation: The COVID-19 pandemic is constraining staff resources in compounding and the pharmacy needs to free up staff time.

Background: Current USP standards for low- and medium-risk compounds require media fill testing every 12 months. Only high-risk compounds require testing every six months. Assessment: The pharmacy does only low- and medium-risk compounding. We assess that it is acceptable to move to a 12-month frequency for media fill testing. Recommendation: Implement 12-month testing intervals until COVID-19–related staffing constraints are resolved. “It’s where you may spend a lot of time talking about the rules, the standards and the regulations. I often use this section to provide references that could help support my transmission of information. Overall, we try to keep SBARs to less than a page, but if there is a lot of content or data, we might make an exhibit for a second page, or use a separate reference section if a lot of technical policies, laws and standards are involved.” SBAR proved very useful to the compounding compliance team during COVID-19, Dr. Tharp said. “For example, our standard had been to do media fill tests for aseptic technique every six months, which was above and beyond the minimum required. It was part of our commitment to best practices and preparing for future standards. But during the pandemic we had a crunch with staffing, and wrote an SBAR to inform senior leadership about what we thought would be a good way to conserve staffing resources [see box]. “After the SBAR was [routed] through our leadership and approved, we posted the SBAR with the decision to our policy webpage as an interim plan during the pandemic,” Dr. Tharp said. “SBAR is also very useful as we audit the work we are doing at our compounding sites. If one of my technicians has found an issue, such as damaged equipment or someone not following a policy, I will ask them to

share an SBAR with a supervisor. They are full of factual information and can take the sting out of a recommendation for improvement.” In addition, SBARs are easy to write, Dr. Tharp said. “I can write even a very detailed SBAR in 90 minutes or less, and if it’s very simple, in a quick fiveminute email. It’s particularly helpful if you have to escalate details to stakeholders outside the pharmacy, because it gives necessary background to people who might not be involved in the dayto-day work. It also provides a useful breakdown of content that allows people who already know the background intimately to zoom right to the recommendations.” The only change Dr. Tharp would make to the SBAR method would be to add a D for Decision at the end. “That’s the piece I think is missing. You should have a section at the end of your SBAR (D) to record what decision was made based on your recommendation. Was it accepted or not? Maybe you gave two options, preferred and alternative, and you need a record as to which one was accepted. It’s amazing how much clarity this method can bring to your decisionmaking process.” —Gina Shaw The sources reported no relevant financial disclosures.

The news you need. Whenever you want.

Get the latest news from the most widely read hospital pharmacy publication in the United States, including multimedia and web-only content, delivered directly to your inbox!

Facebook/pharmacypracticenews

LinkedIn.com/pharmacypractice-news

Interested in more specialty coverage? Register for your FREE print or online subscription at

Brought to you by

www.specialtypharmacycontinuum.com/subscription

7 Habits of Effective COVID-19 Rx Managers

he extraordinary amount of scientific activity marshalled to fight COVID-19 has led to a full pipeline of medications and vaccines—and an opportunity for pharmacists to help deliver the potentially lifesaving treatments to the right patients. At the Academy of Managed Care Pharmacy’s 2021 virtual annual meeting, G. Caleb Alexander, MD, MS, a professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health, in Baltimore, proposed guiding principles to help pharmacists navigate the evolving landscape of COVID-19 medical management. “The evidence base remains completely dynamic and staying up-to-date with treatment guidelines is a must, but there are some overarching principles of effective treatment that can help us achieve the holy grail, which is getting the right drug to the right patient at the right time,” Dr. Alexander said. To help pharmacists in their decision-making process, Dr. Alexander suggested these seven strategies:

Know the evidence base. “Not all evidence is equal,” he said, pointing to reliable syntheses of evidence such as the Infectious Diseases Society of America’s COVID-19 treatment guidelines (bit.ly/3nT6Vvj). He encouraged pharmacists not to be afraid to challenge convention, saying that “if I had a nickel for every time I’ve seen things done clinically because ‘that’s what we do,’ rather than because of good evidence, I could retire a little earlier.” Initial enthusiasm about hydroxychloroquine, despite a lack of evidence, and the subsequent decline in its use after data became available, is a good example of how clinical practice changes as data arise. “There are lots of opportunities to take a close look at the evidence base and improve our application of it,” Dr. Alexander said. Understand the limits of evidence. In his own survey of the COVID-19 literature, Dr. Alexander found significant study design limitations. For example, during the early stages of the pandemic, he found that: • roughly one-third of clinical trials of COVID-19 therapeutics excluded clinical end points; • nearly 50% of trials enrolled fewer than 100 patients; and • roughly two-thirds were open-label. “Once complete, many of these studies are likely to yield only preliminary evidence of a given treatment’s safety and effectiveness,” he said. Other limitations include the use of “usual care” arms—a grab bag of approaches not always defined

in a study. Outcomes in these groups can vary widely, he indicated. For example, he pointed to a meta-analysis of corticosteroids for COVID-19 that found mortality rates in control arms ranged from 16% to 59% (JAMA 2020;324[13]:1330-1341). Stratify treatments based on patient characteristics and severity. “This is a fundamental concept that’s important for us to consider in

selecting treatments,” Dr. Alexander said. Rather than being homogeneous, different groups have different prognoses and “incredibly different mortality rates. We should be thinking about these as we steward what are invariably scarce, and in some cases, incredibly costly treatments.” Recognize the role of virus variants. Variants affect not just the effectiveness of vaccines, but “they

may [also affect] some therapeutics.” This has led the FDA to issue revisions to fact sheets on monoclonal antibodies, addressing possible resistance of SARSCoV-2 variants to this class of drugs. Be familiar with vaccine adverse events. Although

Interested in more specialty coverage? Register for your FREE print or online subscription at

Brought to you by

www.specialtypharmacycontinuum.com/subscription

COVID-19 vaccines are a boon to public health and individual care, instances of thrombocytopenia in patients receiving vaccines manufactured by AstraZeneca and Johnson & Johnson are examples of the challenges of vaccine selection. Don’t skimp on prevention. “We can’t let use of therapeutics come at the expense of preventive intervention,” Dr. Alexander said. In their interactions with patients, pharmacists should underline the

Keep an eye out for inequality. Various racial, ethnic and socioeconomic groups have seen stark differences in rates of infection, hospitalization and death, and vaccine access during the pandemic. “While these differences are multifactorial,” Dr. Alexander said, “they are important for health systems to acknowledge and address when designing interventions.” —David Wild importance of wearing masks, social distancing and handwashing in COVID-19 prevention and highlight

their importance in helping communities achieve a return to normalcy as soon as possible, he said.

The sources reported no relevant financial disclosures beyond stated employment.