Just as each influenza season is different, the effectiveness of annual influenza vaccines is never the same from year to year.

Influenza vaccine components are chosen each year based on the predicted predominant strains.

 Since the choices are made based on predictions, no vaccine reaches 100% effectiveness in preventing seasonal influenza. A vaccine effectiveness of 19% to 60% is historically consistent.

The Centers for Disease Control and Prevention (CDC) reported an early start to the 2019-2020 influenza season during the week of November 9, 2019.2 Influenza B predominated early in the season, with influenza A cases increasing during the remainder of the season. The US Influenza Vaccine Effectiveness Network assessed patients aged 6 months or older who were seen for respiratory illness in the outpatient setting across 5 study sites.

 As of February 2020, among 6879 patients who tested positive for influenza, 37% had received an influenza vaccine. Vaccine effectiveness was 50% against influenza B, 37% against influenza A, and 45% for both types combined.

Baloxavir marboxil (Xofluza) and oseltamivir (Tamiflu) are oral antiinfluenza therapies available in the United States. When deciding which agent to use, it is important to consider their differences, including cost, dosing, indications and populations approved by the United States Food and Drug Administration (FDA), and mechanism of action.

Mechanistically, these drugs attack different targets. Baloxavir marboxil inhibits the endonuclease activity of the polymerase acidic protein, thus inhibiting viral replication, whereas oseltamivir inhibits neuraminidase, which affects the release of viral particles.

Oral oseltamivir is widely used as firstline therapy for the treatment of influenza in clinical practice.

 Baloxavir marboxil received FDA approval after the finalization of the 2018 guidelines, and thus specific recommendations for use were not included. Preliminary 2020-2021 CDC recommendations suggest oseltamivir for hospitalized patients but give equal weight to oseltamivir and baloxavir marboxil for outpatient treatment.

 In addition to the treatment of influenza, oseltamivir is approved for prophylaxis of influenzas A and B. Oseltamivir is approved in patients older than 2 weeks compared with patients older than 12 years with baloxavir marboxil. Although baloxavir marboxil has been used in patients younger than 12 years in some recent studies, additional safety and efficacy data are needed to better define use in this population.

 Although both agents should be initiated within 48 hours of symptom onset, baloxavir marboxil’s long half-life allows a single-dose regimen compared with the 5-day, twice-daily regimen with oseltamivir.

 Adherence to a single pill regimen is certainly an advantage of baloxavir marboxil, but cost is a potentially significant barrier. A single adult-dose of brand-name Xofluza costs about 3 times more than a 5-day course of generic oseltamivir.

Although there is less clinical experience with baloxavir marboxil, because of its recent approval, multiple controlled randomized studies comparing baloxavir marboxil with oseltamivir and a placebo supported its FDA approval. The CAPSTONE I study (NCT02954354)

 included otherwise healthy outpatients with acute uncomplicated influenza in Japan and the United States. In the full cohort, baloxavir marboxil reduced the median time to alleviation of symptoms by 26.5 hours compared with the placebo (P < .001) but found no difference compared with oseltamivir. The CAPSTONE II study (NCT02949011)

 included patients with at least 1 high-risk medical condition and uncomplicated influenza. As in the CAPSTONE I study, a single dose of baloxavir marboxil was found to reduce the median time to improvement of symptoms by 29

 hours compared with the placebo (P < .0001) but was not significantly different compared with oseltamivir. However, in the influenza B subset, baloxavir marboxil reduced the median time to symptom improvement by 27 hours compared with oseltamivir (P < .0251).

Finally, another recent study suggested that baloxavir marboxil also may be effective for prophylaxis of household contacts. Clinical influenza development was significantly lower in a group treated with a single, weight-based dose of baloxavir marboxil after household exposure to influenza compared with the placebo in a controlled, double-blind, randomized trial (1.9% baloxavir marboxil versus 13.6% placebo, P < .001).

A final therapeutic consideration pertains to emerging baloxavir marboxil resistance. In 1 study, emergence of viruses with PA/I38X substitution following baloxavir marboxil treatment was associated with a delay in symptom alleviation and, uncommonly, symptom rebound.

