Pharmacy Practice News ( January 2021)

See e REV VIEW ARTIC CLES inserte ed within n this issue after pages s 10 0 & 26

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The Best-Read Pharmacist’s News Source

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CLINICAL

Making a case for biosimilars ...................

Lessons from COVID vaccine rollout ...............

3

10

OPERATIONS & MGMT

A powerful COVID-19 partnership ......................

16

Erin Fox’s tips for drug formularies and price spikes ...........

22

POLICY

New Drugs 2020-2021: specialty spending still going strong........... 26 USP Chapters still a must-read for 2021 .....

34

340B Rollback Prompts Action

By Stakeholders

T

he dispute between drugmakers and covered entities under the 340B Drug Pricing Program has ramped up, as a number of hospital and pharmacy associations are suing the Department of Health and Human Services to undo manufacturer limitations on 340B discounts.

Their efforts have paid off: On Dec. 30, HHS issued an advisory opinion stating that drug manufacturers are required to deliver 340B discounts on covered outpatient drugs when contract pharmacies are acting as agents of 340B covered entities. Although advisory opinions do not carry the force of law, “they set out the agency’s current views on issues,” HHS said in a statement. “Those views may be reflected in the ... enforcement and oversight powers the federal government has to run the 340B Program.”

Volume 48 • Number 1 • January 2021

Coping tips shared during ASHP, ACCP annual meetings

Pharmacy Shines Amid COVID Darkness

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‘Smart’ Dilution Boosts COVID-19 Vaccine Doses

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ost pharmacists know that every injectable drug includes excess volume, or “overfill.” Manufacturers often do this to allow for waste or spillage. In the case of the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine from Pfizer/ BioNTech, which began shipping across the United States on Dec. 13, pharmacists quickly noticed that they were able to take advantage of that overfill and get six doses from each vial rather than the five doses authorized by the FDA’s emergency Continued on page 8

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fter nearly a year of coping with COVID-19, health-system pharmacies continue to respond with a host of measures. Whether it’s inventory optimization tools to mitigatee shortages of drugs and personal protective equip-ment, or staffing tweaks to bolster coverage in n overwhelmed ICUs, the profession is doing its part. art.

In the following profiles, culled from pharmacy macy meetings and follow-up interviews, hospitals shine hine a light on how to excel at such preparedness strateategies—even during the darkest days of a pandemic. c.

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Clinical

Pharmacy Practice News • January 2021

3

Overcoming Biosimilar Hesitancy B

iosimilars have the potential to significantly reduce costs for medical centers, but the adoption rate is still very low. Fortunately, there are steps that pharmacists can take to increase use of these agents.

At the end of 2019, 17% of the biologics market were accessible to biosimilars, but there was only a 20% adoption rate, noted David Crosby, PharmD, BCOP, BCPS, the pharmacy director of system infusion at Dartmouth-Hitchcock Health, in Lebanon, N.H. Including approved but not yet launched biosimilars, up to 50% of the biologics market could face competition from biosimilars, he said, citing data from IQVIA’s national sales perspectives (www.iqvia.com).

There are six major challenges to biosimilar adoption, Crosby said during a session at the ASHP 2020 Midyear Clinical Meeting and Exposition: 1. Provider comfort and experience.

There has been a fair amount of confusion among some providers about biosimilars, including unfamiliarity with development pathways, and confusion and concern because of a lack of interchangeability status. Just because biosimilars aren’t designated as interchangeable by the FDA doesn’t mean they should not be substituted for the reference product, Crosby said. “Partnering with provider section leadership to enhance education

and minimize inconsistency, but also to champion biosimilar rollout, is key to success,” he said.

2. Patient education. Such efforts are often needed because patients may have some misunderstanding regarding biosimilars, or be concerned when transitioning from a treatment they are familiar with that may be working well. “You really want to evaluate how pharmacy can supplement and support patient education to assist in that transition to biosimilars,” Crosby said. He added that patient education can overlap with provider outreach as well, since clinicians also may harbor negative attitudes toward biosimiliars.

3. Third-party payors. Most biosimilars developed so far are used primarily in outpatient settings, where individual agents require a prior authorization and benefits investigation. Ultimately, if a payor is not going to allow a biosimilar to be used, this can delay utilization. One reason is likely rebates the insurer may be receiving for the reference product, Crosby said. “We’re seeing more payors give preference to either the reference product or a specific biosimilar, and that’s based upon the rebate they receive. It’s a trend becoming more common over time.”

This is an opportunity when negotiating payor contracts to ask that biosimilars be included as an option in your formulary, he said. “You may not be successful

each time, but they may be receptive since you’re really trying to identify cost savings for their beneficiaries.”

4. Financial impact on patients and organizations. Although the cost savings resulting from biosimilar use can be substantial, the bottom-line financial impact for patients and organizations is often much less significant or clear, with third-party payors deriving the greatest benefit, Crosby said. Still, that should at least have a favorable effect on premiums over time. This also can be an opportunity for the payor contracting team.

5. Clinical considerations. Biosimilars span therapeutic areas, and their use may involve multiple specialty and subspecialty providers. “This is where most [pharmacy and therapeutics committees] will need to develop policies, procedures and guidance to ensure consistency in your clinical approach,” Crosby noted.

6. Operational consideration. Even if everyone in your organization is on board with biosimilars and what they represent, if you don’t have a well-thought-out plan to operationalize the rollout, you may struggle to be successful, he said.

Those challenges and caveats aside, biosimilars “are not a failed concept; they are in fact becoming a growing part of affordable treatment options available to payers, physicians and patients,” said Murray Aitken, IQVIA senior vice president

EDITORIAL BOARD

Savings, U.S. billions

Finance

18

19

104

2010-14

2015-19

2020-24

Cohort year

Figure. Biosimilar savings.

Source: IQVIA National Sales Perspectives, Jun 2020; IQVIA Institute, Sep 2020.

and the executive director of the IQVIA Institute for Human Data Science, in an October 2020 report (bit.ly/34xNHDf ).

“It is our estimate that biosimilars could reach $80 billion in aggregate sales over the next five years, including $16 to $36 billion in 2024,” with potential savings in excess of $100 billion (Figure).

Aitken cited, as an example, the recent launches of biosimilar bevacizumab, trastuzumab and rituximab, which “are set to reach nearly 60% volume share by the end of their second year on the market, significantly higher and faster than prior biosimilars,” he said.

—Karen Blum The sources reported no relevant financial disclosures.

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4 Clinical

Pharmacy Practice News • January 2021

Pain Medicine

Health Systems Tackle Addiction in Varied Settings P

harmacists can play key roles in the team-based management of substance use disorders (SUDs) across multiple care settings, from the emergency department (ED) to acute or chronic care, according to a panel of speakers at the American College of Clinical Pharmacy (ACCP) 2020 virtual annual meeting.

The URMC Approach The ED is a critical access point for health care and, in the past decade, has become more widely used by people with SUDs, said Nicole Acquisto, PharmD, BCCCP, an emergency medicine clinical pharmacy specialist at the University of Rochester Medical Center (URMC), in New York. “After an injury, hospitalization or ED visit, there seems to be this teachable moment for those that have a [SUD], ” Acquisto said.

The SBIRT (Screening, Brief Intervention and Referral to Treatment) tool (www.samhsa.gov/sbirt) can help identify patients who use opioids and other substances at risky levels, she said.

It helps establish rapport and screen patients, elicit the patient’s thoughts about making a change, enhance motivation and assess their readiness for change, and negotiate a plan and provide resources for treatment.

In cases of suspected OUD, clinicians assess where patients fall on the Clinical Opiate Withdrawal Scale (COWS) before initiating medications for OUD, such as buprenorphine-naloxone, Acquisto noted.

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A policy released in September 2020 by the American College of Emergency Physicians recommends opioid withdrawal treatment be initiated in the ED with buprenorphine or methadone (Ann Emerg Med 2020;76[3]:e13-e39).

Emergency department treatment guidelines, she added, aim to link patients with OUD to medication-assisted treatment (MAT). Patients who experience an overdose also are linked to care, and those experiencing withdrawal receive treatment for their symptoms in the most clinically appropriate setting. A policy released in September 2020 recommends opioid withdrawal treatment be initiated in the ED with buprenorphine or methadone (Ann Emerg Med 2020;76[3]:e13-e39).

At URMC, the ED provides supportive medications for withdrawal symptoms such as pain, anxiety and nausea.

Patients who have an appropriate COWS score can be given 2 mg of buprenorphine as a test dose, with another 8 mg given 30 minutes later. Then they may be prescribed buprenorphine twice daily, or given a 16-mg dose for a longer duration of action and linked to local substance use programs. A primary care group at a local community hospital in the area sees patients within 72 hours after being started on MAT in the ED. Pharmacists with specialized training play an integral role in many of these interventions, Aquisto noted, adding that she and a clinical toxicology pharmacy specialist helped to develop standardized recommendations for treating OUD patients. They also developed ED and organization-wide guidelines on opioid withdrawal, and developed an order set to assist with ED buprenorphine orders and prescribing.

Both Acquisto and her clinical toxicology pharmacist colleague have also audited an “X” waiver training class, which the Drug Enforcement Administration mandates be taken before a physician can prescribe buprenorphine to a patient with OUD. They also worked with physicians in toxicology and addiction medicine on the development of their MAT guidelines and materials, order sets, patient education handouts for buprenorphine and resources to be given in the ED to help with linkage to care. “We have used these

materials to train our EM [emergency medicine] pharmacists as well as other pharmacists in various practice settings in our department on MAT initiation and buprenorphine, and then on the flip side, how to manage pain in patients coming in to the ED with acute pain and on buprenorphine,” she said.

A Bridge to Community Care In the acute care setting, transitional bridge clinics helps stabilize patients with active opioid addiction and help them assimilate into community-based treatment programs, said Alyssa Peckham, PharmD, an advanced practice pharmacist with Massachusetts General Hospital, in Boston. The goal of such clinics is to reduce barriers so patients have more access to treatment, Peckham said during the ACCP meeting. They work on engagement, trying to ensure patients return for additional care rather than fitting them into a predetermined set of requirements.

Clinics are designed to provide rapid access, offering a mix of scheduled and walk-in appointments.

Unlike other programs, the clinics have a model of harm reduction, not abstinence. “While abstinence is always an excellent goal, it’s not always what patients want at that moment,” Peckham said. “We have to accept the fact that drug use is going to occur and that we want to allow patients to be safe and enhance wellness during that time.”

Massachusetts General Hospital has operated a transitional bridge clinic since 2016, featuring a board-certified psychiatric pharmacist (Peckham) and other multidisciplinary team members. In a study reviewing the clinic’s first two years, personnel saw 800 patients for at least one visit, half of which were walkins. The median time to remain engaged in the clinic was 73 days, although 25% of patients remained in care for more than a year. In surveys, patients reported liking the flexibility and immediate access to care, the harm reduction

model, relationships with a nonjudgmental provider and the availability of peers (J Subst Abuse Treat 2019;107:1-7).

Peckham completed a year of postgraduate training in psychiatry and addiction—experience that she said helps guide her when interviewing patients and discussing modifications to treatment for any opioid, alcohol, stimulant and tobacco use disorders. The training also is a boon, she noted, when ordering lab tests, coordinating care and scheduling follow-up visits. Peckham also performs many other tasks, including leading clinical initiatives in SUDs such as microdosing of buprenorphine in the outpatient setting, conducting training and education seminars, writing protocol and guidance documents, and facilitating a four-week patient group on the neurobiology of addiction.

Collaboration at Gatton College On the chronic care end, collaborative practice agreements also can be effective resources for patients overcoming OUD, Sarah Melton, PharmD, a professor of pharmacy practice at East Tennessee State University’s Bill Gatton College of Pharmacy, in Johnson City, noted during the ACCP meeting. Melton formerly was a clinical pharmacist with Highpower, an interdisciplinary program for OUD patients in Lebanon, Va. The program, started by Melton and her late husband, employs a physician board-certified in addiction medicine, a nurse practitioner and physician assistant, a licensed professional counselor, and peer recovery specialists, with a board-certified psychiatric pharmacist paid by Gatton College.

Professionals with Highpower use motivational enhancement therapy, a counseling approach that helps patients engage in treatment. Participants attend group counseling sessions at varying frequencies depending on their needs; they also are required to get community support through a 12-step program, or have an outside sponsor they can call if stressed. Patients receive urine drug testing and breath alcohol tests at every visit.

Melton performed a range of activities, including providing medication education about buprenorphine, dosing of buprenorphine and participation in groups. Outcomes seen, so far, include increased adherence to buprenorphine, decreased illicit use of opioids, and, thanks to a collaboration with a local OB-GYN practice, a decrease in neonatal abstinence syndrome (NAS).

—Karen Blum Peckham reported that she is a consultant and advisor to Alkermes Inc. The other speakers reported no relevant financial disclosures.

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6 Clinical

Pharmacy Practice News • January 2021

Oncology

ESMO: When to Order Next-Gen Cancer Sequencing I

n looking back on key oncology developments in 2020, clinicians should put new recommendations for using next-generation sequencing (NGS) in metastastic cancer on their short list, according to Jai Patel, PharmD, the chair of the Department of Cancer Pharmacology and Pharmacogenomics at Levine Cancer Institute, Atrium Health, in Charlotte, N.C. Experts at the European Society for Medical Oncology (ESMO) published the new recommendations, using a rigorous methodology to identify advanced cancers with firm evidence supporting the clinical utility of NGS. They also identified cancers with insufficient data to recommend widespread and routine clinical application of this technology (Ann Oncol 2020 Aug 24. [Epub ahead of print]).

“The ESMO guidelines should help streamline the use of multigene sequencing in specific cancers where there is evidence of benefit at minimal added cost,” Patel commented.

The document was developed by a group of genomics experts who used ESMO’s Scale for Clinical Actionability of Molecular Targets (ESCAT) to classify recurrent genomic alterations of specific cancers. The scale helps assess the clinical relevance of such alterations. The experts also evaluated the strength of the evidence supporting the utility of NGS for these cancers.

Based on the strength of the evidence and the clinical relevance of mutations, the ESMO guidelines recommend routine use of tumor NGS in advanced nonsquamous non-small cell lung cancer, prostate cancer, ovarian cancer and cholangiocarcinoma. They also recommend NGS as an alternative to polymerase chain reaction in colon cancer, if it is cost-effective.

ESMO also supports routine tumor mutational burden (TMB) testing for patients with cervical cancer, well- and moderately differentiated neuroendocrine tumors, as well as salivary gland, thyroid and vulvar cancers. Such support reflects the fact that TMB-high tumors in these patients predicted their response to pembrolizumab (Keytruda, Merck) in the KEYNOTE-158 trial ( ClinicalTrials.gov Identifier: NCT02628067). This trial is examining the effectiveness of pembrolizumab by TMB in many solid cancer types.

Although individual institutions and practitioners may decide to use multigene panels outside of the cancers specified in the ESMO guidelines, they should be aware of the “low likelihood of benefit” in those cancers, the authors noted.

Lead author Fernanda Mosele, MD, a medical oncologist at Accord Medical

Table. Selected FDA-Approved NGS Platforms Number of Genes Tested (Cancer Type)

NGS Platform (Maker) Broad molecular profiling tests FoundationOne CDx (Foundation Medicine)

324

MSK-IMPACT (Memorial Sloan Kettering Cancer Center)

468

Tests focused on specific genes/cancer types

Center, in Buenos Aires, Argentina, acknowledged that some clinicians may feel ESMO’s recommendations limit NGS to a relatively narrow group of patients. Some of the recommendations differ from “what happens in daily practice in some countries and institutions.

For example, while use of tumor NGS in breast cancer is commonplace at some institutions, we do not recommend it.”

Patel, who was not involved with the guidelines, said they “somewhat coincide with how NGS is used for cancers in the U.S.” For example, in contrast to the ESMO guidelines, guidelines from the National Comprehensive Cancer Network (bit.ly/3hijMnO) recommend that U.S. clinicians perform multigene profiling for patients with lung adenocarcinoma to identify both common and rare driver mutations for which effective targeted therapies exist.

“A concerted effort by American professional associations to address the broad use of NGS across different tumor types in this country is needed,” Patel said, adding that those guidelines should account for the impact of testing on drug selection and activity as well as the cost-effectiveness of testing.

“As the cost of these diagnostics declines in the United States and data supporting their use in clinical practice increases, coverage of testing will also increase, allowing for greater availability of NGS testing in the community,” Patel added. Oncology practitioners “would greatly benefit from national efforts to streamline the use of NGS across tumor types, including recommendations for who and when to test.”

Therascreen PIK3CA RGQ PCR Kit (Qiagen)

1 (breast cancer)

BRACAnalysis CDx (Myriad Genetics)

2 (breast and ovarian cancers)

Praxis Extended RAS Panel (Illumina)

2 (CRC)

Therascreen KRAS RGQ PCR Kit (Qiagen)

1 (CRC)

Cobas EGFR Mutation Test V2 (Roche)

1 (NSCLC)

Oncomine Dx Target Test (ThermoFisher)

46 (NSCLC)

Therascreen EGFR RGQ PCR Kit (Qiagen)

1 (NSCLC)

Cobas 4800 BRAF V600 Mutation Test (Roche)

1 (melanoma)

THXID-BRAF Kit (BioMerieux)

1 (melanoma)

FoundationFocus CDxBRCA Assay (Foundation Medicine)

2 (ovarian cancer)

MyChoice CDx (Myriad Genetics)

Combined assay (ovarian cancer)

Therascreen FGFR RGQ RT-PCR Kit (Qiagen)

1 (urothelial cancer)

CRC, colorectal cancer; IMPACT, Integrated Mutation Profiling of Actionable Cancer Targets; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer Based on EClinicalMedicine. 2020;25(100487). doi: 10.1016/eclinm.2020.100487

A list of FDA-approved NGS platforms is provided in the Table.

Heed the Differences Martin Gutierrez, MD, a co-chair of thoracic oncology at Hackensack Meridian Health, in New Jersey, applauded the guidelines’ authors for conducting a comprehensive evaluation of NGS use for specific tumors.