 Further study is warranted to better define the risk of posttreatment resistance and potential methods to circumvent it.

Baloxavir marboxil and oseltamivir are both potential options for treating uncomplicated influenza. Treatment decisions should be made on a case-by-case basis for the 2020-2021 influenza season. Oseltamivir is the preferred option for children younger than 12 years. However, emerging data suggest that baloxavir may be efficacious and safe in younger children as well. Patients with adherence barriers to multiple-day dosing may benefit from baloxavir marboxil over oseltamivir, as it is available as a single dose. However, patients with cost barriers may prefer oseltamivir, given the significant cost difference between the 2 agents.

, is an antimicrobial stewardship pharmacist at Hennepin County Medical Center in Minneapolis, Minnesota.

, is a PGY1 resident at the University of Virginia Health System in Charlottesville, Virginia.

, is an antimicrobial stewardship clinical pharmacy specialist at SCL Health in Grand Junction, Colorado. 

Grohskopf LA, Alyanak E, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices — United States, 2019-20 influenza season. 

. 2019;68(3):1-24. doi:10.15585/mmwr. rr6908a1

Dawood FS, Chung JR, Kim SS, et al. Interim estimates of 2019-20 seasonal influenza vaccine effectiveness — United States, February 2020. 

. 2020;69:177-182. doi:10.15585/mmwr.mm6907a1

Jackson ML, Chung JR, Jackson LA, et al. Influenza vaccine effectiveness in the United States during the 2015—2016 season. 

. 2017;377:534- 543. doi:10.1056/NEJMoa1700153

Tamiflu. Prescribing information. Gilead Sciences Inc; 2012. https://www. accessdata.fda.gov/drugsatfda_docs/label/2012/021087s062lbl.pdf

Xofluza. Prescribing information. Shionogi & Co Ltd; 2018. https://www. accessdata.fda.gov/drugsatfda_docs/label/2018/210854s000lbl.pdf

Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):e1-47. doi:10.1093/cid/ciy866

CDC. Influenza antiviral medications: summary for clinicians. Updated October 26, 2020. Accessed October 29, 2020. https://www.cdc.gov/flu/professionals/ antivirals/summary-clinicians.htm#:~:text=The%20recommended%20 treatment%20course%20for,oral%20baloxavir%20for%201%20day

Ikematsu H, Hayden FG, Kawaguchi K, et al. Baloxavir marboxil for prophylaxis against influenza in household contacts. 

 2020;383(4):309- 320. doi:10.1056/NEJMoa1915341

Xofluza. GoodRx. Accessed June 16, 2020. https://www.goodrx.com/xofluza

Tamiflu. GoodRx. Accessed October 27, 2020. https://www.goodrx.com/ tamiflu

Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents.

. 2018;379:913- 923. doi:10.1056/NEJMoa1716197

Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-1214. doi:10.1016/S1473-3099(20)30004-9

Uehara T, Hayden FG, Kawaguchi K, et al. Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza. 

. 2020;221(3):346-355. doi:10.1093/infdis/jiz244

Articles

Health-System Edition

Baloxavir marboxil and oseltamivir are options for treating uncomplicated influenza.

Choose the Most Appropriate Therapy to Fight Influenza

As 2020 ends, it is hard not to reflect on the impact of the coronavirus disease 2019 (COVID-19) pandemic this year. We thank pharmacists and pharmacy staff for stepping up amid this health care crisis.

Pharmacists have always been trusted health care professionals, but they left no doubt that they are heroes during the pandemic. Many worked on the front lines to help patients and put their own health at risk during these unprecedented times. We salute pharmacists and pharmacy staff for their professionalism and courage.

 publications have offered coverage of COVID-19 in print and online through our coronavirus resource center. We have covered news related to this topic and spotlighted pharmacy heroes, those pharmacists and technicians working to make a difference for their patients during the pandemic. In this issue, for example, Gina Dube, PharmD, RPh, CACP, looks at how COVID-19 is linked to cardiovascular complications. We will continue to bring our readers news about COVID-19 into 2021, including pharmacists’ potential role in administering vaccines once they become available. The ability to take on this role promises even more opportunities for pharmacists to cement their value with patients and in their communities.

We also endeavor to bring readers news in many other important areas, as well. In this issue’s cover feature, Andrew J. Donnelly, PharmD, MBA, FASHP, and Jamie Paek, PharmD, explore how to adopt biosimilars into clinical practice. Readers also can find information on choosing the most appropriate therapy to fight influenza and the latest on treatments for renal cell carcinoma. Editor in Chief Curtis Haas looks at attacks on the 340B drug pricing program and how that creates challenges for individuals with low incomes.

 is covering all the major conferences, which are virtual this year. Look for print content and online coverage, including articles and videos, from the American Society of Health-System Pharmacists Midyear 2020 Clinical Meeting and the San Antonio Breast Cancer Symposium, both in December.

As we head into the holiday season, we hope that pharmacists and pharmacy staff get a well-deserved break after working even harder than usual in 2020.

As 2020 ends, it is hard not to reflect on the impact of the COVID-19 pandemic this year. 

Pharmacists Showed They Are Heroes in 2020

The National Cancer Institute estimates that by the end of 2020, there will be 73,750 new cases of kidney and renal pelvis cancer, representing 4.1% of all new  cancer diagnoses, with 14,830 new deaths.

The 5-year relative survival rate has slowly increased each year for the past 4 decades. Figure 11 shows the rates for relative 5-year survival by stage at diagnosis.

In addition to the risk factors listed in Figure 21-4, unmodifiable factors, such as age, gender, and race are also associated with an increased risk for renal cancer. African Americans, men, and older individuals have a higher risk.

 Older patients also have a higher rate of death from kidney and renal pelvis cancer.

Renal carcinomas can present in many ways, with the most common form being renal cell carcinoma (RCC), representing about 85% of diagnoses. RCC develops in the epithelium of the proximal renal tubules and can occur in a hereditary or nonhereditary manner. Regardless of the disease’s etiology, a structural alteration in the short arm of chromosome 3 is responsible for the development of cancer.

 Common hereditary syndromes are also summarized in Figure 2.

The National Comprehensive Cancer Network (NCCN) does not offer screening recommendations for RCC. For patients presenting with symptoms or those with a family history of RCC, clinicians can perform an abdominal CT scan, as well as a renal ultrasound, for diagnosis.

 Table 1 outlines common symptoms of RCC.

Patients can  also undergo other tests, such as a bone scan, chest x-ray, cranial MRI, and needle biopsy to aid in tumor staging.

Determining histology subtype is important for choosing an appropriate systemic therapy regimen, as well as for establishing a risk group using a prognostic factor model discussed in the guidelines.

The role of systemic therapy is primarily in stage IV, or metastatic disease, according to the NCCN guidelines. For patients with stage I through III RCC, the preferred treatment is a partial or radical nephrectomy. For patients with stage IV RCC, the recommended algorithm is outlined in Online Figure 3.

The first-line preferred systemic therapies are summarized in Online Table 2.5 For those with clear cell histology, clinicians determine treatment based on the patient’s risk group, either favorable risk or intermediate or poor risk.

Recently, investigators reported significant results in the setting of metastatic or advanced clear-cell RCC in the CheckMate 9ER phase 3 trial (NCT03141177). The trial compared cabozantinib plus nivolumab to sunitinib, an active comparator. The investigators looked at objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and safety, finding that all these measures were statistically significant favoring cabozantinib plus nivolumab versus sunitinib with an acceptable safety profile. The ORR and PFS were both doubled in the intervention group versus sunitinib. The effects on OS and PFS were consistent among each risk group. The follow-up time for this trial was 18 months, which may not be long enough to determine the lasting effects of this regimen, but the results have been promising thus far.

The methodology of treating RCC has evolved rapidly in the past few years, leaning more toward combination therapies and less toward monotherapy, particularly in the setting of metastatic clear-cell RCC.

 A vast number of clinical trials are continuing, some of which are outlined in Online Table 3. Investigators anticipate that results will be released in the next few years, which could greatly affect how clinicians treat metastatic RCC.