However, similar to Patel, he noted differences between the American and European settings, such as TMB testing for pembrolizumab candidates. “By and large, Europeans tend to be a little more restrictive and conservative than in the United States in TMB testing,” he said. Whereas ESMO guidelines recommend testing TMB only for cervical, salivary gland, vulvar and thyroid cancers,

and neuroendocrine tumors, American clinicians test TMB in any cancer for which pembrolizumab is approved, and they consider such patients with TMBhigh cancer to be good candidates for pembrolizumab.

Gutierrez said the guidelines will need to be frequently updated, given the rapid pace of approvals of novel checkpoint inhibitors and small-molecule inhibitors. “These are comprehensive guidelines,“ he said, “but the speed at which new agents are approved means guidelines will need to evolve.”

—David Wild Patel reported a financial relationship with VieCure. Mosele reported no relevant financial disclosures. Gutierrez reported a financial relationship with Guardian 360.

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8 Clinical

Pharmacy Practice News • January 2021

Covid-19 Pandemic

Bumping Up COVID-19 Vax

on Thursday morning, we got additional information from the FDA, ASHP and other organizations telling us to be frugal and use those additional doses. Then the state told us that if we could get six doses, to use six, so we’re back to that now.�

During the public meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee on Dec. 17, Doran Fink, MD, PhD, the deputy director of the FDA’s Division of Vaccines and Related Products Applications, part of the Office of Vaccine Research and Review, Center for Biologics Evaluation and Research,

continued from page 1

that,� said Dana Darger, RPh, the director of pharmacy for Rapid City Hospital in South Dakota, part of the Monument Health system. “We did that all day Tuesday and into Wednesday morning, but early in the afternoon we received an email from the state in big, bold letters telling us not to take additional doses out of the vials, and we had to get all that information to vaccinators. Then

use authorization (EUA) for the vaccine.

There has been some confusion about whether pharmacies were allowed to use those extra doses, given the terms of the EUA. “On Monday morning, I was on a call with Pfizer and heard them say that there was probably extra vaccine in the vials, and if we could get a sixth dose out of the vial, we should go ahead and do

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was asked about the additional doses. “The instructions for the vaccine are to add 1.8 mL of diluent to the 0.45 mL of vaccine in the multidose vial,� he said. “That gets you to 2.25 mL. So with a dose volume of 0.3 mL per vaccine, it is not at all unexpected that there would be more than five doses in these vials.�

Not every institution is able to get six doses out of every vial of the vaccine, said Anna Legreid Dopp, PharmD, ASHP’s senior director of clinical guidelines and quality improvement. “Some of our members are saying that they are consistently getting six doses, while others are not because of differences in needles and syringes that they’re using.�

Darger said so far, there have been few, if any, vials from which they have been unable to squeeze a sixth dose. “There

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Clinical

Pharmacy Practice News • January 2021

9

Covid-19 Pandemic kits of syringes and needles, and now we’re scrambling to get extra supplies to administer those extra doses, because we will run out,� Tichy said. “We wanted to buy supplies five or six months ago, but the government had pretty much bought out the whole market of vaccine syringes in anticipation of having to give hundreds of millions of doses. It’s a good problem to have, but something we will have to sort out. We’re hopeful now that the FDA has recognized [the safety of ] those extra doses, we can also get the additional supplies.�

are 195 vials in a flat of vaccine, so that gives us 195 extra doses of ‘free’ vaccine per flat,� he said.

The University of Utah, in Salt Lake City, also has been able to get an additional dose out of almost every vial of vaccine it has received, said Erin R. Fox, PharmD, an adjunct associate professor of pharmacotherapy. “It’s a really nice surprise,� she said. “As soon as we got the OK from the FDA, we began using the extra doses, which for us was in the middle of the day on Wednesday. It’s important for the public to understand that Pfizer didn’t make a mistake, that this is very common in multidose vials. They want to ensure that everybody can at least get five doses out at the minimum.�

In a statement e-mailed to Pharmacy Practice News, a Pfizer spokesperson said the company could not provide a recommendation on the remaining amount of vaccine from each vial. But the company did offer some caveats. “Each dose must contain 0.3 mL of vaccine. After dilution, the multidose vial contains enough vaccine for at least 5 doses. The amount of vaccine remaining in the multidose vial after removal of 5 doses can vary, depending on the type of needles and syringes used,� the spokesperson said. “If the amount of vaccine remaining in the vial cannot provide a full additional dose of 0.3mL, vaccinators must discard the vial and any excess volume. Excess vaccine from multiple vials must never be pooled. We continue to closely coordinate with the FDA on this matter.�

Eric Tichy, PharmD, MBA, the vice chair of supply chain management for Mayo Clinic in Rochester, Minn., agreed that dilution strategies need to be done carefully. In doing so, “like many other hospitals, we’ve found that we can get an extra dose or two out of every vial,�

Tichy said. “That was a huge bonus. It meant the equivalent of an additional 20% of vaccine for every 5-dose vaccine vial. That was very significant because for every 1,000 doses we were getting an extra 200. I was telling people that was like our Christmas miracle.�

The additional doses pose another challenge: running out of syringes. “The government is supplying us with

Stretching Moderna’s Vaccine The Pfizer vaccine may not be the only one that can be boosted with creative dosing strategies. In early January, scientists at the National Institutes of Health and Moderna announced that they are analyzing data to see if they can double the supply of the company’s mRNA-1273 vaccine by cutting doses in half. NIH officials said results of the analysis should take about two months.

In an Operation Warp Speed call with reporters on Jan. 6, Health and Human Services Secretary Alex Azar offered

another useful tip for hospitals seeking to maximize the impact of COVID-19 vaccination efforts: not to let too fine a focus on logistics get in the way of optimal distribution. “It’s better to vaccinate lower-priority populations than micromanage this process and leave vaccines in the freezer,� Azar said. “Faster administration can save lives right now.� —Gina Shaw, Marie Rosenthal, Bruce Buckley The sources reported no relevant financial disclosures.

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10 Clinical

Pharmacy Practice News • January 2021

Covid-19 Pandemic

Leading the First Phase of COVID-19 Vaccine Rollout A

s expected, pharmacists have been on the front lines of the COVID-19 vaccination rollout, administering the Pfizer/BioNTech and Moderna vaccines to thousands of health care workers and other at-risk people nationwide. But it hasn’t been easy.

The early days have been marked by vaccine deliveries falling far short of projections, refrigeration breakdowns and other cold chain challenges, and in several states, vaccination gaps that have led officials to threaten hospitals with fines and reductions in future vaccine allotments. Yet through it all, pharmacy directors say they have been able to avoid breakdowns in vaccine delivery, thanks in part to careful planning and scheduling processes that had to be continually revised on the fly as guidance from federal and state agencies changed almost daily.

“The process around handling these vaccines, particularly [from] Pfizer, has to be like clockwork, and our members have practiced for that, even rehearsing the process of removing the Pfizer vaccine from the thermal shipper and placing it in the ultracold freezers,” said Anna Legreid Dopp, PharmD, the senior director of clinical guidelines and quality improvement for ASHP. “But we knew that there would be some bumps and some learning opportunities in the first weeks of vaccine distribution. For example, there were cases where some vaccine came in even colder than the allotted temperature range, which was something unexpected. We had been more concerned about warmer temperature excursions rather than colder, but this incident alerted us to the potential for lower temperature excursions as well.”

Legreid Dopp said ASHP has received multiple reports from member institutions about getting fewer allotments of vaccines than they were told to expect.

“It’s likely a combination of raw material shortage impacting supply amounts, as well as the federal government holding back some doses,” she said. “We have also heard of some instances where vaccines have had to be replaced due to temperature variations in shipping.”

Delivery shortfalls may not be the only hindrance to more widespread vaccinations; some hospitals are struggling to administer even on-hand vaccines quickly. In New York, for example, state officials reported that the city’s public health hospitals had received about 38,000 doses, but as of Jan. 3, had vaccinated only 12,000 eligible employees. While state health officials attributed the gap to “logistical challenges,” Gov. Mario Cuomo said the culprit also was some health systems’ “lack of urgency” regarding COVID-19 vaccinations. He threatened to fine

Jim Jorgenson, RPH, the CEO of pharmacy consultancy Visante, echoed Legreid Dopp’s comments. “Hospitals are stretched to the Nth degree already, and you’re going to fine them for not giving the vaccine fast enough when they’ve been at ground zero?” he said. “The federal government has left it up to the states to organize this process.

And the hospitals are at the mercy of their states. The last people in the world we should be blaming are hospitals.”

As the following profiles show, health systems are navigating these vaccinations challenges with a variety of operational strategies.

but two are very small and can only service their own location. Six others, in Sioux Falls; Bismarck and Fargo; and Moorhead, Worthington and Bemidji, Minn., have enough capacity to continue to serve as hubs. “Our location in Moorhead is not providing vaccine supply to other hospitals in that west central region at present, but the state wanted us to keep that freezer available for subsequent tiers of front-line health care staff that may be more clinic based, as well as when we get to distribution for the public. It gives us more options.”

Breidenbach said Sanford had received fewer doses of vaccine during the later weeks of distribution, as the states began gearing up for their partnerships with pharmacies, including CVS Health and Walgreens, to vaccinate long-term care residents, which Sanford is not directly involved in. As of Dec. 28, the system had administered more than 11,000 vaccines.

“Overall, it’s gone very well. The lack of a steady supply has caused us to have to tweak our vaccination clinics a little bit, because we’re always watching how many doses we have received and how many we have given, how many we think we’re getting, and then how many we know we’re getting once we get shipping confirmation. It’s always a moving target, and that’s been the biggest challenge.”

South Dakota: Monument Health Rebecca Doerr, PharmD, a clinical pharmacist at Monument Health, in Rapid City, S.D., shows her vaccination card after receiving the vaccine as a front-line health care worker.

hospitals up to $100,000—and redirect future vaccines to other facilities—if they failed to close the gap quickly.

Legreid Dopp pushed back strongly against Cuomo’s criticisms. “Our hospitals are trailblazers. They have been giving 110% to this effort, but the capacity and resilience of our ... health care workforce is stretched thin,” she said. “They’ve been overwhelmed with treating critically ill COVID patients for almost a year now. They’ve been receiving information at the last minute about how many vaccines they will get and when.”

Legreid Dopp added that when it comes to the Moderna vaccine, some of the problems have stemmed from a communications loop that initially shut hospitals out, with McKesson serving as the centralized distributor to state departments of health.

“We have some hospitals that have been able to form good, consistent, transparent communications with their departments of health, and in other states that has not happened,” she said. “Where there is that disconnect, hospitals are flying blind.

We’ve been told that starting next week, hospitals will be included directly in that communications chain.”

South Dakota: Sanford Health Sanford Health, the nation’s largest rural nonprofit health system, was among the first systems to receive doses of the Pfizer vaccine on Dec. 14, with 3,900 doses delivered to its hub in Sioux Falls, S.D., and 3,400 doses to its locations in Fargo and Bismarck, N.D. Frontline health care workers began receiving the vaccine the same day. “During that first week, 3,100 of the doses received at our hub in Sioux Falls were given to the top tier of front-line health care workers in the region,” said Jesse Breidenbach, PharmD, the senior director of pharmacy. “The remaining 800 doses were redistributed to other Sanford sites in the region and also to independent area hospitals, based on a plan we worked out with the state. The doses delivered to Bismarck and Fargo were all for our toptier, front-line health care workers.

“We have continued to receive allocations of vaccines from both Pfizer and Moderna,” Breidenbach added. “Some states are trying to focus the Moderna vaccine more in rural areas because of its easier handling and distribution.”

Sanford has eight ultracold freezers,

Serving western South Dakota and eastern Wyoming, the Monument Health system received its first shipment of the Pfizer vaccine on Dec. 14, the same day as its neighboring system, Sanford. “South Dakota is a very rural state, so the health department has relied on us, Sanford, and Avera Health, the other large system serving the state, to do a lot in the first couple of phases of vaccine distribution,” said Dana Darger, RPh, the director of pharmacy at Rapid City Hospital, part of the Monument system. “Most of the vaccine doses in South Dakota are being shipped through one of our three organizations and delivered out from there.”

Rapid City Hospital received a single flat of 975 doses of the Pfizer vaccine with that first shipment, which it stored in the only ultracold freezer it currently has—a bone freezer, used for preserving

human bone for allografts in orthopedic surgery, housed in the surgical department—and finished administering that same week.

Darger said that on his facility’s first day of vaccinations, “we did our first five doses—one doctor and four nurses—for the media, which did a good job of covering the event for us. It felt like one of those monumental days, like the first step on the moon. If we can get the community to see that the doctors, nurses, pharmacists

Clinical

Pharmacy Practice News • January 2021

11

Covid-19 Pandemic up any days especially with the holiday coming up,” Tichy said. “But one good thing for us with having been on the later side of receiving these doses was that we were alerted to the extra dose in the vial.

Some organizations wasted those extra doses at first, but now every level of government is saying to get at least a sixth and, if possible, a seventh dose. We’ll capture all of that, which is a bonus.”

University of Utah Mayo Clinic medical staff members, in Rochester, N.Y., inspect a box of Pfizer/ BioNTech’s BNT162b2 COVID-19 vaccine as it arrives for initial storage and administration. The hospital received less than half of its initial projected doses and, like many other institutions, finds that it can get an additional 1-2 doses per vial from the Pfizer vaccine. (See page 1 story for more details.)

and others in the hospital are getting vaccinated at high rates and we believe this is safe, I hope that it will help the community accept it better.”

There were some logistical challenges, Darger acknowledged, such as scheduling vaccination appointments to coincide appropriately with thawing. “Ideally, you thaw the vaccine in the refrigerator for three hours,” he said. “You can do it for 30 minutes at room temperature, but if you do that you can’t put it back in the refrigerator. So, on our first days we had a couple of snafus where the vaccine wasn’t quite ready for people who were waiting for their appointments, but we didn’t want to do the room-temperature thaw because then you can’t refrigerate again. On the other hand, you don’t want people standing around waiting in line, because that violates social distancing rules. Scheduling people for these immunizations is logistically very different from how we would typically do a mass vaccination.”

With some practice, Rapid City Hospital reached a pace of approximately 10 to 12 people per vaccinator per hour, Darger said.

As of Dec. 28, Walgreens, CVS Health and smaller independent pharmacies in South Dakota had begun vaccinating long-term care residents and staff in the state, and once that phase of distribution is complete, Darger said Monument will again take a leading role in vaccinating high-risk individuals in the general population.

Connecticut: Yale New Haven Hospital A central hub for the five-hospital Yale New Haven Health System, Yale New Haven Hospital received its first doses of the Pfizer vaccine on Dec. 15, began vaccinating the next day, and had administered all of the initial 2,000 doses to its front-line staff by Dec. 22. Like most other institutions, Yale New Haven made vaccination voluntary rather than mandatory at this point. “An employee will receive an emailed invitation to schedule their vaccine appointment, and then it is up to them whether they schedule it,”

said Nilesh Amin, PharmD, the supervisor of pharmacy procurement and operations. That option also poses some difficulties when it comes to knowing how many daily vaccine doses to send to the hospitals. “If everyone signed up for all the available slots, then we could easily determine ahead of time how much to

The University of Utah, in Salt Lake City, has three ultracold freezers and a fourth on the way. Given those cold storage capabilities, the system is expected to primarily receive only the Pfizer vaccine. “In Utah, regulations require that we can only administer these vaccines at the site where they are delivered, and we do have the capacity to use the vaccine that requires special storage,” said Erin R. Fox, PharmD, an adjunct associate professor of pharmacotherapy. “The Moderna vaccine will be much more useful in the rural parts

are front-line COVID caregivers, so our group of people who need the vaccine in the first phase keeps expanding.

We’re just trying to get those doses into everybody’s arm as quickly as possible.”

The University of California, San Francisco Farther north in the Bay Area, the University of California, San Francisco is a “multi-county entity” or MCE—the state Department of Health’s term for a vaccine hub—one of seven locations in the state that received syringe kits ahead of time to prepare for the vaccine rollout. The institution began vaccinating its front-line, highest-exposure health care workers on Dec. 16, reaching a pace of 500 per day by the end of that week and then increasing to 600 per day.

“We went completely through the weekend and were open 12.5 hours a day,” said Desi Kotis, PharmD, the chief pharmacy executive for UCSF Health. UCSF had finished that phase of immunizations by Dec. 23—a total of nearly 11,000

‘If we can get the community to see that the doctors, nurses, pharmacists and others in the hospital are getting vaccinated at high rates and we believe this is safe, I hope that it will help the community accept it better.’

—Dana Darger, RPh send to each hospital; but since that is not the case, we are often waiting late into the day before we can determine what we are sending. At roughly 3 to 4 p.m., the schedule is closed for the following day, and that’s when we assess the numbers and send the appropriate amount of vaccine to each hospital.”

Minnesota: Mayo Clinic Pharmacy leaders at Mayo Clinic in Rochester, Minn., initially worried about whether their ultracold freezers, which can store approximately 15,000 vials, would have the capacity to manage its role as a distribution hub for the Pfizer vaccine. They needn’t have worried, said Eric Tichy, PharmD, the vice chair of supply chain management. “We first received less than 3,000 doses at our big hospital in Rochester—basically, three personal pizza box–sized trays of vaccine with 195 vials in each tray,” Tichy said. “The original guidance was that we would get more than twice as much, but then they started dropping down their estimates of how much we were going to get.”

Mayo also experienced a slight delay in its first Pfizer vaccine shipments, expecting to receive doses on Dec. 14, but ultimately not receiving them until the 16th..

“Because of that, we opted to vaccinate through the weekend, not wanting to give

of the state, where our population is really spread out, so it should go to the hospitals in those locations.”

With COVID-19 cases surging in California and the Southwest, the University of Utah is facing critical demand. “We’re the only academic medical center for a long way, and we are getting calls from surrounding states, such as from Las Vegas, which would normally go to Los Angeles where they are inundated,” Fox said. “We have more patients than ever before and, thus, more health care workers who

doses. They were set to open additional vaccine clinics on Jan. 4, to immunize the remainder of its health care workers and expected “to be vaccinating 1,440 people per day in two separate clinics at that point,” she said.

Kotis noted that all UCSF COVID-19 vaccine clinics are run by pharmacists, with primary staffing from pharmacy student volunteers. “Pharmacists in California are providers, and while we have received interdisciplinary volunteers from the medicine, nursing and see VACCINE ROLLOUT, page 12

A Mayo Clinic health care worker in Florida receives the Pfizer/BioNTech COVID-19 vaccine.

12 Clinical

Pharmacy Practice News • January 2021

Covid-19 Pandemic

Overdose Deaths Accelerating During Pandemic C

OVID-19 has caused a lot of collateral damage to patients from decreased vaccinations to decreased cancer care. Its effects on the opioid epidemic, unfortunately, means a 38.4% increase in overdose deaths, according to the CDC. The CDC looked at a 12-month span from June 2019 to May 2020 and found more than 81,000 overdose deaths—the highest number of overdose deaths ever recorded in a 12-month period.

Synthetic opioids—especially illicitly manufactured fentanyl—appear to be the primary driver, increasing overdose deaths to 38.4% in that period, according to the CDC. During this period: • 37 of the 38 U.S. jurisdictions with available synthetic opioid data reported increases in synthetic opioidinvolved overdose deaths; • 18 of these jurisdictions reported increases greater than 50%; and • 10 Western states reported over a 98% increase in synthetic opioidinvolved deaths.

Although overdose deaths already were increasing in the months preceding the COVID-19 pandemic, the agency admitted, the latest numbers suggest an acceleration of overdose deaths during the pandemic. “The disruption to daily life due to the COVID-19 pandemic has hit those with substance use disorder hard,” CDC Director Robert Redfield, MD, said in a statement.

Steven J. Martin, PharmD, the dean and a professor at Ohio Northern University Rudolph H. Raabe College of Pharmacy, in Ada, said his group has been watching this unfold in his rural area all year. “Unfortunately, opioid-related deaths have reversed the trend we saw in

VACCINE ROLLOUT continued from page 11

dental schools, the vaccinators are primarily our pharmacy students. Students with pharmacist oversight are drawing up every dose, reconstituting, labeling, ensuring the needles are attached, logging the barcode scans on every syringe, and ensuring the utmost safe environment. It’s really an extraordinary effort.”

In Wisconsin, a Moving Target Froedtert & the Medical College of Wisconsin (MCW) health network received its first 2,925 doses of the Pfizer vaccine around 5 p.m. on Dec. 17, and began vaccinating the next day.

“Things have been evolving almost hourly in Wisconsin with the initial vaccine

2018 and 2019, and COVID-19 is largely responsible,” Martin told Pharmacy Practice News.

Although much of the escalation is due to illegal opioid procurement, there are several actions that health care workers, particularly pharmacists, can take, said Martin, who also sits on the Pharmacy Practice News editorial advisory board.

“Pharmacists must check state PDMP [prescription drug monitoring program] databases to identify opioid misuse patterns; educate every patient who receives an opioid prescription about the management of pain, risk of addiction and use of naloxone for those at higher risk; and partner with prescribers to reduce coprescribing of opioids and benzodiazepines and prescribing opioids at more than 50 MME [morphine milligram equivalents] per day,” Martin said.

“All health care professionals should provide basic screening for persons suffering from drug use disorders, and provide direction to services in their community that can address addiction,” he said, and “this is particularly important in the rural setting where access to the health care system is limited, and treatment programs may not be available without significant travel.”

Not Just Opioids Overdose deaths involving cocaine also increased by 26.5%, according to the CDC. Based on earlier research, these deaths are likely linked to combined use or contamination of cocaine with illicitly manufactured fentanyl or heroin. Overdose deaths involving psychostimulants,

rollout,” said Philip Brummond, PharmD, the chief pharmacy officer for the Froedtert & MCW health network. Noting that “there was a phased approach” across the state, he said, “we received our initial shipment later than expected.”

MCW received another shipment of 4,300 doses by the end of December, and at press time was anticipating an additional 9,000 doses of vaccine—some combination of the Pfizer and Moderna vaccines—the first week of January.

Brummond also stressed the logistical challenges of thawing time and appointment scheduling. “We’re giving 60 vaccines per hour in one of our clinics, so it’s taken us some time to calculate planning for thawing and reconstitution,” he said.

“The first few days were a challenge for us to make sure every single dose we drew up was used in the appropriate

‘Unfortunately, opioid-related deaths have reversed the trend we saw in 2018 and 2019, and COVID-19 is largely responsible.’

—Steven J. Martin, PharmD such as methamphetamine, increased by 34.8%. The number of deaths involving psychostimulants now exceeds the number of cocaine-involved deaths, the agency said.

“The increase in overdose deaths is concerning.” said Deb Houry, MD, MPH, the director of CDC’s National Center for Injury Prevention and Control. “CDC’s Injury Center continues to help and support communities responding to the evolving overdose crisis. Our priority is to do everything we can to equip people on the ground to save lives in their communities.”

The CDC recommended these actions: • Expand distribution of naloxone and overdose prevention education.

• Expand awareness about and access to and the availability of treatment for substance use disorders.

• Intervene early with individuals at the highest risk for overdose.

• Improve detection of overdose outbreaks to facilitate more effective response.

Education should be a priority, Martin added. Pharmacists can provide education in their communities about the dangers of opioid misuse, and help to reduce the stigma of addiction as a criminal activity. He said it is important for everyone, including health care workers, to recognize it as a medical concern.

“As we continue the fight to end this pandemic, it’s important to not lose sight of different groups being affected in other ways. We need to take care of people suffering from unintended consequences,” Redfield said.

For more coverage of OUD, see page 4.

administration timeframe.”

Brummond said he anticipates “additional logistical issues” as the vaccination efforts pick up steam, including “scheduling patients for second doses while we are also scheduling first doses, all while preparing to do community immunizations within our clinics. I’m very encouraged [that] we have been able to coordinate getting the vaccine administered at the pace we have. It speaks well to our system’s ability to provide vaccines to the community in an expedited fashion.”

to put the full force of the public health system behind this effort now,” Legreid Dopp said. “We’ve been advocating for a long time that this will take mobilization of traditional and non-traditional immunizers and immunizing locations, and now it’s time to move beyond the walls of hospitals and health systems.

That includes community pharmacies, ambulatory health clinics, even schools and faith-based institutions. Hospitals and health systems have been carrying the baton for this first leg of the relay, but now it’s time to bring in the rest of the relay team too. A lot more vaccines are coming down the pipeline and now is the time to get this right.”

—Gina Shaw

Next Steps ASHP’s Legreid Dopp expressed relief at the Jan. 6 announcement from Health and Human Services Secretary Alex Azar that community-based pharmacy immunizations would be rolled out sooner than expected. “We applaud that, but we need

—Marie Rosenthal The sources reported no relevant financial disclosures.

The sources reported no relevant financial disclosures.

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14 Clinical

Pharmacy Practice News • January 2021

Personalized Medicine

Room for Growth in PGx-Guided Transplants

D

rug treatment based on pharmacogenomics, already a significant factor in oncology, psychiatry, pain management and anticoagulation therapy, is poised to play an important role in transplant medicine, a leading pharmacogenomics expert noted during the American College of Clinical Pharmacy 2020 virtual annual meeting.

The number of transplant patients who could benefit from personalized

medicine is huge: one recent study found that 100% of nearly 900 organ transplant patients had at least one actionable pharmacogenomic phenotype that could explain suboptimal therapeutic responses to immune-suppressing agents (J Clin Pharm Ther 2020 Jul 14. [Epub ahead of print]. doi: 10.1111/jcpt.13223).

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released guidelines involving several

drugs that would have some application on in organ transplantation, including tacroolimus, voriconazole, clopidogrel, selecctive serotonin reuptake inhibitors, 5-HT T3 agonists, thiopurines and proton pump mp inhibitors. Another key source is the he FDA, which regularly updates its “Table of Pharmacogenomic Biomarkers in Drug Labeling” (bit.ly/3hh5qnx).

“Over 100 of those drugs are relevant to transplantation,” said Pamala Jacobson,

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PharmD, a distinguished professor in the Department of Experimental and Clinical Pharmacology and the director of the Institute of Personalized Medicine at the University of Minnesota College of Pharmacy, in Minneapolis. “So, although the FDA is not providing recommendations here, it is providing data suggesting that these are legitimate drug-gene pairs that could be used in clinical practice.”

Jacobson pointed to a study involving 853 kidney transplant recipients (J Clin Pharm Ther 2020 Jul 14. [Epub ahead of print]. doi: 10.1111/jcpt.13223).

“Each transplant recipient had at least one actionable CPIC pharmacogenomic phenotype from 13 pharmacogenes,” she said. Moreover, “58% of the study participants had three or four [phenotypes], and over 20% had five or more.”

Jacobson cited tacrolimus as one example of a drug with significant pharmacogenomics potential in transplantation.

“We know that transplant recipients with low tacrolimus troughs are more likely to develop donor-specific antibodies, which can lead to other immune problems, in particular rejection,” she said. “The threshold is 8 ng/mL, and we want everybody above that if at all possible.”

Jacobson pointed to cytochrome enzyme CYP3A5 polymorphisms as particularly relevant to tacrolimus therapy, contributing to clinically significant differences in tacrolimus bioavailability between individual patients. Up to nine different alleles have been identified in CYP3A5, with *1 (normal function) and *3 (loss of function) being most common and best studied (Pharmgenomics Pers Med 2018;11:23-33).

Studies have identified differences in tacrolimus metabolism between white and Black transplant recipients based on CYP3A5 variants, Jacobson added. “For example, a genome-wide association study of tacrolimus troughs in African American transplant recipients found that there are three genetic variants that are extremely important: CYP3A5 *3, CYP3A5 *6 and CYP3A5 *7. In the African American population, when you combine clinical variables with these loss-of-function variants, you can explain more than 54% of the variability in trough concentrations” (Am J Transplant 2016;16[2]:574-582).

Earlier trials of genotype-directed dosing of tacrolimus have had mixed results, she said. A French study found that patients who received genotype-directed dosing of the drug were more likely to

Clinical

Pharmacy Practice News • January 2021

Personalized Medicine

Of 853 kidney transplant recipients: 100% had at least one actionable CPIC pharmacogenomic phenotype

58% had 3-4 20%+ had 5 or more Source: J Clin Pharm Ther 2020 Jul 14. doi: 10.1111/jcpt.13223 [Epub ahead of print]) CPIC, Clinical Pharmacogenetics Implementation Consortium

be in the appropriate therapeutic range at days 3 and 10 after transplant, but no difference in rejection and graft outcome was found at five-year follow-up (Pharmacol Ther 2010;87[6]:721-726; Am J Transplant 2016;16[9]:2670-2685). A Dutch trial found no differences in troughs or graft outcomes, but also no differences in adverse events, so Jacobson noted that it suggested safety of this dosing approach (Am J Transplant 2016;16[9]:2670-2685).

However, the trials had limitations, Jacobson said. “For example, they studied only a single polymorphism, directing dosing just at allele *3, and we now know many others are important.”

genetic testing in all patients for dosing of voriconazole would save an estimated $4,700 per patient compared with historical controls. This suggests that broad pharmacogenetic testing in an entire transplant group could be cost-effective.”

Jacobson stressed the importance of combining pharmacogenomic information with clinical variables, such as age and drug–drug interactions, in dosing models. In going so, “you can explain more than half of the variability in tacrolimus trough concentration,” she said (Am J Transplant 2016;16[2]:574-582).

Jacobson and her team developed a model that combined these factors, which resulted in the first reported African American–specific, genotype-guided tacrolimus dosing model (Pharmacogenomics J 2017;1:61-68). “To determine the dose, the model includes the genotypes, whether the patient is receiving steroids and/or antivirals, and their age,” she said, adding that the model is for immediaterelease tacrolimus and that a new model will be needed for the once-daily product.

“This approach highlights where we need to go with pharmacogenomics

writ large as well as in transplant specifically,” Dunnenberger said. “Genomics don’t affect patients in a silo. You have to think about clinical and genetic factors together to identify the right medication and the right dose for each patient.” The goal, he added, is to get into “the Goldilocks zone,” where “you have just the right amount of data that can be turned into action, without overburdening the system.”

—Gina Shaw The sources reported no relevant financial disclosures.

Like What You Read in Pharmacy Practice News?

‘A Huge Opportunity’ The transplant field represents an early success and “a huge opportunity for pharmacogenomics,” said Henry “Mark” Dunnenberger, PharmD, the director of pharmacogenomics at NorthShore University HealthSystem, in Manhasset, N.Y., with tacrolimus dosing at the forefront. “Tacrolimus dosing is complicated and has a narrow therapeutic window,” he said. “We had long known about dosing variability from the package insert, which states that the data in kidney transplant patients indicate that Black patients required a higher dose to attain comparable trough concentrations to [whites]. The original clinical studies weren’t looking for genetic variation but they saw the trend, and now we have the genetic reason behind it.”

Another agent commonly used for transplant patients, voriconazole, is primarily dependent on the CYP2C19 genetic pathway, Jacobson noted. She cited a recent study of genotype-directed dosing in patients receiving allogeneic hematopoietic cell transplants (J Clin Pharmacol Ther 2020;107[3]:571-579). “Poor metabolizers, intermediate metabolizers and normal metabolizers initiated voriconazole therapy at a standard dose of 200 mg twice daily, while rapid and ultrarapid metabolizers were started at 300 mg twice daily,” Jacobson said. “Only about 30% of the study population were in the subtherapeutic range for trough concentrations, compared with 50% of historical controls. The difference was particularly dramatic in the rapid and ultrarapid metabolizers: Only about 16% of them were subtherapeutic, compared with 70% of historical controls.”

The authors also conducted a cost analysis. “One fungal infection costs about $50,000 to treat in these patients,” Jacobson said. “They found that doing

15

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16 Operations & Management

Pharmacy Practice News • January 2021

Covid-19 Pandemic

The wholesaler and the health system:

A Powerful COVID-19 Partnership A

dd the University of Chicago Medicine (UCM) health system to the list of facilities that are sharing their successes in meeting patients’ needs during even the early days of the COVID-19 pandemic.

Rapid intervention emerged as one of the most important tools for ensuring optimal clinical outcomes, Kevin Colgan, MA, FASHP, UCM’s vice president and chief pharmacy officer, told Pharmacy Practice News. The 1,296-bed health system estimated that nearly 80% of its relatively early COVID-19 admissions in 2020 were at high risk for a severe disease course.

Senior leaders at UCM had prepared for this “very sick population” with weekly command meetings starting in January that became daily in March.

Part of that planning, he noted, focused on the importance of maintaining adequate stocks of medications. On Jan. 31, 2020, he noted, “I raised concerns that much of the APIs [active pharmaceutical ingredients] were made far away in China with long shipping times, and

massive drug shortages were emerging worldwide. I requested additional space to store drugs and got permission to stockpile five months’ worth,” Colgan said. “Within one week, we identified 180 critical drugs for all patients—such as for surgeries, cancer and clinical trials we run—not just COVID-19.”

Colgan recognized early that routine wholesaler allocations to hospitals based on historical medication usage would be insufficient in the pandemic. “You have to allocate based on the number of COVID-19 patients. McKesson [UCM’s wholesaler] had to throw out old ways of doing things” and channel more inventory to hospitals as hot spots shifted to Detroit, Chicago, New Orleans, New York City and elsewhere, he said.

Preferred Therapies Maintained Ample inventory enabled UCM physicians to continue prescribing their preferred drugs for COVID-19 patients, with one exception, Colgan said: For five weeks, UCM needed to

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switch to rocuronium as an infused neuromuscular blocker when cisatracurium wasn’t available. McKesson told Pharmacy Practice News that orders for cisatracurium increased by about 500% nationwide between February and March 2020. “We saw demand for many medications far outpace what historical ordering patterns suggested,” said Dave Ehlert, PharmD, MBA, area vice president at McKesson Health Systems.

“We were successful treating patients because we had access to drugs,” said Colgan, adding that McKesson “was instrumental in getting our orders filled and bringing us information on what manufacturers were doing. We also had a newer hospital with more negative-pressure rooms and an emergency department retooled” for the influx of patients.

The health system collaborated with McKesson’s RxO division for domestic and global outreach to sustain sourcing. Teams at UCM also searched daily for new peer-reviewed literature on COVID-19, prepared treatment algorithms and adapted as needed. As soon as UCM learned of promising agents based on the early experiences of other centers managing the disease, including those in Wuhan, China, where the outbreak began, the health system moved quickly to obtain the medications.

Colgan cited, as examples, lopinavirritonavir (Kaletra, AbbVie) and tocilizumab (Actemra, Genentech), both of which gained some early traction as COVID-19 therapies. “We wanted enough [of these medications] to treat at least 400 to 500 severely ill COVID patients, and we weren’t the only ones,” he said.

(Many early COVID-19 treatments have not held up to scrutiny. In the case of lopinavir-ritonavir, a study found that in hospitalized adult patients with severe COVID-19, no benefit was observed with the combination treatment beyond standard care [N Engl J Med 2020;382(19):1787-1799]).

Mixing It Up Among urgent efforts to keep UCM ahead of the pandemic, Colgan said McKesson redistributed medications from other states less affected by the virus, assisted with drug supply for a shared canister program of albuterol metered-dose inhalers practically overnight, and put him in direct contact with a manufacturer of tocilizumab, which drop-shipped his orders to McKesson.

Because tocilizumab is a specialty pharmaceutical for rheumatoid arthritis patients, it took more resourcefulness to secure a supply, he explained.