In addition to newer drug therapies, there has been an increasing interest surrounding the role of genetic biomarkers in predicting a patient’s response to targeted therapy. A recent study presented at the European Society for Medical Oncology Virtual Congress 2020 analyzed the relationship between the expression of effector T cell and angiogenesis signatures and response to treatment with nivolumab in patients with metastatic RCC. The authors recognized that patients with a high-effector T cell and low angiogenesis expression had a higher response rate and median PFS, whereas patients with low-effector T cell and low angiogenesis expression had a poor response rate. They also recognized that patients with low numbers of stromal cells had a higher response rate and longer median PFS.

RCC can often be cured if it is diagnosed and treated surgically while still confined to the kidney and the immediately surrounding tissue. The probability of a cure is commensurate with the degree or stage of tumor dissemination. Even when regional lymphatics or blood vessels are involved, a high percentage of patients can attain prolonged survival and a probable cure. However, once the tumor has metastasized to stage IV status, surgical cure is improbable and reliance is placed upon pharmacological agents, such as immunological and targeted therapies, but disease-free survival is poor. Because most patients receive their diagnosis when the tumor is still relatively localized and amenable to surgical resection, about three-fourths of all patients with RCC survive for 5 years. As with most solid malignancies, early surgical intervention confers the best benefit.

Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP

, are clinical pharmacists in Pensacola, Florida. 

 is a PharmD candidate at the University of Florida College of Pharmacy in Gainesville.

Cancer stat facts: kidney and renal pelvis cancer. National Cancer Institute. Accessed October 1, 2020. https://seer.cancer.gov/statfacts/html/kidrp.html

Kidney cancer. Cancer.Net. March 27, 2019. Accessed October 1, 2020. https://www.cancer.net/cancer-types/kidney-cancer

Sachdeva K. Renal cell carcinoma. Updated June 8, 2020. Accessed October 1, 2020. https://emedicine.medscape.com/article/281340-overview

World Cancer Research Fund. Worldwide cancer data. American Institute for Cancer Research. Accessed October 1, 2020. https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data

Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 1.2021 NCCN Clinical Practice Guidelines in Oncology. July 15, 2020. Accessed October 1, 2020. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

New first-line treatment option for metastatic kidney cancer, according to results of phase 3 study [news release]. Lugano, Switzerland; September 19, 2020: European Society for Medical Oncology. September 19, 2020. Accessed October 1, 2020. 

https://www.esmo.org/meetings/esmo-virtual-congress-2020/meeting-resources/news/esmo2020-metastatic-kidney-cancer-nivolumab-cabozantinib-checkmate9er

 Khetani VV, Portal DE, Shah MR, Mayer T, Singer EA. Combination drug regimens for metastatic clear cell renal cell carcinoma. 

  2020;11(8):541-562.doi:10.5306/wjco.v11.i8.541

US National Library of Medicine. S0931, everolimus in treating patients with kidney cancer who have undergone surgery. ClinicalTrials.gov. Updated June 25, 2020. Accessed October 1, 2020. https://clinicaltrials.gov/ct2/show/NCT01120249?recrs=ad

US National Library of Medicine. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma. ClinicalTrials.gov. Updated August 28, 2020. Accessed October 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03937219?recrs=ad.

US National Library of Medicine. Immunotherapy with nivolumab and ipilimumab followed by nivolumab or nivolumab with cabozantinib for patients with advanced kidney cancer, the PDIGREE study. ClinicalTrials.gov. Updated October 23, 2020. Accessed October 28, 2020. https://clinicaltrials.gov/ct2/show/study/NCT03793166

US National Library of Medicine. Lenvatinib/everolimus or lenvatinib/pembrolizumab versus sunitinib alone as treatment of advanced renal cell carcinoma. ClinicalTrials.gov. Updated July 31, 2020. Accessed October 1, 2020. https://clinicaltrials.gov/ct2/show/NCT02811861?recrs=ad

US National Library of Medicine. A study of TQB2450 injection combined with anlotinib hydrochloride capsule versus sunitinib in subjects with advanced renal cancer. ClinicalTrials.gov. Updated July 31, 2020. Accessed October 1, 2020. https://clinicaltrials.gov/ct2/show/NCT04523272?recrs=ad