The health system largely secured what it needed because Colgan provided UCM treatment algorithm information and patient volume data as they occurred to McKesson. The data detailed UCM’s fluctuating counts of confirmed and suspected COVID-19 patients, patients in ICU settings, and patients who were mechanically ventilated. UCM sent the data to McKesson account executive Kristina Cole, who shared it with McKesson’s supply chain and RxO teams to accurately forecast and fulfill UCM’s upcoming medication needs. Cole also relayed back to Colgan the continuously renewed supply chain insights disseminated by McKesson RxO’s newly formed Critical Care Drug Task Force.

McKesson formed the task force—a working group of 20 professionals across McKesson, including data scientists, procurement, distribution and regulatory experts, and pharmacists experienced in health-system pharmacy operations and optimization—to support hospital pharmacies as they identify drug therapies needed to treat COVID-19 patients.

The task force also forecasted demand based on dosing requirements and discussions of alternative therapies based on reference literature, according to Barbara Giacomelli, PharmD, MBA, McKesson RxO’s VPAdvisory, Pharmaceutical Solutions and Services. Task force members continue to track 222 critical care medications on its master list—not yet including investigational vaccines— and color-code each one red, yellow or green by the degree of supply constraint and critical need, she said.

The task force has broad access across McKesson to bring intelligence from many disciplines to health-system customers. Its members obtain and interpret data about finished drug supplies at manufacturers and in the pipeline, as well as location and availability timing of preferred and alternative therapies;

Operations & Management

Pharmacy Practice News • January 2021

17

Covid-19 Pandemic back to about 46% in person, and it should maintain there for a while.”

Colgan said he expected UCM’s telehealth and mail-order shipment expansions to help its specialty pharmacy patient count grow from 1,750 to 2,000 per month by the end of 2020. “We asked specialty patients we mail to monthly if they had other pharmaceuticals they didn’t want to go to the drugstore for.

When they said yes, we filled their maintenance medication prescriptions and mailed it to them,” he explained. “COVID was much less a factor for us in terms

they then filter the information to sales leadership and local account executive teams, who in turn share it with hospital customers, such as UCM. They mine the data using multiple McKesson tools—Utilization Analytics, 340B Purchasing Dashboard, and Patient Assistance Recovery Software and Connect Reporting—to help optimize medication flow, mitigate spend and optimize revenue for hospitals.

The task force also interviews hospital customers about their dosing, and reviews national and international clinical recommendations and treatment guidelines, and newer protocols being investigated, Ehlert added.

“We never knew which way the pandemic curve would go, so I consistently ordered 25% more than I thought I’d need, and I was never disappointed,” Colgan said. “[Yet] if I had extra medications and another hospital needed some, I’d share.”

Amid the COVID-19 surge, Colgan said he recognized the importance of collaborating with McKesson not only to protect UCM’s ability to care for patients, but also to avoid putting other hospitals in a bind by cornering scarce resources. “I knew if I stockpiled a fivemonth supply of mission-critical drugs for UCM, it would cause disruption to McKesson,” so he called to alert them first before increasing his orders.

Specialty Pharmacy Responds For specialty pharmacy at UCM, the COVID-19 challenge was mostly about keeping in contact with patients who stopped their clinic and ambulatory visits to stay at home, and still needed their medications.

The health system stepped up its telehealth and mail-order initiatives to protect patient health and add convenience.

As visit counts fell, “telehealth grew overnight [to the point] we’re now at 80% pre-COVID volume of business,” Colgan said. “Our clinic visits are now

of specialty drug supply than was being reported by others.”

Still, “there are several specialty medications being investigated for COVID-19,” such as anakinra (Kineret, Sobi) and tocilizumab, noted Dave Ehlert, PharmD, MBA, FASHP, area vice president, McKesson Health Systems.

In the case of tocilizumab, the most recent data are not promising. In December, a study concluded that the interleukin-6 receptor blocker was not effective for preventing intubation or death in moderately ill hospitalized

patients with COVID-19 (N Engl J Med 2020;383:2333-2344).

—Al Heller The sources reported no relevant financial disclosures other than their stated employment.

Only on the Web: 6 Best Practices to Manage COVID-19–Related Drug Shortages See expanded article at pharmacypracticenews.com.

18 Operations & Management

Pharmacy Practice News • January 2021

Covid-19 Pandemic continued from page 1

At NYC Hospital, Medication Bundling Tops the List

T

wo strategies—medication “bundling” and savvy tweaks to automated dispensing cabinets (ADCs)— helped Jawad Saleh, PharmD, the clinical manager of pharmacy services at New York City’s Hospital for Special Surgery, navigate the COVID-19 crisis at his hospital.

The ADC changes were particularly helpful in transforming hospital areas into ICUs and identifying key workflow modifications during COVID-19, Saleh said at the ASHP 2020 Midyear Clinical Meeting and Exhibition. When hospitals adapt other spaces, such as operating rooms (ORs) or PACUs, into COVID-19 ICUs, he noted, placement of ADCs and pumps is a key consideration.

“These need to be strategically placed in clean areas, with the goal of decreasing pharmacy staff exposure and decreasing medication contamination,” Saleh said.

“Speak to your engineering and network teams to place adequate electrical outlets.

Remember that ADCs moved to a different unit must be renamed temporarily to prevent staff confusion.”

Two refrigerators per unit would be ideal, he noted, with one allotted to patient-specific medications and the other containing bins for the most common noncontrolled infusions. He also recommended temporarily increasing medication par levels to decrease the frequency of restocking and reducing traffic to the ADCs, while also removing slow-moving medications to help with capacity.

Placing pumps outside of COVID-19 ICUs has been a strategy used to preserve personal protective equipment (PPE) and reduce the frequency of exposure for nurses, as previously reported in Pharmacy Practice News (bit. ly/3os0K1s). But it’s not a universal fit, Saleh said. “It’s best for isolated patient rooms, preferably single-patient [rooms], and not practical for open-suite units and OR rooms, which are too big.”

Saleh added that pumps outside of rooms work best with central lines, and arterial line blood pressure monitoring is preferred. “Small bore extension tubing has less volume in the tubing between the infusion and patient, so it reaches the patient more quickly,” he said. “Additionally, use caution with very high infusion rates, because resistance to the flow may occur. It’s also important to label lines and tubing at the pump and end of extension tubing, to help nurses identify medications at site of connection to patients.”

Some medications are preferred with extension tubing, including vasopressors (excluding vasopressin), inotropes, sedatives and analgesics, Saleh noted. The following are discouraged with extension

tubing: amiodarone; vasopressin; chemotherapy; electrolyte replacements (to avoid accidental bolus); insulin, which requires blood glucose monitoring every one to two hours; heparin, because changes are only made every six hours; drugs requiring large bolus volumes for proper flushing; and maintenance fluids.

Saleh added that increased drug waste is common with extension tubing.

During a surge, staff may step into roles they are not accustomed to, so regular education is essential. “For example, inpatient nurses utilize Pyxis [BD] machines, and operating room nurses who aren’t familiar with Pyxis must be trained,” he said. “CRNAs [certified registered nurse anesthetists] don’t have access to Pyxis, because they usually use Omnicell when in the OR. Get a staff list from the manager of that specific unit and grant access immediately while providing in-service trainings regularly.”

Based on the acuity of COVID-19 patients, the Pyxis override list will likely need to be expanded, he added, increasing the amount of medications that can be overridden in an emergency without having an order in place. “If access and training are done properly, it will alleviate a lot of pressure from both pharmacy and the ICU and prevent delays in patient care.”

Medication Bundling Medication bundling was another key strategy for Saleh and his colleagues during the pandemic. The practice, which they continue to employ, involves consolidating medication times together to help limit how often nurses need

to enter and exit patient rooms. Done correctly, medication bundling “helps minimize health care professionals’ exposure to the virus, limit contamination and conserve PPE,” Saleh said. “At our hospital, for example, our medication times were 10 a.m. and 10 p.m. You can piggyback your scheduling based on time-sensitive medications that must be given priority, such as antibiotic or drugs for Parkinson’s disease.

So if there’s a Parkinson’s medication that must be given at 7 a.m., then you’d stack everything at 7 a.m. and 7 p.m.

And when you have known drug–drug interactions, separate those medicaslots.”” tions based on the chosen time slots Saleh offered guidance on bundling medication regimens for several specific indications: Bowel Regimens

Polyethylene glycol and senna-based laxatives are preferred to options that must be given more frequently, such as lactulose. For stress ulcer prophylaxis, he said, patients with a creatinine clearance greater than 50 mL/min should be given pantoprazole-esomeprazole 40 mg orally or by nasogastric tube daily. Patients who are on non-oral regimens should receive a slow IV push to reduce fluid intake and maintain stock in the ADC. For patients with a creatinine clearance less than 50 mL/min, he recommended famotidine 20 mg daily, unless there are other indications for a proton pump inhibitor.

Glycemic Control

Minimizing fingersticks by needles reduces another source of potential exposure, Saleh said, adding that “arterial blood is best for glucose measurements in this setting.” If there is no arterial line, “use Novastat [Taconova] machines, which are good for accounting for variances. You can also employ

patients’ own home-based intermittent glucose monitoring and continuous glucose monitoring (CGM) systems.

There’s a huge value for nonintubated patients to be able to scan themselves if they have the FreeStyle Libre [Abbott; CGM system] and the reader in place.”

These systems have not been approved by the FDA for use in hospital settings, but the agency has temporarily waived this limitation during the pandemic to limit fingerstick blood glucose testing for monitoring and insulin administration. An agency statement released on July 9 stated: “The FDA recognizes that home-use ““T The h FD blood meters may be an option b bl ood o glucose gl to provide provvi relief and support to health care in hospital and longcca are professionals prro term ter te rm care rm ca facility settings seeking to reduce re edu duccee interactions between patients and care providers, thereby liman nd health hea to COVID-19, and coniiting it tin ing exposure ex serving se ser erv rvin ng PPE, whenever possible.”

For F Fo or gglycemic management, Saleh again ag g ai ain n recommended longer-acting products, pr p roducct such as insulin glargine, once daily, plus d da dail ail ily, p l shorter-acting products such insulin a insu as ul regular human (Humulin R, Lilly, or Novolin R, Novo NordEli Lilly Li i isk) orr insulin lispro (Humalog, Eli isk is k) o Lilly), L Li lly), depending on supply. “Once blood glucose is stable, thee patient’s pat pa yyou yo ou may may consider the use of Humalog 75/25, with total daily insulin require75/2 / 5,, w in two, twice daily,” he ments split s “Consider holding these products said. “C tube feeds are held, such as in when tu prone p positioning; when tube feeding stopped for 18 hours; or extubation, is stopp when it is stopped for six hours.”

Opportunistic Infection Prophylaxis

Before recommending infection prophylaxis, Saleh noted, pharmacists should confer with the hospital’s infectious disease service about regimens that minimize exposure. “In the ICU, we recommend daily fluconazole, which can be crushed, for antifungal prophylaxis rather than clotrimazole troches or topical nystatin. For antiviral prophylaxis, [use] once-daily valacyclovir over acyclovir, which has much more frequent dosing.”

Cardiovascular Regimens

“In general, we recommend longacting medications—XL, XR, SR—if the patient is hemodynamically stable and able to swallow,” Saleh said.

He recommended that hospitals consider increased jurisdiction for pharmacists to be allowed to make some of these changes automatically in light of the pandemic. “You are protecting everyone on your clinical staff—medical, nursing and pharmacy—by bundling and minimizing the frequency of people going into and out of the rooms of patients with COVID-19.”

Continued on facing page

Operations & Management

Pharmacy Practice News • January 2021

19

Covid-19 Pandemic

3 Strategies for Preserving Quality And Safe Practices in Critical Care

T

he COVID-19 pandemic has stretched ICU resources at an unprecedented fashion. A shortage of certain drugs and PPE, the inclusion of some non–ICU-trained physicians to manage patients, and families barred from live visits can insert barriers to best practices in ICU patient care honed over time.

Two critical care pharmacists offered strategies for overcoming these challenges during a session at the ASHP annual meeting.

1. Watch out for delirium. Many hospitalized patients with COVID-19 will develop the condition, noted Janelle Poyant, PharmD, BCPS, BCCCP, a critical care clinical pharmacy specialist at Tufts Medical Center, in Boston.

Encephalitis and encephalopathy with acute psychosis have been well documented in the context of influenza, and some data suggest that this may result as a consequence of the intense systemic and brain inflammatory responses (Eur Geriatr Med 2020;11[5]:857-862).

In patients with COVID-19, delirium may result from direct central nervous system invasion of the virus, or factors such as prolonged mechanical ventilation time, polypharmacy and experimental treatments. This is coupled with environmental factors that include

extreme isolation and the inability to freely ambulate, she said.

2. Rely on sedation bundles, when possible. There is a need to implement sedation protocols to limit rates of delirium and other complications of ICU stays, Poyant said. The Society of Critical Care Medicine’s A-F Bundle (www.sccm.org/ICULiberation/ABCDEF-Bundles) of elements is one way to align and coordinate care that includes a range of activities, from assessing pain to choosing the right sedation and promoting early mobility.

The bundle strives to optimize pain management, avoid d deep sedation, eep sedat atio io on, reduce delirium and shorten duraho orten th thee du uraation of mechanical ventilation, nttilation n, am aamong mon on ng other goals.

Still, there are many C COVID-19–relatOVID--19 1 –r –rel elaat ated issues and barriers that preclude haat mayy pr p eclu l de de the use of these practices, “particularly es, “par articu culaarl rly at hospitals experiencingg patien patient surges” nt surg su urg rges es” es es” during COVID-19, said B Brianne Ritchie, riannee R Ri itc tchi hie, e PharmD, BCCCP, BCPS, critical S,, a crit ticaal ca ccare aree clinical pharmacist with Health th CHI HII H ealt ea ltth Lakeside, in Omaha, Neb. Neb. Increased Inc ncre reeas ased ed d patient volumes with overflowing verflow ve wingg IICUs CU Us and hospitals, shortages important es of im mpo ort rtan aan nt medications and equipment, pment,, policies pol olic iciie ic ies on masking, and restrictions on visiictions o n vi vis sisisi tors all can negatively affect affect the th hee ways way ay s in which ICU staff assess manage ess and d ma m ana naggee nage

pain, agitation and delirium, and optimize mobility and family engagement, Ritchie said. The need to adopt social distancing and increased workload demands have further pushed multidisciplinary care and collaboration away from ideals.

“Because the A-F Bundle is so effective at optimizing ICU liberation, we as clinicians must recognize these challenges exist and apply strategies to overcome them in an effort to mitigate the negative consequences of ICU care, and subsequent post-discharge morbidity as best possible,” she said.

3. Keep an eye on workflow. Applying the bundle elements to reduce mechanical ventilation duration and decrease ICU length of stay seems like a perfect match

for the pandemic, Ritchie said. However, this requires substantial clinician resources and time that many institutions struggled to provide even pre-pandemic.

There have been a number of changes in ICU care as hospitals prepared for and managed surges, as well as shifts in daily interprofessional team rounding practices, Ritchie noted. In such conditions, patient care decisions often revert to isolated conversations outside the robust input of multidisciplinary colleagues that has become best practice, she warned.

“Maintaining the interprofessional team may require novel approaches,” Ritchie said, “such as virtual participation from colleagues and other areas of the hospital, as well as family members at home.”

made everything go smoother, and now that we are facing a second wave it’s nice that everything is already built out on the ground,” Clark said.

cabinets to meet the needs of this new critical patient population.

“Early on,” he said, “we decided to prebuild some machines in anticipation of this surge.” Some were pulled back and new ones ordered. In a conference room, he added, an ICU and a non-ICU setup sat ready to deploy, connected to the network and prefilled with medications. “We had to use this several times as we opened areas and moved patients into them.

“Very valuable in that process was knowing what our data told us were the typical medications and par levels we needed for the type of patients moving into those areas,” Webster added. “The advantage of having this tool live was that we could look at what we needed to load into those machines. We used it pretty extensively as we saw patient populations shifting pretty quickly.”

Strong Memorial’s Approach To Maintaining Stronger ICUs

A

t Strong Memorial Hospital, part of the University of Rochester Medical Center, clinical pharmacists were concerned about non–ICUtrained physicians having to take care of critically ill COVID-19 patients during a surge in cases. So they crafted a strategy aimed at ensuring that such patients are treated optimally.

“We wanted to create a model that really would help out the physician group and entire interdisciplinary team by creating guidelines and building order sets in the medical chart to make things foolproof,” said Jenna Clark, PharmD, BCCCP, a clinical pharmacy specialist for the hospital’s medical ICU, in Rochester, N.Y. Clark and her colleagues created an admission order set in the hospital’s electronic health record, critical drug shortage guidance documents for IV analgesics and sedatives, and a clinical practice guideline for COVID-19 pharmacotherapy, she noted during a COVID-19 session at the American College of Clinical Pharmacy (ACCP)

2020 virtual annual meeting.

They eting. The et heyy al he also so o initiated enhanced VTE TE prophylaxis proph ph hyl ylax ax xiss dosing and developed initiatives to preserve PPE and minimize nursing exposure, among other tasks. This included bundling the timing of medications to prevent nurses from entering patient rooms as often, and using continuous infusions from outside the rooms.

Then, as the hospital accumulated its own population of COVID-19 patients, critical care pharmacists rotated covering the COVID-19 ICUs and reviewing patient charts daily to optimize pharmacotherapy and discuss recommendations with the covering providers.

Among 137 COVID-19 patients hospitalized between March 30 and May 15, the pharmacists enacted 1,322 interventions, such as adjusting medication doses, altering pain and sedation regimens or recommending changes in bowel regimens. Pharmacists also adjusted guidance documents, as necessary, based on medication shortages or updated treatment guidelines.

“It was a lot of work but it definitely

A Boon During COVID-19 Surge URCM has developed another COVID-19 coping strategy: an inventory optimization tool that demonstrated its value during a rapid build-up to meet an anticipated surge in COVID-19 patients.

“We had to go quickly from about 900 beds to 700 additional beds,” said David Webster, RPh, MSBA, the director of acute care operations at the New York hospital. The hospital’s cafeteria, gymnasium and some underused ambulatory clinics were among the areas designated to fill the expected demand.