US National Library of Medicine. A study of bempegaldesleukin (NKTR-214: BEMPEG) in combination with nivolumab compared with the investigator's choice of a tyrosine kinase inhibitor (TKI) therapy (either sunitinib or cabozantinib monotherapy) for advanced metastatic renal cell carcinoma (RCC). ClinicalTrials.gov. Updated September 30, 2020. Accessed October 1, 2020. https://clinicaltrials.gov/ct2/show/study/NCT03729245

US National Library of Medicine. A study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma (RENAVIV). ClinicalTrials.gov. Updated January 7, 2020. Accessed October 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03592472

A study of TQB2450 injection combined with anlotinib hydrochloride capsule versus sunitinib in subjects with advanced renal cancer. ICH-GCP. Accessed October 1, 2020. https://ichgcp.net/clinical-trials-registry/NCT04523272

Bempegaldesleukin (NKTR-214). Nektar. Accessed October 1, 2020. https://www.nektar.com/pipeline/rd-pipeline/nktr-214

Indicators of outcome are identified for nivolumab treatment of patients with metastatic clear cell renal cell carcinoma. European Society of Medical Oncology. September 21, 2020. Accessed October 1, 2020. https://www.esmo.org/meetings/esmo-virtual-congress-2020/meeting-resources/scientific-news/indicators-of-outcome-are-identified-for-nivolumab-treatment-of-patients-with-metastatic-clear-cell-renal-cell-carcinoma

National Institutes of Health. Renal Cell Cancer Treatment (PDQ®)-Health Professional Version. National Cancer Institute. Accessed October 5, 2020. https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq

Early diagnosis, surgery while cancer is confined to kidney are key, but pharmacological agents are used for Stage IV.

Renal Cell Carcinoma is Treatable and Curable

The United States Pharmacopeia (USP), along with the American Society of Health-System Pharmacists (ASHP) and the Association for Professionals in Infection Control and Epidemiology (APIC), has identified collaboration between infection preventionists (IPs) and pharmacists as a necessary component of successful compliance with USP General Chapter <797>.

There are several issues underscoring the need for this interdepartmental partnership, including accountability to government and accrediting organizations, IPs’ expertise in environmental monitoring and mitigation, recognition of the role that the environment plays in infection transmission risk, and what is at stake when contamination of compounded sterile preparations (CSPs) occurs. Compliance with USP <797>, however, may increasingly require that this collaboration include reliance on emerging technologies to address environmental risk in the clean room.

The foundation of USP <797> is prevention of patient harm through contaminated or improperly formulated compounded medica- tions.1,2 The IP’s role in USP <797> compli- ance is rooted in the prevention of microbial contamination.

This is a critical undertaking because, as stated by USP <797>, CSPs pose an especially hazardous threat to patients “when administered into body cavities, central nervous and vascular systems, eyes, and joints, and when used as baths for live organs.”

Outbreaks, such as the 2012 fungal infections caused by contaminated methyl- prednisolone preparations that resulted in 64 deaths and 793 illnesses across 20 states, highlight the contamination risk if proper environmental controls and monitoring are not in place.

 In this instance, failures in environmental monitoring and mitigation within the compounding pharmacies were responsible for the subsequent devastating morbidity and mortality associated with the outbreak.

USP <797> addresses CSP contamination risk through guidelines on the “quality status of the components incorporated, the process utilized, personnel performance, and the environmental conditions under which the process is performed.”

The chapter provides detailed guidance on aseptic technique, engineering controls, environmental monitoring and quality assurance, and facility design. Both the ASHP and USP guidelines charge compounding personnel with responsibility for all elements of USP <797>, including cleaning and disinfection, environmental monitoring, and prompt corrective action for any unacceptable moni- toring or measurement results (see Table 1).

 They also recommend, however, that the environmental elements be addressed in collaboration with infection prevention and control personnel.

The ASHP further advises that clean room personnel consult the facility’s “appropriate authority [eg, the Infection Control Committee] on choice of cleaning and disinfection products and ensure a root cause-analysis, including participation by other facility experts such as infection control Personnel,” is completed for any actionable monitoring or measurement failures (see Online Table 2).