Fortunately, the number of cases never tested the increased capacity.

Still, Webster noted, with cases rising, the challenge was how to increase and repurpose automated dispensing

Continued on page 20

20 Operations & Management

Pharmacy Practice News • January 2021

Covid-19 Pandemic continued from previous page

Cooper University: 4 Steps to Tame VTE

M

echanically ventilated patients with COVID-19 face a significantly increased risk for developing venous thromboembolism (VTE) compared with non-critically ill patients with the disease, according to Lauren A. Igneri, PharmD, a critical care clinical pharmacy specialist with Cooper University Healthcare, in Camden, amden, N.J. “Coagulopathy has been n observed in 15% to 39% of COVID-19 19 patients requiring mechanical ventilation,” entilation,” Igneri said during the ASHP SHP annual meeting, citing one recent cent study (Blood 2020;136:489-500). ). “Early observations suggested that at elevated D-dimer levels were associated ted with an increased risk of mortality, and this suspicion was further heightened ghtened with autopsy results that found und fibrin thrombi within the he small vessels and capillaries and extensive extracellular fibrin deposition.”

To date, Igneri said, the he clinical utility of abnormal coagoagulation tests to predict bleededing, thrombosis and severerity of illness remain to bee determined, but the Ameri-can Society for Hematology (ASH) reports that elevated D-dimer at admission and markedly increasing D-dimer levels (three- to fourfold) over time are associated with high mortality, “likely reflecting coagulation activation from infection/sepsis, cytokine storm and impending organ failure.

“COVID-19 thrombotic risk is increased by high circulating viral RNA loads, leading to endotheliitis, hyperinflammation—with a higher degree of tissue damage seen on pathology than expected—and platelet dysfunction,” Igneri explained. “These patients have a true hyperinflammatory response.”

Igneri suggested taking the following steps for managing anticoagulation in COVID-19 patients: 1. Follow the evidence. Igneri said a good place to start is an observational

cohort study involving more than 2,700 patients with COVID-19 who had been mechanically ventilated. The study showed that patients who received anticoagulant therapy had a significantly reduced mortality rate (29.1%) compared with those who did not (62.7%).

Longer duration of anticoagulant treatment was also associated with reduced mortality (adjusted hazard ratio, 0.86 per day; 95% CI, 0.82-0.89; P<0.001) ((J Am

Table.

T Tabl Ta abl ble e.. M Modified odif od ifi fie ied IIM IMP MPR PROV PROV OVE VTE VTE Ri VT Risk sk s k IMPROVE Score Score Risk Factor

VTE Risk Score

Previous VTE

3

Known thrombophilia

2

Current lower limb paralysis or paresis

2

History of cancer

2

ICU/CCU stay

1

Complete immobilization ≥ 1 day

1

Age ≥60 years

1

VTE, venous thromboembolism

Coll Cardiol 2020;76[1]:122-124). However, there was no difference in in-hospital mortality for COVID-19 patients

In South Texas, Managing 100% of COVID-19 Remotely

P

in the anticoagulation and no-anticoagulation therapy groups, respectively (22.5% vs. 22.8%).

2. Look to treatment guidelines.

This can be helpful when deciding on a clinical strategy for VTE prophylaxis in COVID-19 patients. ASH recommends that, in the absence of bleeding, all hospitalized patients with COVID-19 receive standard prophy-

harmacists don’t always have to be on the front lines to make a difference in COVID-19 care; they can play effective roles remotely, according to a study presented at the ACCP annual meeting. When COVID-19 cases began rising in Bexar County, Texas, in March 2020, all acute care clinical pharmacy specialists with the South Texas Veterans Health Care System, in San Antonio, were deployed to 100% telework to conserve the hospital’s limited PPE and reduce patient and employee exposure to the SARS-CoV-2 virus, said Dana Douglass, PharmD, BCPS, a clinical pharmacy specialist with the medical center.

lactic dosing of low-molecular-weight heparin (LMWH). For patients with contraindications to anticoagulants, mechanical VTE prophylaxis, such as elastic compression and intermittent pneumatic compression devices, is the only other option. “Combining chemical and mechanical prophylaxis is not recommended,” Igneri said.

3. For dosing clues, learn from other centers. Igneri noted that Cleveland Clinic has an algorithm that uses D-dimer and point-of-care ultrasound to determine the most appropriate anticoagulant dosage. If the D-dimer level is <3µg/mL FEU (fibrinogen equivalent units), a standard dose of LMWH is given and D-dimer is reassessed ed every 48 hours. If the level is ≥3µg/mL mL FEU, the next step is ultrasound. Iff VTE is

Strategies for communication were left to the pharmacists, who were granted remote access to electroni-cally review patient charts and perform patient care activities from home. Some who normally participate in daily bedside rounds in areas like internal medicine, cardiology and infectious diseases instead participated in rounds by listeningg over the phone. Some chose to talk with clinicianss before or after rounds, or used internal instant messsaging platforms to contact physicians with medicaation recommendations.

Patient education also took place over the phone,, with pharmacists calling patients on their cellphoness or the phones assigned to hospital rooms. In casess

detected, the patient receives therapeutic anticoagulation; if findings are negative or ultrasonography is not available, the patient receives high-intensity prophylaxis. “There is a preference for enoxaparin when available,” she said.

“It’s important to recognize that you may just need to treat this patient if you have a very high suspicion for VTE, even if you can’t get a confirmatory test,” Igneri said, “particularly if the patient rapidly deteriorates from a pulmonary or cardiac standpoint, or shows rapid change in neurologic function or sudden, localized loss of peripheral perfusion. At our institution, during the peak of our surge, we had many cases of pulmonary embolism, MI and ischemic stroke in COVID-19 patients with no other real risk factors.”

4. Be ready for extended therapy.

In some cases, extended thromboprophylaxis may be needed after a patient is discharged, Igneri noted. Although it is not routinely recommended, this strategy may be beneficial on a caseby-case basis, she said. A recent retrospective analysis of data from the MAGELLAN study on in-hospital thromboprophylaxis looked at the efficacy of extended thromboprophylaxis for VTE after discharge, using the modified IMPROVE VTE risk score (Table).

The investigators found that patients identified as high risk for thromboembolism, with a score of 4 or more (or 2 and 3 with an elevated D-dimer greater than twice the upper limit of >2 times the upper limit of normal) had a significantly reduced incidence of VTE when prescribed a post-discharge course of up to 35 days of rivaroxaban (relative risk, 0.68; P=0.008) (TH Open 2020;4:e59-65).

“It’s very important that we think about what happens to COVID patients once they leave the hospital,” Igneri said. “At the time of discharge, consider the patient’s VTE risk factors, including reduced mobility and bleeding risk, when deciding whether or not to initiate extended post-discharge thromboprophylaxis.”

Operations & Management

Pharmacy Practice News • January 2021

21

Covid-19 Pandemic

Maryland Pharmacy Relies on IV Robots, Batch Compounding to Cope

A

s the COVID-19 pandemic surged in spring 2020, the pharmacy at the University of Maryland Medical Center, in Baltimore, faced several challenges affecting inventory management and pharmacy operations. By tweaking its in-house IV robot compounding process and transitioning to making some highly used products in batches instead of patient-specific doses, the pharmacy team quickly accommodated emerging inventory needs.

The main challenge was to come up with solutions that worked for both under- and overstocked medications— both of which occurred, paradoxically, as a result of the panemic. For example, inventory for many normally used medications such as succinylcholine and phenylephrine accumulated because of a fall-off in patient admissions and surgical procedures, Yevgeniya Kogan, PharmD, the hospital’s sterile compounding operations manager, said during the ASHP annual meeting. Other drugs, such as hydromorphone IV bags, went into critical shortages because they were being purchase from 503B vendors, had supply chain issues. many of which h pandemic itself both increased The pandem for critical care products demand fo

and generated staffing problems, as some employees stayed home to provide child care or because of a need to quarantine after potential exposure to the SARS-CoV-2 virus.

To overcome these challenges, Kogan and her colleagues quickly learned to adapt, turning to systems already in place for in-house IV compounding processing by robots, an inventory batch management analysis strategy and a prescribing trends review.

First, Kogan reviewed the pharmacy’s production schedule to make sure all compounds were still needed, flagging neostigmine for potential removal. The medical center typically used 700 syringes of the drug per month, but only 243 syringes were being used at the height of the pandemic. As COVID-19 evolved, the medical center was seeing a high demand for IV infusions of azithromycin 500 mg, cefepime 6 g, epinephrine 8 mg, furosemide 200 mg, hydromorphone 20 mg, pantoprazole 80 mg and rocuronium 400 mg. She and her colleagues determined they needed an estimated 600 weekly doses of these drugs combined and created a new schedule to batch the medications, in which hydromorphone

where pharmacists could not connect with patients, they asked physicians to provide patie patients with information sheets on toppa ics ic like anticoagulation.

Douglass and her colleagues observed workload metrics for 10 acute care clinical pharmacy specialists from the six weeks prior to implementation (Feb. 10-March 20) and the six weeks after (March 23-May 1). Chart notes increased by 39%, from 533 to 742 total notes. Interventions tracked by a documentation tool

and epinephrine would be produced by the IV robots while the remaining five products would be made manually by pharmacy technicians. They produced 8,547 doses of these medications in March through April and 11,464 doses in April through May. During this period, the pharmacy team continued to carefully monitor inventory of these and other needed medications produced by the robots, such as heparin and vancomycin, including what was on hand and what was expected to be released from their quarantine process each week. They tried to keep three weeks’ worth of extended-dated IV robot products available at all times to account for any increase in demand or production issues.

From June through July, the pharmacy had steady use of azithromycin, pantoprazole and furosemide, and decreases in the need for cefepime as the number of COVID-19 patients began to fall, and in rocuronium as the preferred paralytic agent shortage resolved.

Among the robotic compounded products, hydromorphone remained in high use. In contrast, the team temporarily stopped production of hydromorphone because one vendor shipped four weeks’ worth of back-ordered product that had been on shortage.

Among other robotically made products, rocuronium syringes also

increased by 57%, from 350 to 549, for an estimated cost savings of $24,741 during the second phase. It’s likely pharmacists were intervening more all along but had less time to document their work due to time spent on rounding or other activities, Douglass said.

Since study completion, although the pharmacists have begun rotating back on-site, there is talk about implementing some long-term work-from-home arrangment. “There are going to be beneficial aspects of making interventions face-to-face,” Douglass said.

“But this was successful because our pharmacy service had been in place for a long time, and we have built rapport with physicians, so they were receptive to our recommendations no matter the format.”

experienced a significant shortage due to insufficient vial supply, so the pharmacy had to be wise in managing inventory, Kogan said. They were able to get one of their vendors to outsource the product to stay ahead of the need, she noted. When the vial shortage stabilized, the pharmacy quickly resumed production.

By using these strategies, the pharmacy estimated a cost savings of more than $37,000 in April, over $45,000 in May, about $4,500 in June and about $8,600 in July from producing drugs as needed and not having them sit on the shelf and expire. “It’s important to develop a dynamic inventory review to adjust quickly to whatever is thrown your way,” Kogan advised. “And an IV robot compounding program may help buffer the pharmacy department from 503B vendor product shortages.”

It’s also important to be adaptable.

During the current surge of COVID-19 cases, she noted, the Maryland team had to take another careful look at all of their compounding and inventory management strategies and make the necessary adjustments to ensure proper stocks. “It hasn’t been easy to balance that with surging patient care needs, but at least we have tools in place from our experiences in the Spring,” Kogan said.

“So far, we are managing to stay about one step ahead of the flood.”

The internal messaging system also was helpful, she said. With physicians frequently rounding, visiting patients or doing other things, pharmacists could always reach them.

—Karen Blum, Bruce Buckley and Gina Shaw The sources reported no relevant financial disclosures.

More on the Web A daily dashboard helps streamline medication management during COVID-19.

For details, access an expanded version of this article on pharmacypracticenews.com.

22 Operations & Management

Pharmacy Practice News • January 2021

Finance

5 Strategies for Controlling Drug Formulary Costs

M

onitoring FDA approvals, forecasting potential price spikes and having good team communication are activities that hospital pharmacists can do to manage high-cost drugs in their formularies, an expert said during the American College of Clinical Pharmacy (ACCP) 2020 virtual annual meeting.

Few laws address drug prices, said Erin R. Fox, PharmD, the senior director of drug information and support

‘Use the same strategies that you use to manage a shortage to manage a price spike, because at the end of the day, you’re just going to need to use less so that you can still afford that product.’

—Erin R. Fox, PharmD

services at the Universityy o off Utah Health, in Salt Lake City. ty.

And there’s not much help p from the various regulatory agencies that have some oversight over therapeutics.

For example, Medicare, the he he largest payor, is forbidden from negotiating prices.

The Federal Trade Commission has some influencee on pricing, but it focuses its pricing efforts primarily around the narrow area of antitrust laws and “pay-to-delay” deals in which brandname and generic drug companies pay others to delay the introduction of cheaper alternatives. The FDA cannot consider drug pricing in its approval decisions. However, its approvals have indirect results on pricing, whether it is for me-too drugs, orphan drugs or those with slight changes in formulation that extend patents.

As for the states, although they often have price gouging laws, those typically apply to price hikes of items such as gas, not medications.

Focus on the Patient When managing your formulary, Fox said, beyond considering a drug’s efficacy and therapeutic use, think about its intended patient population. If it’s a targeted treatment or product that will be used in a small number of patients, budgeting it may be very difficult. In an inpatient setting, “even one to two patients can really knock your budget out of whack,” she said. Also bear in mind any administration and monitoring challenges brought by products, including what setting is most appropriate. In many cases, new specialty products are for chronic illnesses; because they are not given on a daily basis, they could wait until a patient is in the outpatient setting, which shifts the costs to a different site of care.

Finally, don’t forget about Risk Evaluation and Mitigation Strategy (REMS) requirements; you may need to develop specific procedures for how your organization will handle REMS. In addition, Fox said, try to prepare for potential spikes in drug prices. There are a number of risk factors to watch.

One important consideration is whether the drug is subject to the Unapproved Drugs Initiative, which the FDA created in 2006 to reduce the number of “grandfathered” drugs on the market that didn’t go through a formal FDA approval process. (Before 1938, drugs weren’t required by law to be approved by the FDA.) The initiative offered manufacturers market exclusivity for drugs they took through the regulatory process, but

Operations & Management

Pharmacy Practice News • January 2021

23

Finance Confer with the experts. Finally, Fox said, make friends with your specialty clinicians, and learn what they’re hearing about at meetings. “You can sometimes get a heads-up on something based on the latest abstract that you may not have caught under your normal surveillance,” she said.

5

‘Everybody Has a Stake’ In Managing Costs that inducement had an unintended consequence: It allowed drugmakers to raise prices with virtually no competition.

Two cases in point: vasopressin and epinephrine, which saw price increases after FDA approval ranging from 75% to 471%, Fox said. This may now change; on Nov. 20, the Department of Health and Human Services announced it was terminating the program. Still, drugs produced by a sole manufacturer or for a small market also may see some opportunistic pricing, so Fox said it’s important to keep an eye on the number of players in a given market segment. Drug shortages, too, can result in price increases due to manufacturing costs, raw materials changes or company mergers, she noted.

Fox cited five additional steps pharmacists can take to prepare for the impact of new drugs on a hospital’s formulary: Monitor and track new drug approvals. It’s worth the time to devote resources to tracking FDA approvals of new drugs for several reasons, not the least of which is to start estimating how much those new approvals will cost, and how much of a dent in your drug budget they may cause.

Flag a page in your drug shortages handbook. “It’s really nice when you can pull out your drug shortage tool kit,” Fox said. “Use the same strategies that you use to manage a shortage to manage a price spike, because at the end of the day, you’re just going to need to use less so that you can still afford that product.” Finding new uses for older, less expensive drugs also can help, she said.

Share what you’ve found. Proactive information on the effects of newly approved and/or launched medications is too precious to keep to yourself, Fox stressed. To that end, be sure to create systems that not only help you make quick therapeutic and operational assessments of new products, but also to effectively communicate those strategies and findings to your stakeholders.

Keep an eye on drug utilization.

It’s worth setting up some type of surveillance of drug usage at your own institution, even if it’s informal, to try to catch some increased use of older drugs, Fox noted. COVID-19 has presented a wild card, in that everything is off-label.

Vet drug usage through your infectious disease clinicians.

Talking and collaborating with others to find creative solutions to manage high-cost drugs in the formulary

are key, commented Steven T. Johnson, PharmD, the session moderator and vice president of clinical services for Comprehensive Pharmacy Services.

“Everybody has a stake,” Johnson said, noting that average annual health care costs are rising at a pace exceeding the gross domestic product. “We have to work together, and we really have to do it now. It’s looking at every possible avenue to drop the cost of health care so that we all can afford quality health care and ensure equitable access to care, whether it’s ensuring appropriate use

for a hyperinflationary drug or eliminating access if it’s truly not providing value for the class.”

For additional resources, Johnson suggested ACCP’s Drug Information Practice and Research Network, which has a paper on formulary management challenges and opportunities (J Am Coll Clin Pharm 22 Sep 2020. https://doi. org/10.1002/jac5.1332).

—Karen Blum The sources reported no relevant financial disclosures.

Read Specialty Pharmacy Continuum Anywhere, Anytime!

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www.specialtypharmacycontinuum.com

24 Policy

Pharmacy Practice News • January 2021

Reimbursement Matters

2021 Payment Rules Affecting Pharmacy

A

s we move into the new outpatient/ambulatory payment year still in the midst of the COVID-19 pandemic, navigating payment rules across sites of care and ensuring that pharmacy is in sync with their organization’s overall strategies are essential.

Themes finalized in the rule sets are: embrace patient centricity, continue to simplify (electronic health record requirements and reporting, regulations), cut costs and save money, and

Table. Antibody Infusion Codes Short Descriptor

Product

HCPCS

Long Descriptor

Regeneron’s antibody casirivimab and imdevimab (REGN-COV2)

Q0243

Injection, casirivimab and imdevimab, 2400 mg

casirivimab and imdevimab

M0243

Intravenous infusion, casirivimab and imdevimab includes infusion and post-administration monitoring

casirivi and imdevi infusion

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“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health.