This is critical not only for patient safety but because of the accountability standards to which health care facilities and practitioners are increasingly held.

The USP sets standards for pharmacy practice, but it is not an enforcement body.

State pharmacy boards provide the primary oversight for compounding pharmacies, and an increasing number of them mandate compliance with USP <797>.

A 2018 report by the Pew Charitable Trusts found that 32 state boards of pharmacy mandated compliance, with an additional 4 having pending policy changes regarding compliance.

In turn, under Title 42, §482.25, the Centers for Medicare & Medicaid Services identifies adherence to state laws regarding compounding pharmacy practice as a condition of participation.

 The Joint Commission accreditation similarly requires compliance with state law and, thus, compliance with USP <797> where mandated.

Although IP-pharmacist collaboration in the clean room may be an intuitive partnership in achieving compli- ance with governmental and professional standards

and ensuring patient safety, there is some evidence that challenges remain.

In its most recent published survey of hospital pharmacists across the nation, the ASHP reported that 71% of pharmacists from 687 hospitals had used an environmental sampling program, and 83% reported preparing chemotherapy (ie, sterile) medications in their pharmacies.

 This suggests that 12% of surveyed facilities might be compounding sterile preparations but not performing appropriate environmental oversight. Further, just 44% of those facilities performing environmental monitoring reported those sampling results through their organization’s quality reporting pathways.

In a report on 2018 survey results from sterile medication compounding pharmacies, Robert Campbell, PharmD, the director of medication management for the Joint Commission Enterprise, noted that “there is a continuing trend of pharmacy leaders not reviewing their testing and certification reports in detail. As a result, important components of engineering controls are undergoing testing, but are not in compliance with the required values; in some cases, they are not being treated at all.”

The dramatic advancements in environmental technologies have been in direct response to the growing body of evidence demonstrating the inadequacy of manual cleaning and disinfection. As such, it has been a fail-safe of sorts, providing an added measure of certainty in mitigating environmental contamination risk. The aforementioned pharmacy survey statistics suggest that the clean room environment may need a fail-safe of its own, because of the reported suboptimal execution of environmental monitoring and mitigation strategies. Research has shown that environmental technologies, such as hydrogen peroxide vapor systems and ultraviolet-C light, can effectively reduce environmental bioburden as an adjunct to manual cleaning.

 Evaluation of the method of disinfection (episodic versus continuous), impact on workflow, and compatibility with clean room materials are among the many factors that must be considered in choosing a technology, and are best assessed by integrating the IP’s environmental risk expertise with the pharmacist’s clean room operational expertise.

Despite the statistics, there is evidence that collaboration can lead to successful outcomes. One such example is the partnership between the IP and the pharmacist at an inpatient hospital in Indiana, a state in which USP <797> compliance is mandated. Over a period of 2 and a half years, the IP and pharmacist collaborated to investigate and address recurring actionable air sampling results in the hospital’s clean room (see Online Figure). Although the air and surface sampling within the actual intravenous (IV) hoods consistently yielded passing grades, there were continuing issues with viable growth in the air sampling in areas associated with IV mixing.

Investigations identified several environmental sources for the monitoring failures, including a faulty HVAC filter, personnel practices, and a water-damaged wall. Although these sources were individually addressed, the ongoing nature of these challenges made it clear to the team that an environmental mitigation strategy that could provide continuous bioburden reduc- tion was needed. Aligning with the charge from both the ASHP and APIC that new technologies be integrated where appropriate to achieve quality assurance,

 the IP subsequently recommended the implementation of dry hydrogen peroxide (DHP) technology (Synexis), which in previous research had been shown to provide continuous and effective microbial reduction of air and surfaces in the health care setting.

 The IP-pharmacist team determined that the ability of DHP technology to operate continuously would help address active shed- ding and contamination in real time without disrupting pharmacy workflow. Additionally, the DHP would be compatible with clean room surface materials as well as being safe. Deployment of the technology 24 hours a day, 7 days a week resolved the monitoring failures and enabled successful compliance with USP <797>.

IPs and pharmacists share responsibility for ensuring patient safety. In the clean room, this shared responsibility is achieved through the prevention of contaminated CSPs. Both professions are charged by their respective professional organizations, and increasingly by government mandate, to employ solutions that ensure the highest degree of quality assurance.

 Environmental technologies are used in other health care settings for this purpose and should be similarly deployed in the clean room, particularly when evidence suggests environmental monitoring and mitigation processes are not being executed appropriately. Although the USP recently remanded the proposed changes to USP <797> to its Compounding Expert Committee, should the proposed revisions regarding more stringent monitoring frequencies and enhanced cleaning requirements be adopted, and the trend for more states demanding USP <797> compliance continue, collaborative deployment of these technologies may become even more imperative.

, is the pharmacy manager of the pharmacy department at Saint Joseph Health System Plymouth Medical Center in Minnesota. 

, is a registered nurse at Saint Joseph Health System in Kokomo, Indiana.

General chapter <797> pharmaceutical compounding — sterile regulations. USP. Accessed October 19, 2020. https://www.usp.org/compounding/general-chapter-797

ASHP guidelines on compounding sterile preparations. ASHP. Accessed October 20, 2020. https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/compound- ing-sterile-preparations.ashx

Billings C, Bernard H, Caffery L, et al. Advancing the profession: an updated future-oriented competency model for professional development in infection prevention and control. 

 2019;47(6):602-614. doi:10.1016/j.ajic.2019.04.003

January 31, 2018: New England compounding center pharmacist sentenced for role in nationwide fungal meningitis outbreak. Press release. FDA. January 31, 2019. Accessed October 20, 2020. https://www.fda.gov/inspections-compliance-enforce- ment-and-criminal-investigations/press-releases/january-31-2018-new-england-com- pounding-center-pharmacist-sentenced-role-nationwide-fungal#:~:text=Boston%20 %2D%2D%20The%20former%20supervisory,District%20Court%20Judge%20 Richard%20G

Rutala WA, Weber DJ. Best practices for disinfection of noncritical environmental surfaces and equipment in health care facilities: a bundle approach. 

 2019;47S:A96-A105. doi:10.1016/j.ajic.2019.01.014

Report: majority of states have adopted policies to make compounded drugs safer. The Pew Charitable Trusts. February 26, 2018. Accessed October 20, 2020. https:// www.pewtrusts.org/en/about/news-room/press-releases-and-statements/2018/02/26/ report-majority-of-states-have-adopted-policies-to-make-compounded-drugs-safer

Pharmacy rules/regulations by state for compliance with USP 797 medication compounding. The Joint Commission. February 28, 2017. Accessed October 20, 2020. https://www.jointcommission.org/-/media/deprecated-unorganized/imported-assets/ tjc/system-folders/assetmanager/feb_2017_state_compounding_regulationspdf.pdf?d- b=web&hash=B798BA9124A9C98DD7F10F0223EBC639

Revised hospital guidance for pharmaceutical services and expanded guidance related to compounding of medications. Centers for Medicare & Medicaid Services. October 30, 2015. Accessed January 28, 2020. https://www.cms.gov/Medicare/Provider- Enrollment-and-Certification/SurveyCertificationGenInfo/Policy-and-Memos-to- States- and-Regions-Items/Survey-and-Cert-Letter-16-01

Schneider PJ, Pedersen CA, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration — 2017. 

. 2018;75(16):1203-1226. doi:10.2146/ajhp180151

Campbell R. The Joint Commission compliance update. Pharmacy Purchasing & Products. 2019;16(3):10. Accessed January 28, 2020. https://www.pppmag.com/ article/2356

Herman CK, Hess J, Cerra C. Dilute hydrogen peroxide technology for reduction of microbial colonization in the hospital setting. 

. 2015;43:S25-S26. Accessed October 20, 2020. https://www.ajicjournal.org/article/S0196-6553(15)00307- 7/pdf

Appeals panel decisions on USP <795>, <797>, and <825>. USP. March 12, 2020. Accessed October 20, 2020. https://www.usp.org/sites/default/files/usp/document/our- work/compounding/decisions-appeals-fs.pdf

Collaboration Is a necessary component of successful compliance with USP , and technology can help.
 