Please email the author at bonniekirschenbaum@ gmail.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP, FCSHP

not lose focus on pharmacy’s efforts to combat the opioid crisis.

2021 OPPS Effects Our September issue (bit.ly/3rW3VQt) summarized the proposed Outpatient Prospective Payment System (OPPS) rules. The components of the rules most affecting pharmacy include: 1. Focus on site of care. Site-neutral payments remain in place.

2. Patient centricity. Continue to give beneficiaries more affordable choices on where to obtain care with the potential for lower out-of-pocket expenses, including those for surgeries. The inpatient-only list is phasing out within three years, beginning with 300 musculoskeletal-related services in 2021 and loosened restrictions for physician-owned hospitals. Criteria for adding surgical procedures to the ambulatory surgery center covered procedures list changed with 267 new ones.

3. Price transparency of hospital standard charges. Without changes from the proposed rules, transparency is required Jan. 1, 2021.

4. Prior authorization. Beginning July 1, 2021, the Centers for Medicare & Medicaid Services (CMS) is implementing a prior authorization process for cervical fusion with disk removal and implanted spinal neurostimulators in hospital outpatient departments. The current requirements for five categories of services, including the use of botulinum toxin injections, continues.

5. Payment rates for Medicare Part B drugs. For a summary, see the table in the expanded version of this article on pharmacypracticenews.com.

These OPPS changes apply only to Medicare patients treated in an OPPS setting and include continuing the current policy of paying hospitals average sales price (ASP) minus 22.5% for 340B-acquired drugs.

Most Favored Nation Rule

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This approach to reduce drug costs is temporarily on hold. See the sidebar for more details.

Policy

Pharmacy Practice News • January 2021

25

Reimbursement Matters

CMS Floats Most Favored Nation Model for Drug Payment

S

kipping the normal rulemaking process, which requires weeks for public comment, the Centers for Medicare & Medicaid Services (CMS) issued what is known as an “interim final rule”—a move typically only reserved for rules that need to go into place quickly.

The rule, which was slated to take effect Jan. 1, 2021, but is now on hold due to a temporary restraining order (TRO), creates a new mandatory payment model for separately payable Part B drugs that ties reimbursement to prices that other countries (i.e., Most Favored Nation [MFN]) pay for the same drugs. The rule only applies to traditional Medicare beneficiaries, not for people with private insurance. The administration is pushing the rule to lower traditional Medicare drug spending.

The Participants • • • •

Medicare-participating physicians Nonphysician practitioners Supplier groups (such as group practices) Hospital outpatient departments including 340B covered entities • Ambulatory surgerycenters • Other providers and suppliers that receive separate Medicare Part B fee-for-service payment for the model’s included drugs • Excludes cancer hospitals, children’s hospitals, critical

2021 Physician Fee Schedule The 2021 physician fee schedule (PFS) permanently expands telehealth services, alters physician payments and coding, and expands some clinicians’ scope of practice. Here are some key details: Telehealth

Medicare added 60-plus services to its reimbursable list of 144 services covered via telehealth, as part of the COVID-19 public health emergency (PHE).

According to CMS, “these additions allow beneficiaries in rural areas who are in a medical facility … to continue to have access to telehealth services such as certain types of emergency department visits, therapy services, and critical care services.” Category 1, covering services similar to office visits or psychiatry services and consultations, was expanded to add group psychotherapy, home visits and psychological testing. CMS also expanded category 3, including emergency department visits, therapy services and hospital discharge day management. It’s important to note that CMS doesn’t have statutory authority to permanently expand telehealth coverage beyond a rural benefit in Medicare; such an expansion requires an Act of Congress.

Additionally, CMS revised the “direct supervision” definition in its telehealth regulations to include the virtual presence of the supervising physician or practitioner using real-time video communications technology, including interactive audio and video. What is your health care organization’s virtual care strategy? Is pharmacy a part of this team? With hospital capacity a critical issue, has it invested in remote patient monitoring to enhance care in alternate sites? If so, how does this dovetail with Category 3 expansion,

access hospitals, rural health centers, federally qualified health centers and Indian Health Service facilities, providers in the Maryland Total Cost of Care Model that have an annual global budget for health care spending; additionally, participants can request exemption based on financial hardship.

The Details CMS will pay for the 50 costliest Medicare Part B drugs “at comparable amount to the lowest adjusted price paid by any country in the Organization for Economic Co-operation and Development that has a gross domestic product (GDP) per capita that is at least 60% of the U.S. GDP per capita,” according to the agency.

The model will introduce an MFN price for 50 drugs, 38 of which are oncology related. After a price is established, the model will phase it in with the applicable average sales price (ASP): by 25% per year for performance years 1 to 3, and reach 100% by performance years 4 to 7. The goal is to give providers “time to adjust to the model payment amounts and formulas.” Complicating this fluctuation is a 6% add-on payment that is replaced by a flat fee add-on, regardless of product cost, and which will be calculated based on 6.1% of the 2019 historical spending on all of the MFN drugs in total, adjusted every year based on inflation. CMS sets the

medication management or other clinical reimbursable services you could offer, such as the Medicare Diabetes Prevention Program?

Evaluation and Management (E/M) Coding and Payment

CMS has increased the relative value of several PFS payments to prioritize CMS’s investment in primary care and chronic disease management.

The payments allow for nonphysician practitioners to provide the care they were trained and licensed to give, and encourage health care professionals to practice at the top of their license and spend more time with patients. In general, the payments support clinicians who manage the ongoing care of patients with a host of chronic diseases. But more specific care settings are also incentivized, including patient transitions between hospitals, nursing facilities and the home, including those with dementia.

For more information, check out the following resources: PFS 2021 fact sheet: go.cms. gov/34xzczp; PFS final rule: go.cms. gov/3rh3UX6 Medicare Diabetes Prevention Program: go.cms.gov/2Kt6DfB OPPS final rule: go.cms.gov/2Xm FBZW; go.cms.gov/3osjldd

COVID-19 Antibody Treatment Medicare has announced it will cover and pay for casirivimab and imdevimab, two monoclonal antibody infusions developed by Regeneron, the same way it covers and pays for COVID-19 vaccines—when furnished consistent with the FDA’s emergency use authorization (EUA) for the infusions.

CMS identified specific code(s) for the monoclonal antibody products

fixed add-on payment for administering the drugs quarterly: The per-dose add-on for first quarter 2021 will be $148.73. If a drug becomes in short supply, the price will revert to ASP. The manufacturer’s price remains the same and won’t be lowered to compensate for the MFN price. Involve your group purchasing organization to determine any anticipated decreases in contracted costs, effective Jan. 1, 2021, that parallel decreased reimbursement for MFN Model drugs for traditional Medicare beneficiaries. Providers may have to develop mechanisms such as rebates or discounts with the manufacturer. Success depends on providers negotiating drug prices down to meet reduced reimbursement levels, but it‘s unclear whether or by how much manufacturers would actually lower the prices they charge health care providers. If unsuccessful, providers have to choose whether to offer the drugs at a financial loss. Beneficiaries will pay lower coinsurance for these high-cost Part B drugs and will not pay coinsurance on the add-on payment.

As for the TRO placed on the MFN Model, it was issued on Dec. 23 to allow time for the issuing court to hear arguments on permanently blocking the rule.

and specific administration code(s) for Medicare payment, effective Nov. 21, 2020 (Table). For more information, see the FDA’s fact sheet on the casirivimab and imdevimab EUA at bit.ly/3h8ixar.

Additionally, CMS finalized a new

For more information, see the CMS MFN fact sheet at go.cms.gov/34xKx2l.

requirement for all hospitals to report their inventory of COVID-19 therapeutics to provide information needed to track and accurately allocate therapeutics to the hospitals that need additional inventory to care for patients and meet surge needs.

■

26 Policy

Pharmacy Practice News • January 2021

New Drugs

Inflammatory Conditions Help Drive Another Strong Year for Specialty F

orty-eight percent of drug spending in pharmacy was for specialty medications in 2019, according to Express Scripts’ 2019 Drug Trend Report, the latest available report.

Aimee Tharaldson, PharmD, a senior clinical pharmacist of Emerging Therapeutics at Express Scripts, predicted that specialty drugs would outpace traditional medications in 2020 and that trend would continue in 2021.

Inflammatory conditions stood out in the Express Scripts report, Tharaldson noted during the AMCP Nexus 2020 virtual meeting. “This was by far the No. 1 therapy class based on per member per year [PMPY] spending,” she said, citing two dominant contributors: Humira [adalimumab, AbbVie] and Enbrel [etanercept, Amgen].

Quite a few novel competitors are expecting approval in 2021, according to Tharaldson, who highlighted specialty medications to watch for this year.

Bimekizumab (UCB) is an interleukin-17A and IL-17F inhibitor expecting approval on July 22 for moderate to severe plaque psoriasis. It’s also in development for psoriatic arthritis and ankylosing spondylitis. In phase 3 trials, bimekizumab demonstrated improved efficacy compared with adalimumab, secukinumab (Cosentyx, Novartis) and ustekinumab (Stelara, Janssen Biotech).

Deucravacitinib (Bristol Myers Squibb [BMS]) is a novel tyrosine kinase inhibitor that could also be approved this year for psoriasis. “This is an oral medication that, so far, seems like a really safe option,” she said. It appears more effective than apremilast (Otezla, Amgen), on par with adalimumab and ustekinumab, and less effective than the IL-17 and IL-23 inhibitors like ixekizumab (Taltz, Lilly) and guselkumab (Tremfya, Janssen), Tharaldson noted.

Another IL-23 inhibitor, mirikizumab (Lilly), is expecting approval for psoriasis this year. A phase 3 trial released last summer showed that it was more effective than the IL-17 inhibitor secukinumab, but it seems undifferentiated compared with the other IL-23 inhibitors, she said.

Mirikizumab is also being developed for ulcerative colitis and Crohn’s disease.

“But it’s unclear how much market share is actually going to be captured in such a crowded market,” Tharaldson said.

Filgotinib is an oral Janus kinase (JAK) inhibitor previously in development for the treatment of moderate to severe rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis, psoriatic arthritis and ankylosing spondylitis. In August, Gilead/Galapagos received a complete

response letter from the FDA requesting data from two ongoing studies to assess whether filgotinib affected sperm parameters. The FDA also expressed concerns regarding the overall benefit-to-risk profile of the 200-mg dose. Answering these concerns will likely delay approval until late in the year or longer.

In December, Gilead and Galapagos announced they discontinued the U.S. development for RA and other inflammatory conditions. However, Gilead has the option to continue pursuing development for Crohn’s disease and ulcerative colitis, if it is deemed viable.

Atopic dermatitis (AD) has a healthy pipeline that could see the approval of five medications in 2021. Almost 6 million children and adults in the United States have moderate to severe AD. Three JAK inhibitors could receive an additional indication for AD, but one JAK inhibitor, abrocitinib (Pfizer), could be a novel entry. Several phase 3 trials have demonstrated efficacy in treating moderate to severe AD. However, some patients have seen decreases in platelets and serious infections, which will need to be monitored if approved, she said. Approval is expected in April. JAK inhibitors carry boxed warnings for infections, malignancy and thrombosis. “So it’s likely that the JAK inhibitors will be used in patients who don’t respond to Dupixent [dupilumab, Sanofi/Regeneron], even though they’re oral rather than subcutaneous,” Tharaldson explained.

One JAK inhibitor, ruxolitinib (Jakafi, Incyte), is available as an oral formulation for myelofibrosis and steroidrefractory graft-versus-host disease. But Incyte is developing a topical formulation for AD, which will likely compete with crisaborole (Eucrisa, Pfizer), a topical phosphodiesterase-4 inhibitor.

The Prescription Drug User Fee Act (PDUFA) date for the first IL-13 inhibitor for AD, tralokinumab (LEO Pharma A/S), is May 9 for the treatment of adults with moderate to severe AD. It is given as a subcutaneous injection every two weeks.

Three phase 3 trials have demonstrated efficacy and safety with or without concomitant use of a topical corticosteroid.

Other Growth Areas Cancer

Even though most cancer spending is under the medical benefit, cancer therapy was the second-leading category in specialty drug spending. Each year in the United States, about 1.8 million new cases of cancer are diagnosed, and more than 600,000 Americans die

from the disease, although the death rate has dropped about 25% since 1991 due to reductions in smoking, earlier detection and improved treatments.

The gene therapy lisocabtagene maraleucel (lisocel, Bluebird bio/BMS) had been expecting approval in 2020 for adults with relapsed or refractory large B-cell lymphoma after at least two prior therapies, but the companies received an FDA response letter saying the agency would not meet the Nov. 16 PDUFA date, because it could not inspect a third-party manufacturing facility in Texas due to COVID-19 travel restrictions. Therefore, the FDA deferred action on the application until the inspection can be completed.

“We are committed to bringing lisocel to patients with relapsed or refractory large B-cell lymphoma who still have significant unmet need,” said Samit Hirawat, MD, the executive vice president and chief medical officer of global drug development at BMS. The biological license application is based on the safety and efficacy results from the TRANSCEND NHL 001 trial, evaluating liso-cel in 268 patients with various types of relapsed or refractory large B-cell lymphoma. The overall response rate (ORR) was 73% (95% CI, 67%-78%), and the complete response (CR) rate was 53% (95% CI, 47%-59%).

There are seven other novel cancer drugs with PDUFA dates for the first half of the year.

Two are seeking an indication for refractory multiple myeloma (MM).

Melphalan flufenamide (Oncopeptides) is a first-in-class aminopeptidase-targeting peptide–drug conjugate that rapidly delivers an alkalizing agent into tumor cells that is expecting approval on Feb. 28 for use with dexamethasone for adults with triple-class–refractory MM. Results of the pivotal phase 2, single-arm, multicenter HORIZON study of 157 heavily pretreated patients found an ORR of 29%, a median progression free survival (PFS) of 4.2 months and a median overall survival of 11.6 months.

Idecabtagene vicleucel (Bluebird bio/BMS), a CAR-T therapy also seeking an indication for relapsed or refractory MM—the first CAR-T with this indication. An early-phase study

demonstrated an 85% ORR. The PDUFA date is March 27.

Dostarlimab (GlaxoSmithKline) is a programmed death-1 monoclonal antibody seeking approval for the secondline treatment of patients with advanced recurrent endometrial cancer. An updated analysis of the GARNET trial demonstrated that dostarlimab provided clinically meaningful results in women with recurrent or advanced mismatch repair–deficient (dMMR) endometrial cancer who progressed on or after a platinum-based regimen.

The analysis included patients with dMMR endometrial cancer who had measurable disease at baseline and six months or more of follow-up by the data cutoff (n=71). Treatment with dostarlimab showed an ORR of 42% (95% CI, 31%-55%) and a disease control rate of 58% (95% CI, 45%-69%). Overall, 13% of patients had a CR and 30% of patients had a partial response.

“There are limited treatment options for women with advanced or recurrent endometrial cancer, and prognosis of these patients is poor. The results observed in the GARNET trial indicate the potential of dostarlimab to offer a new treatment option for women with this challenging disease,” said Ana Oaknin, MD, the head of the Gynaecologic Cancer Program at Vall d’Hebron Institute of Oncology, in Barcelona, Spain, and primary investigator of the GARNET trial, when the results were released last April.

The PDUFA date is Jan. 14.

Trilaciclib (G1 Therapeutics) is an infused cyclin-dependent kinase 4/6 inhibitor designed to preserve bone marrow and immune system function in

Policy

Pharmacy Practice News • January 2021

27

New Drugs

Cancer

25% patients with small cell lungg cancer being treated with chemotherapy. In clinical trials, trilaciclib significantly reduced d chemotherapy-induced myelo-suppression, infections and d hospitalizations compared with t th patients receiving chemotherapy a apy alone. Approval is expected by Feb. eb b. 15.

Tepotinib (EMD Serono) is a mesenchymal–epithelial transition (MET) ( inhibitor that’s pending approval v for val the treatment of patients with metamet static non-small cell lung cancer, whose tumors have mutations that lead to MET exon 14 skipping—about 4% of cases of non-small cell lung cancer. “It’s an aggressive type of lung cancer with poor prognosis,” Tharaldson said. In a phase 2 study, the objective response rate was 46%. The PDUFA date is Feb. 25.

Umbralisib is a tyrosine kinase inhibitor for patients with previously treated marginal zone lymphoma or follicular lymphoma (FL). Marginal zone lymphoma represents 8% of non-Hodgkin lymphoma cases, accounting for approximately 7,500 new cases per year in the United States. Approximately 15,000 patients are diagnosed with FL each year in the United States. Approval is expected by Feb. 15 for marginal zone lymphoma and June 15 for FL. Tivozanib (Aveo Oncology) will be the seventh vascular endothelial growth factor inhibitor for renal cell carcinoma in refractory patients. Although phase 3 results showed improved progressionfree survival by 1.7 months compared with sorafenib (Nexavar, Bayer), it didn’t improve overall survival. Tharaldson predicted that tivozanib will

Orphan Other

52%

23%

Specialty Drug Pipeline Most specialty drugs being developed today are for orphan diseases.

An orphan disease affects fewer than 200,000 people in the United States, or is a common disease that has been ignored because it is not prevalent here.

have a difficult time competing in a “very saturated market.”

Gene Therapies

Gene therapies modify a person’s genes to treat or cure disease. Most are viral vectors for gene replacement therapies and patient-derived gene products, such as CAR-T. Human gene editing technology, such as clustered regularly interspaced short palindromic repeats, or CRISPR, may someday be used for gene therapy treatments. It is estimated that the market will be more than $16 billion per year by 2024, according to Tharaldson.

More than 600 gene therapies are in U.S. clinical trials. Several are expecting approval for cancer in 2021. In addition to isocabtagene and idecabtagene,

PDUFA dates are expected for aglatimagene besadenovec (Advantagene), an immunotherapy for prostate cancer; ciltacabtagene autoleucel (Janssen), a CAR-T immunotherapy for MM; and nadofaragene firadenovec (Ferring) for bladder cancer.

Outside of cancer, eladocagene exuparvovec (PTC Therapeutics), a gene replacement therapy, is seeking an indication for aromatic L-amino acid decarboxylase deficiency, a genetassociated with defects in ic disease asso neurotransmitter synthesis that cause neurotransmitt low muscle tone, ton developmental delay, movement disorders and premovem mature death. About 100 m patients have this disease p in the United States.

Eladocagene is given as a one-time intracerebral infusion. in nfusio Three clinical studies n demonstrated that it improved de mons cognitive and language milemotor cogni stones stone es in cchildren, improving the ability abil lity to sit, walk and talk.

SRP-9001 (Sarepta TherapeuSRP-9 S tics), tiiics), a micro-dystrophin gene therapy, may be the first gene t therapy for Duchenne muscut lar dystrophy (DMD) to reach the market. DMD affects about one in 3,500 male births worldwide and is typically recw ognized between 3 and 6 years o off age. It is caused by mutations in the t DMD gene, which decrease functioning muscle protein dysfunct trophin. trophin n Gene therapy for DMD could potentially be used in a wide pot patient population.

Current therapies p target specific genetic mutations, such spe as eteplirsen eteplirs (Exondys 51, Sarepta), for patients with DMD mutations amenable to exon 51 skipping, which represents about 14% of patients. Although SRP9001 is looking for approval in 2021, Tharaldson called that “optimistic.”

Another DMD drug, which is not a gene therapy, that is expecting approval on Feb. 25 is casimersen, also by Sarepta.

Casimersen will be the first drug approved to treat patients with mutations amenable to exon 45 skipping, which represents about 8% of patients. It’s administered as a weekly IV infusion, and filing is based on early-phase studies showing that it increased dystrophin levels.

Hemophilia

Hemophilia gene therapy is an area of focus for many companies. They’re given as a one-time IV infusion, and early-phase studies look promising.

Etranacogene dezaparvovec (CSL Behring), a gene therapy for hemophilia B, which was seeking approval in 2021, looked like it would be the first. However, it was placed on clinical hold in December while a case of liver cancer was being investigated.

Hemophilia A affects about 16,000 U.S. patients, whereas hemophilia B affects about 4,000 patients. Bleeding can be prevented and treated with infused factor VIII for patients with hemophilia A and infused factor IX for hemophilia B. About 15% to 20% of people with hemophilia develop an inhibitor that prevents the clotting factors from being able to clot the blood and stop bleeding.

Fitusiran (Sanofi), an investigational once-monthly, subcutaneously administered RNA interference therapy for the treatment of hemophilia A and B, was placed on clinical hold in November due to the potential clotting risks.

Monthly subcutaneous dosing with fitusiran in patients with hemophilia A and B, with or without inhibitors, demonstrated sustained antithrombin lowering (a reduction of ~75% from baseline), resulting in median peak thrombin values at the lower end of the range observed in healthy volunteers.

“While efficacy has been demonstrated, risks will need to be carefully assessed,” Tharaldson said.

Orphan Diseases

Pegunigalsidase alfa (Protalix BioTherapeutics) is a long-acting enzyme replacement therapy for Fabry disease, a rare genetic disorder that affects about 7,000 U.S. patients. Those with Fabry disease cannot make the enzyme alphagalactosidase A, which is responsible for breaking down globotriaosylceramide, a type of fat used as a building block for the body’s cells. It can cause peripheral neuropathy and end-organ damage, primarily the kidneys.

A phase 3 study found that it improved renal function in patients switched from the enzyme replacement therapy. The PDUFA date is April 17.

Arimoclomol (Orphazyme) amplifies the production of heat shock proteins in Niemann-Pick disease type C, which is a rare storage disorder. It affects about 200 U.S. patients who cannot break down lipids, which build up in the liver, lungs, spleen and brain, eventually losing nerve function and leading to death.

In a phase 2/3 study, arimoclomol survival favored arimoclomol with a hazard ratio of 0.77 (95% CI, 0.32-1.80) compared with routine clinical care. The PDUFA date is June 17.

Vosoritide (BioMarin) is a C-type natriuretic peptide analog for the treatment of children who have achondroplasia, which is the most common form of disproportionate short stature. A phase 3 trial showed that children receiving daily vosoritide injections grew an average 0.6 inches more during the first year of treatment compared with placebo.

The PDUFA date is Aug. 20.

—Marie Rosenthal

TREATMENT FOR NOSOCOMIAL PNEUMONIA HAS ARRIVED

In HABP/VABP and cUTI caused by susceptible Gram-negative microorganisms

OUTSMART RESISTANCE Fetroja outsmarts pathogens by using iron to gain cell entry, like a Trojan horse.1,2

Fetroja—the world’s only siderophore cephalosporin—overcomes Gram-negative antibacterial resistance1 INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja.

WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients with CarbapenemResistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenemresistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

Stable in vitro against all known classes of ϐ-lactamases, including serine-carbapenemases (such as KPC and OXA) and metallo-ϐ-lactamases (such as VIM, IMP, and NDM)1 Active against pathogens with porin channel deletions and efflux pump up-regulation1,3,4 The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Fetroja has an extensive Gram-negative spectrum that includes hard-to-treat pathogens1 Fetroja has demonstrated activity against the following Gram-negative bacteria, both in vitro and in HABP/VABP: Acinetobacter baumannii complex, Escherichia coli*, Enterobacter cloacae complex*, Klebsiella pneumoniae*, Pseudomonas aeruginosa*, Serratia marcescens *Also included in cUTI indication.

In a seriously ill patient population with HABP or VABP, Fetroja exhibited non-inferiority to extended-infusion, high-dose meropenem1

Fetroja is highly active in vitro vs Gramnegative carbapenem-NS pathogens5 In this study, susceptibility of >38,000 Gram-negative clinical isolates from multiple countries (2013-2018) was tested against Fetroja

• Study highlights:

In vitro activity does not necessarily correlate with clinical efficacy.

Enterobacteralesa Overall

Enterobacteralesa carbapenem-non-susceptible

P aeruginosaa P aeruginosaa

100%

(n=814)

97%

– 60% of patients were ventilated, while approximately 33% had failed empiric treatment1,5

98%

– The top 5 baseline Gram-negative pathogens were K pneumoniae, P aeruginosa, A baumannii, E coli, and E cloacae5

95%

(n=1416)

carbapenem-non-susceptible

A baumannii complexa A baumannii complex

a

85%

(n=2274)

carbapenem-non-susceptible

S maltophilia b

100%

(n=1565)

Overall

• At Day 14, all-cause mortality (primary endpoint) in the mITT population was 12.4% for Fetroja vs 12.2% for extended-infusion, high-dose meropenem (95% CI, -7.2, 7.7)1

90%

(n=4185)

Overall

(inherently carbapenem-resistant)

(n=25,995)

(n=6213)

Overall

5,7

0

– Meropenem was used as a comparator in the trial and was optimized (2 grams IV over 3 h q8h) for seriously ill patients with a multidrug-resistant Gram-negative infection in the ICU1

20

40

PERCENT

60

80

100

In a phylogenetic reclassification performed in 2016, the nomenclature of Enterobacterales was proposed, which includes formerly established Enterobacteriaceae family and other genera such as Proteus spp, Providencia spp, Photorhabdus spp, and Serratia spp.8

In vitro susceptibility study design Clinical isolates of Gram-negative bacteria were collected from 4 global surveillance studies (SIDERO-WT-2014, SIDERO-WT-2015, SIDERO-WT-2016, and SIDERO-WT-2018) that included Enterobacterales* and non-fermenter strains. The global surveillance study (Proteeae†) collected clinical isolates from 2013-2016, and were tested centrally (IHMA Inc., Schaumburg, IL, USA). Fetroja MICs were determined by microbroth dilution using irondepleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as approved by the Clinical and Laboratory Standards Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. FDA breakpoints were used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex‡ MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for S maltophilia MIC ≤4 μg/mL. Carbapenem-nonsusceptible strain was defined as meropenem MIC ≥2 μg/mL for Enterobacterales strains (including Proteeae) and MIC ≥4 μg/mL for P aeruginosa and A baumannii complex.5 a FDA breakpoints used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex MIC ≤1 μg/mL. b CLSI investigational breakpoint used for S maltophilia MIC ≤4 μg/mL. *E coli, K pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. † Morganella morganii, P mirabilis, Proteus vulgaris, and Providencia rettgeri. ‡ A baumannii complex consists of A baumannii, A calcoaceticus, A dijkshoorniae, A nosocomialis, A pittii, and A seifertii.

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) Hypersensitivity Reactions (continued) Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs.

Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

• Fetroja exhibited comparable safety vs extended-infusion, high-dose meropenem in HABP/VABP1 Study Design Multicenter, double-blind, parallel-group, randomized, active-controlled Phase 3 study in approximately 300 adults with documented nosocomial pneumonia caused

by Gram-negative bacteria. Subjects were randomized (1:1) to either cefiderocol, 2 grams, administered IV over 3 hours every 8 hours (q8h) or extended-infusion, high-dose meropenem, 2 grams, administered IV over 3 hours q8h. Randomization was performed by the stratified randomization method using their infection diagnosis (HABP, VABP, and HCABP) and Acute Physiology And Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16) as allocation factors. Linezolid was administered for at least 5 days to subjects in both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA), and to maintain the study blind.1,5 CI=confidence interval.

FOR MORE INFORMATION, VISIT

Fetroja.com Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued.

Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%).

Please see a Brief Summary of Prescribing Information on following page.

References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2020. 2. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289. 3. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7):1-5. 4. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7) (suppl):S1-S3. 5. Data on file. 6. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012;25(1):2-41. 7. Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gramnegative bacilli. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0. 8. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the 'Enterobacteriales': proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov. Int J Syst Evol Microbiol. 2016;66(12):5575-5599. © 2020 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved.

Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. USFET-0209 09/20

30 Policy

Pharmacy Practice News • January 2021

FDA Watch

New Breast Cancer Rx: Margenza

T

he FDA approved margetuximabcmkb (Margenza, MacroGenics) with chemotherapy for the treatment of adults with metastatic HER2-positive breast cancer who have received two or more anti-HER2 regimens.

The approval was based on the randomized, multicenter, open-label SOPHIA trial (ClinicalTrials.gov Identifier: NCT02492711). In the trial, 536 patients with HER2-positive metastatic breast cancer who had received treatment with

other anti-HER2 therapies were randomly assigned to receive chemotherapy plus either margetuximab-cmkb or trastuzumab. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine or vinorelbine), number of lines of therapy in the metastatic setting (≤2, >2), and number of metastatic sites (≤2, >2). The main efficacy outcome measures were progression-free survival (PFS) and overall survival. Additional efficacy outcome measures were objective

response rate (ORR) and duration of response (DOR) assessed by a blinded independent central review.

Median PFS in the margetuximabcmkb arm was 5.8 months (95% CI, 5.57.0 months) compared with 4.9 months (95% CI, 4.2-5.6 months) in the control arm (hazard ratio, 0.76; 95% CI, 0.590.98; P=0.033). Confirmed ORR was 22% (95% CI, 17%-27%), with a median DOR of 6.1 months (95% CI, 4.1-9.1 months) in the margetuximab-cmkb arm compared with an ORR of 16% (95% CI, 12%-20%) and median DOR of 6.0 months (95% CI,

FETROJA (cefiderocol) for injection, for intravenous use Initial U.S. Approval: 2019 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA® is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex [see Clinical Studies (14.1) in the full prescribing information].

1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA is indicated in patients 18 years of age or older for the treatment of hospitalacquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens [see Clinical Studies (14.2) in the full prescribing information].

1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs.

Hypersensitivity was observed in FETROJA-treated patients in clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

4.0-6.9 months) in the control arm.

The most common adverse drug reactions—occurring in at least 10% of patients—with margetuximab-cmkb in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusionrelated reactions, palmar–plantar erythrodysesthesia and extremity pain.

The prescribing information (bit. ly/39dFu8P) includes a boxed warning

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment.

Adjust FETROJA dosing based on creatinine clearance [see Dosage and Administration (2.2) in the full prescribing information]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficile-associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1gram/1gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4.7%) cUTI patients treated with FETROJA and 12/148 (8.1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%).

Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1.

Table 4

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1

Adverse Reaction

FETROJAa (N = 300)

Imipenem/Cilastatinb (N = 148)

Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs.

Discontinue FETROJA if an allergic reaction occurs.

Diarrhea

4%

6%

Infusion site reactionsc

4%

5%

5.3 Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

Constipation

3%

4%

Rashd

3%

< 1%

Candidiasise

2%

3%

Cough

2%

< 1% < 1%

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

Elevations in liver testsf

2%

Headache

2%

5%

Hypokalemiag

2%

3% (continued)

Policy

Pharmacy Practice News • January 2021

31

FDA Watch advising health professionals about the risks for left ventricular dysfunction and embryo-fetal toxicity.

New Rituxan Biosimilar Approved

I

n January, clinicians should have at least one more biosimilar to help reduce the cost of therapy for patients with certain cancers and inflammatory conditions, following the approval of rituximab-arrx (Riabni, Amgen) for the

Table 4

treatment of adults with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis.

Rituximab-arrx, the third biosimilar to U.S.-licensed Rituxan (rituximab, Genentech), is a CD20-directed antibody that has the same amino acid sequence as the reference product. The approval was based on a study that evaluated the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of rituximab-arrx compared with

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa (N = 300)

Imipenem/Cilastatinb (N = 148)

Nausea

2%

4%

Vomiting

2%

1%

Adverse Reaction

cUTI = complicated urinary tract infection. a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function). b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. d Rash includes rash macular, rash maculopapular, erythema, skin irritation. e Candidiasis includes oral or vulvovaginal candidiasis, candiduria. f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. g Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders: thrombocytosis Cardiac disorders: congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders: abdominal pain, dry mouth, stomatitis General system disorders: pyrexia, peripheral edema Hepatobiliary disorders: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders: drug hypersensitivity Infections and infestations: C. difficile infection Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hypocalcemia, fluid overload Nervous system disorders: dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders: dyspnea, pleural effusion Skin and subcutaneous tissue disorders: pruritis Psychiatric disorders: insomnia, restlessness Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). In this trial, 148 patients received FETROJA 2 grams every 8 hours infused over 3 hours, and 150 patients received meropenem 2 grams every 8 hours infused over 3 hours. Doses of study treatments were adjusted based on renal function. The median age was 67 years, approximately 59% of patients were 65 years of age and older, 69% were male, and 68% were White. Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36.5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26.4%) patients treated with FETROJA and 35/150 (23.3%) patients treated with meropenem.

Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8.1%) of patients treated with FETROJA and 14/150 (9.3%) of patients treated with meropenem.

The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests.

Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial.

Table 5

Selected Adverse Reactions Occurring in ≥ 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 FETROJAa N = 148

Meropenemb N = 150

Elevations in liver testsc

16%

16%

Hypokalemiad

11%

15%

Diarrhea

9%

9%

Hypomagnesemia

5%

< 1%

Atrial fibrillation

5%

3%

Adverse Reaction

HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. a 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). b 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). c Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminesemia. d Hypokalemia includes blood potassium decreased.

rituximab in people with grade 1, 2 or 3a follicular B-cell NHL and low tumor burden. The primary end point, an assessment of overall response rate by week 28, was within the prespecified margin for rituximab-arrx compared with rituximab, showing clinical equivalence. PK, PD, safety and immunogenicity of rituximabarrx were similar to rituximab. The package insert is available at bit.ly/2Lzg5hO. Rituximab-arrx is being made available at a wholesale acquisition cost (WAC) of $716.80 per 100 mg and $3,584.00 per 500-mg

Other Adverse Reactions of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2:

Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose.

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 Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours.

In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed.

In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose.

8.2 Lactation Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocolderived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition.

single-dose vial, 23.7% less than the WAC for Rituxan, 15.2% less than the WAC for the biosimilar rituximababbs (Truxima, Teva), and matching the WAC for biosimilar rituximabpvvr (Ruxience, Pfizer). At launch, rituximab-arrx will be priced 16.7% below the current Rituxan average selling price, according to Amgen, which added the product will be available from both wholesalers and specialty distributors.

—Pharmacy Practice News Staff

32 Policy

Pharmacy Practice News • January 2021

Finance

340B Players Square Off continued from page 1

Beginning in mid-2020, a growing number of drug companies have restricted discounted sales of almost all drugs to covered entities dispensing 340B drugs through contract pharmacies, which a majority of 340B covered entities use as a channel for providing the discounted drugs. As per the 340B statute, manufacturers and covered entities cannot file lawsuits against one another, which

is why HHS is the defendant for all of the covered entity lawsuits targeting manufacturer actions.

“Ideally, this should have been worked through in a collaborative fashion,” said Madeline Carpinelli Wallack, PhD, the owner of Rx|X Consulting, a firm in Portland, Maine, that helps entities join and comply with the 340B program.

“Instead, because of this perceived act

of aggression [manufacturers cutting off discounts to entities dispensing through contract pharmacies], we are now dealing with lawsuits.”

As industry expert Marcy Imada explained at the 2020 ASHP Midyear Clinical Meeting and Exhibition, drugmakers say they have had to take direct action to limit the use of contract pharmacies, which they see as having no 340B oversight, and to eliminate duplicate discounts, which occur when a manufacturer has to pay an up-front discount to a 340B provider and then a back-end

Data

Patients Receiving CRRT

Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.

A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. While on CRRT, a patient’s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage.

8.4 Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established.

8.5 Geriatric Use cUTI

Patients with CLcr 120 mL/min or Greater

Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients.

CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older.

The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups.

Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age and 75 years of age and older were 60%, 77.5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4%, and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5%, and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8%, and 9.1%, respectively.

8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol.

Dosage adjustments are not necessary in patients with impaired hepatic function.

10 OVERDOSAGE There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered.

Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3) in the full prescribing information].

cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) in the full prescribing information].

8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min.

Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

Manufactured by Shionogi & Co., Ltd. Osaka 541-0045 Japan Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932 FET-PI-02A USFET-0247 09/20

Between 2012 and 2019,

30% of 1,536 covered entities submitted duplicate discount claims.

Source: HHS audits.

rebate to the state Medicaid program.

Imada, a managing director at Deloitte & Touche LLP, in Los Angeles, said that preventing duplicate 340B discounts “has proven to be a challenging and longstanding problem for the industry, and in particular for manufacturers. There have been numerous government studies and recommendations provided over the years to try to address this duplicate discounts challenge,” but little progress has been made, she said.

A Revealing GAO Report One report Imada pointed to was issued by the U.S. Government Accountability Office (GAO) in January 2020 (bit.ly/3nuBPt9bi). The report concluded there is limited federal oversight of the 340B program and that “HHS does not have reasonable assurance that states and covered entities are complying with the prohibition on duplicate discounts.”

A more recent GAO report issued in December 2020 found that roughly 30% of 1,536 audits of covered entities conducted by HHS’s Health Resources and Services Administration (HRSA) between 2012 and 2019 had submitted duplicate discount claims (www.gao. gov/products/GAO-21-107).

With little help from government, Imada said, manufacturers have to take “more proactive steps” and implement “new strategic initiatives,” including limiting 340B discounted prices to covered entities using contract pharmacies and, in some cases, asking covered entities for claims-level data to identify instances of duplicate discounts.

‘Flaws in the System’ But Ted Slafsky, the former president and CEO of 340B Health, a trade group for 340B hospitals, and currently publisher and CEO of 340B Report, a news service covering the 340B program, said duplicate discounts are the result of “flaws in the system; they are not intentional.” Although “there needs to be better systems in place to prevent duplicate discounts, the pharmaceutical industry should not be the ones collecting claims data,” he stressed. In fact, “claims data requests go way beyond the scope of what is required by the 340B law and add significant burden to safety net providers, which takes them away from serving patients.”

Policy

Pharmacy Practice News • January 2021

33

Finance “an inordinate amount of resources into compliance with Medicaid billing and auditing claims, and the scope of this task keeps growing.”

Hopeful on Government Action

In a statement issued to Pharmacy Practice News, The P Pharmaceutical Research and ManPh ufacturers of America (PhRMA), a trade ufactur group representing drugmakers, accused some 340B entities of “[taking] advantage of the lax oversight of the 340B program to pad their bottom lines. The 340B program was created for the benefit of vulnerable or uninsured patients, not for the financial benefit of wealthy non-profit hospitals and for-profit retail pharmacies.” PhRMA added that contract pharmacies not only lack regulatory oversight, but “there is also little-to-no evidence that contract pharmacy participation in 340B has improved patients’ access to medicines.”

A spokesperson for 340B Health challenged the idea that there is no evidence in support of 340B. “Congress said the purpose of the program is ‘to stretch scarce federal resources as far as possible, reaching more eligible patients and providing more comprehensive services,’ and there is very clear evidence that it does just that.” The spokesperson cited, as an example, a study demonstrating how a safety-net hospital used 340B savings to provide effective multidisciplinary care for patients with hepatitis C virus (bit. ly/2KynrBu).

Allegations from both sides of the 340B dispute are unlikely to subside anytime soon. But Peggy Tighe, a principal at Powers Law and the legislative counsel to Ryan White Clinics for 340B Access, one of the plaintiffs in the lawsuit against HHS, is betting the lawsuit will succeed in pushing the

government to action in favor of covered entities and patients, who she said “are being harmed because manufacturers are limiting access to drugs.”

Whether that action includes refunds and punitive steps called for by the 340B plaintiffs remains to be seen.

“The advisory opinion does not address enforcement matters; those are the purview of HHS/HRSA,” the 340B Health spokesperson said. “We continue to urge the department to enforce the law and direct the manufacturers to stop their actions and refund overcharges to

the hospitals, health centers and clinics affected. The other matter is whether or not to impose civil monetary penalties on manufacturers for ‘knowingly and intentionally’ overcharging. Those decisions would be made by the HHS Office of the Inspector General. We have urged HHS/HRSA to refer these matters to the OIG for such purposes.”

The sources reported no relevant financial disclosures.

Read Pharmacy Practice News Anywhere, Anytime!

340B Limits ‘Unconscionable’ 340B Report’s Slafsky said limiting the availability of 340B pricing is not only illegal, it is “unconscionable.” He added, “These providers [who make use of 340B discounts] take care of our most vulnerable patients and rely on contract pharmacy relationships to provide care to patients closer to home. Without the savings from partnering with community-based pharmacies, it makes it very difficult to provide the comprehensive services needed to treat patients with highly complex, expensive conditions.”

Carpinelli Wallack, a 340B consultant who has also worked with HHS and conducted several program evaluations of the 340B program, cited “unclear policy and a lack of transparency from the state” as “the primary reason” why duplicate discount claims get filed. “No one wants to create duplicate discounts, but states often communicate their expectations and billing instructions to entities in a vague or limited fashion,” she said. Most covered entities, she added, try in earnest to avoid duplicate discounts, investing

—David Wild

www.pharmacypracticenews.com

34 Policy

Pharmacy Practice News • January 2021

Compounding

95% USP Adherence at Ascencion a Team Effort C

omplying with compounding guidance is an onerous task for any institution, but rolling out a standardized compounding compliance program across 146 health systems and achieving 95% adherence is Herculean— and a feat that Ascension can claim to have achieved.

According to Shewan Aziz, RPh, PhD, the vice president of pharmacy at Ascension Texas, in Austin, the key to his facility’s success has been implementing standardized system-level guidance while also meeting the needs of individual hospitals.

“In addition to working on a national level to develop best-practice compounding guidance, we work with each hospital to provide them with the resources and tools they need to assess their own compounding preparation management risk and to create action plans, implement best practices and track their in-house compliance,” Aziz explained at the ASHP 2020 Midyear Clinical Meeting and Exposition.

The path to near-perfect USP compliance at Ascension started in 2012, when the organization created a compounding subcommittee. The committee, which consisted of compounding experts from individual Ascension hospitals, scoured existing compounding guidance documents, literature and best practices issued not only by USP but by the National Institute for Occupational Safety and Health, the Occupational Safety and Health Administration, and state boards of pharmacy, Aziz said. Using these sources, the task force developed two Ascension-specific guidelines: one for nonhazardous compounds and one for hazardous compounds, he explained.

According to Aziz, the guidelines outline a variety of best practices for everything from IV room contamination management to use of compounding robotics, IV workflow systems and standardized closed system drug-transfer devices for chemotherapy.

The subcommittee also created documents that include compliance tips and “pearls,” he added, and they developed standardized policies and procedures that individual hospitals could implement, as well as training and competency assessment modules they could use for their staff.

When it came to procuring funds for capital projects, the national team also provided this to each hospital, helping them design and build USP-compliant IV rooms.

To further enhance the safety of compounded drug management, the national compounding subcommittee even created auxiliary warning labels with

handling instructions for all IV hazardous drug preparations, and they built in hazardous drug alerts for automated dispensing cabinets and electronic medication administration systems, Aziz said.

Finally, the team developed key performance indicators and compounding metrics to help individual hospitals ensure they are complying with the national-level guidance, he said.

“In 2012, before we undertook this standardization initiative, we had 55% compliance with USP <797>, and that’s gone up to 95% today,” said Aziz, noting that the outlying 5% of hospitals are expected to be compliant with the Ascension compounding guidance by August 2021.

With regard to USP <800> compliance and any additional changes that might be contained in the revised USP <795> and <797> chapters once they are finalized and made official, “given all the work and effort that has gone on at our hospitals to adhere to our own compounding

guidances, we will be ready to meet all compounding standards when the USP appeals are resolved,” Aziz said.

“I think our experience shows that if you want to implement best practices and improve care, you can do it,” he said.

Still Some Confusion Ascension’s success doesn’t mean there isn’t work to be done regarding USP compounding compliance. With the appeals process for USP General Chapters <795> and <797> now over and the chapters remanded, and with <800> currently informational, healthsystem pharmacies may be confused about which protocols and procedures they should be implementing.

“None of us know what the future will hold” with regard to changes to these chapters, Robert Campbell, PharmD, the director of clinical standards interpretation for hospital and ambulatory programs at the Joint Commission, in Oakbrook Terrace, Ill., said

The Joint Commission’s Top Reasons for USP Noncompliance

T

he reasons for noncompliance with USP compounding standards vary and change from year to year, ranging from inadequate competency assessments to incomplete environmental testing. But “one thing we continue to see that hasn’t changed since day one is that those responsible for compounding are not taking the time to fully review their testing certification reports,” said Robert Campbell, PharmD, the director of clinical standards interpretation for hospital and ambulatory programs at the Joint Commission, in Oakbrook Terrace, Ill. “Too often, facilities getting the testing done do not hand the results to leadership, or pharmacy leadership takes a look at the front page of a report and does not look at the nuts and bolts of the report’s findings,” Campbell said at the ASHP 2020 Midyear Clinical Meeting and Exposition.

Apart from a lack of attention to reports, Campbell pointed to several other top reasons for noncompliance, including: • for personnel: a lack of competency assessments completed, a lack of didactic testing scoring and incomplete initial competency assessments; • for products: drug shortages leading to changes in compounding products that are not accompanied by necessary changes to environment and beyonduse dating, and a lack of proper labeling; and • for environmental standards: incomplete testing and certification reports and improper resolution of these report results.

Going back to the basics of USP compliance—the need to review reports in detail—“any issues identified by a certifier need to be examined,” Campbell said.

—D.W.

at the ASHP Midyear meeting.

For the time being, Brian Serumaga, PhD, RPh, a scientific liaison at USP, in Rockville, Md., said his organization “has continued to emphasize through stakeholder engagement and webpage updates that due to the remand of the 2019 revisions of <795> and<797>, the currently official versions of <795> and <797> are those last revised in 2014 and 2008, respectively.”

Although the appeals focused on the framework for establishing beyond-usedates (BUDs) for sterile and nonsterile compounded preparations, and for extending BUDs beyond the defaults in the chapters, “the Compounding Expert Committee may consider additional changes,” Serumaga said.

“In March 2020, the USP appeals panel made a decision remanding the chapters to the compounding expert committee, with a recommendation that the committee carry out further stakeholder engagement on the issues touched on in the appeals,” added Serumaga, who spoke at the ASHP meeting.

In regard to USP <800>, Serumaga said USP considers it informational only, but the organization “encourages” early adoption of the chapter, and “regulatory bodies and oversight organizations may make their own determinations regarding the applicability and enforceability of <800> for entities within their jurisdiction.”

Indeed, for early USP <800> adopters, Campbell said the Joint Commission surveyors will be surveying according to criteria from that chapter, and <800> guidelines will supersede the 2008 version of <797> when the two chapters conflict, Campbell said.

“For example, the 2008 version of USP <797> states that you cannot compound hazardous drugs in a segregated compounding area, whereas <800> allows for compounding these preparations in a contained segregated compounding area,” Campbell noted. “If you want to adopt <800>, you need to meet all the requirements for a contained area.”

Campbell emphasized that early adopters of USP <800> who are in the midst of construction projects, and therefore can’t be tested for full compliance, should ensure they are protecting staff and patients during the transition. The Joint Commission’s surveyors will be verifying that hazardous drug vapors are not escaping and personal protective equipment is being worn by compounding staff, he said.

—David Wild The sources reported no relevant financial disclosures.

®

®

Simplist DILAUDID INJECTION (hydromorphone hydrochloride) for intravenous, intramuscular, or subcutaneous use, CII BRIEF SUMMARY OF PRESCRIBING INFORMATION This brief summary does not include all the information needed to use DILAUDID INJECTION safely and effectively. Please see full prescribing information, including BOXED WARNING, for DILAUDID INJECTION atwww.fresenius-kabi.com/us.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISK FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse DILAUDID INJECTION exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing DILAUDID INJECTION and monitor all patients regularly for the development of these behaviors and conditions Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of DILAUDID INJECTION. Monitor for respiratory depression, especially during initiation of DILAUDID INJECTION or following a dose increase.

Neonatal Opioid Withdrawal Syndrome Prolonged use of DILAUDID INJECTION during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of DILAUDID and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

• Limit dosages and durations to the minimum required.

• Follow patients for signs and symptoms of respiratory depression and sedation.

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

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

CONTRAINDICATIONS DILAUDID INJECTION is contraindicated in patients with: • Significant respiratory depression.

• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.

• Known or suspected gastrointestinal obstruction, including paralytic ileus.

• Known hypersensitivity to hydromorphone, hydromorphone salts, sulfitecontaining medications, or any other components of the product.

WARNINGS AND PRECAUTIONS (also see BOXED WARNING) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely at initiation, dose titration. See Contraindications for use in patients with bronchial asthma.

• Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

• Adrenal Insufficiency: If diagnosed, wean the patient off of the opioid and treat with physiologic replacement doses of corticosteroids.

• Severe Hypotension: Monitor during dosage initiation and titration.

Avoid use in patients with circulatory shock.

• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of DILAUDID INJECTION in patients with impaired consciousness or coma.

• Risks of Use in Patients with Gastrointestinal Conditions: The hydromorphone in DILAUDID INJECTION may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase.

Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

• Increased Risk of Seizures in Patients with Seizure Disorders: Monitor patients with a history of seizure disorders for worsened seizure control.

• Withdrawal: When discontinuing DILAUDID INJECTION in a physicallydependent patient, gradually taper the dosage. Do not abruptly discontinue therapy in physically-dependent patients.

• Risks of Driving and Operating Machinery: DILAUDID INJECTION may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of DILAUDID INJECTION and know how they will react to the medication.

• Sulfites: DILAUDID INJECTION contains sodium metabisulfite. See Contraindications.

• Increased Risk of Hypotension and Respiratory Depression with Rapid Intravenous Administration: should be given very slowly.

ADVERSE REACTIONS (see Boxed Warning and Warnings and Precautions) Serious adverse reactions: Addiction, abuse, and misuse, lifethreatening respiratory depression, neonatal opioid withdrawal syndrome, interactions with benzodiazepines and other CNS depressants, adrenal insufficiency, severe hypotension, gastrointestinal adverse reactions, seizures, withdrawal, respiratory depression and apnea, circulatory depression, respiratory arrest, shock, and cardiac arrest.

Most common adverse reactions: Lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. Less frequently observed adverse reactions: tachycardia, bradycardia, palpitations, blurred vision, diplopia, miosis, visual impairment, constipation, ileus, diarrhea, abdominal pain, weakness, feeling abnormal, chills, injection site uticaria, fatigue, injection site reactions, peripheral edema, biliary colic, anaphylactic reactions, hypersensitivity reactions, increase in hepatic enzymes, decreased

appetite, muscle rigidity, headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence, agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams, urinary retention, urinary hesitation, antidiuretic effects, erectile dysfunction, bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling, injection site pain, urticaria, rash, hyperhidrosis, flushing, hypotension, hypertension, serotonin syndrome, and androgen deficiency.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA at 1-800-551-7176 option 5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm (see BOXED WARNING for neonatal opioid withdrawal syndrome).

• Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

Naloxone must be available for reversal. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

• Lactation: Low levels of opioid analgesics have been detected in human milk. Monitor infants for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydromorphone is stopped, or when breast-feeding is stopped.

• Females and Males of Reproductive Potential: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

• Pediatric Use: The safety and effectiveness of DILAUDID INJECTION in pediatric patients has not been established.

• Geriatric Use: Patients 65 years of age or older may have increased sensitivity to hydromorphone. Start at the low end of the dosing range, titrate the dosage slowly and monitor for signs of CNS and respiratory depression.

• Hepatic and Renal Impairment: Start patients on one-fourth to onehalf the usual starting dose depending on the degree of impairment and closely monitor during dose titration.

DRUG INTERACTIONS Clinically significant drug interactions with DILAUDID INJECTION: benzodiazepines and other CNS depressants, serotonergic and anticholinergic drugs, monoamine oxidase inhibitors (MAOIs), mixed agonist/antagonist and partial agonist opioid analgesics, muscle relaxants, diuretics.

OVERDOSAGE Acute overdose with DILAUDID INJECTION can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.

Marked mydriasis, rather than miosis, may be seen with hypoxia in overdose situations. In case of overdose, reestablish patent and protected airway, institute assisted or controlled ventilation, manage circulatory shock, pulmonary edema, cardiac arrest or arrhythmias, as indicated. Administer opioid antagonists only for clinically significant respiratory or circulatory depression. Carefully monitor the patient until spontaneous respiration is reestablished. Administration of opioid antagonist in aphysically dependent patient should be initiated with care and by titration with smaller than usual doses of the antagonist.

For full Prescribing Information please go to www.simplist-us.com

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Dilaudid 0.2 mg per 1 mL presentation available in a ready-to-administer prefilled syringe helps reduce waste and eliminates steps in medication preparation.

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

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

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

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

Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.

Severe hypotension: Monitor during dosage initiation and titration. Avoid use in patients with circulatory shock.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness: Monitor for sedation and respiratory depression. Avoid use patients with impaired consciousness or coma.

See full prescribing information for complete boxed warning.

DILAUDID INJECTION contains sodium metabisulfite. There is a risk of anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people.

• DILAUDID INJECTION exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions.

• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase.

• Prolonged use of DILAUDID INJECTION during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

Additional serious adverse reactions: Apnea, circulatory depression, respiratory arrest, shock, cardiac arrest, seizures, withdrawal, anaphylaxis. Most common adverse reactions: Lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage: Acute overdose can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, miosis (or mydriasis when hypoxia is present), and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.

This Important Safety Information does not include all the information needed to use DILAUDID safely and effectively. Please see full prescribing information, including BOXED WARNING, for DILAUDID INJECTION available at www.simplist-us.com.

Please see Brief Summary of Prescribing Information on the following page.

Ready-to-administer prefilled syringes

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