Infection Specialists and Pharmacists Share Responsibility for Ensuring Patient Safety

The 340B Drug Pricing Program has grown considerably in the past decade due to a combination of provisions in the Affordable Care Act that expanded the definition of qualifying covered entities and guidance in 2010 from the Health Resources & Services Administration (HRSA) that expanded contract pharmacy programs.

There is little doubt that the pharmaceutical industry is not a fan of the 340B program and believes that HRSA lacked the statutory authority to expand contract pharmacy relationships.

 In 2020, several large pharmaceutical companies decided to directly confront the issues surrounding contract pharmacies, with many more likely to follow. These moves could have a devastating financial impact on safety net providers participating in the 340B program.

Although there are certainly strong opinions in the health care world concerning the true value of the 340B program, I believe it much of it fueled by misinformation and mischaracterization of the intent of the program, those directly involved in caring for the underserved and uninsured see firsthand the value. The 340B program has been successful at achieving its intent. The savings realized contribute to the operating margin for safety net providers, which allows for reinvestment in their communities through expanding and improving clinical services, hiring clinicians to care for the underserved, modernizing and updating facilities, offering unreimbursed wraparound services that address social determinants of care, and providing more access to care in the most vulnerable communities. It is local dollars leading to local improvements in health where it is most needed. There is no evidence that there is widespread fraud by nonprofit safety net providers that are somehow diverting savings for nefarious purposes.

The coronavirus disease 2019 pandemic has shone a bright light on disparities in health care in the United States. During the pandemic, Black people have died at a much higher percentage rate than their representation in the population. Health care providers across the country have sustained devastating financial losses because of their response to the pandemic, with many facing the worst financial crises since their founding that will require many years to recover, if they ever do. Even before the financial impact of the pandemic, rural health care systems were in distress, with more than 120 closing since 2010, and another 453, or 1 in 4, struggling to keep their doors open.

 Then the pandemic hit, worsening these financial forecasts for rural providers. More than half of 340B covered entities are rural health care providers. The recent moves by the industry causing financial harm to safety net providers in both rural and urban settings will result in a reduction of services they can provide and a widening of health care disparities. These changes will have no discernible impact on health care providers located in wealthy communities who are not eligible for 340B discounts. Intended or unintended, these decisions to undermine the contract pharmacy programs of safety net providers are discriminatory and hurt the most vulnerable communities.

While health care providers have sustained significant losses, patients have lost employment and health care coverage, small businesses have failed, and several large industries have taken significant financial hits, many of the large pharmaceutical companies have actually fared quite well with growth and increased value for their stockholders.

There will be continuing legal challenges to these actions, and it is unknown what outcome will result. In the interim, underserved patients will suffer, the cost to taxpayers will likely increase, and some safety net providers may fail, leaving their communities unserved, all while high-cost lawyers fight to maximize shareholder value for corporations with double-digit profit margins. Public statements by these same large corporations supporting fairness and inclusion will likely continue as well.

is the chief pharmacy officer for the University of Rochester health care system in New York.

Lee J. HHS power over drug discounts put to test in looming legal fight. Bloomberg Law. September 23, 2020. Accessed October 30, 2020. https://news.bloomberglaw.com/ pharma-and-life-sciences/hhs-power-over-drug-discounts-put-to-test-in-looming-legal-fight-3

340B at a glance. 340B Health. Accessed October 30, 2020. https://www.340bhealth.org/ files/340B_AtAGlance_-_FINAL.pdf

Yet those directly involved in caring for the underserved and uninsured see its value firsthand. 

Attacks on 340B Drug Pricing Create Challenges for Low-Income Populations

This article was updated November 23, 2020 to include all authors.

Opioid use in the United States has evolved significantly during a recognized opioid epidemic. Related morbidity and mortality, along with regulatory scrutiny, have led to fear of opioid prescribing among clinicians. Within this landscape, opioid stewardship programs in hospitals have become popular, particularly to reduce overall daily morphine equivalent doses, traditional opioid use, and total days of therapy.

 Moreover, pharmacists and physicians have favored the use of nonopioid adjuvants for preemptive analgesia, such as acetaminophen, nerve blocks, nonsteroidal anti-inflammatory drugs, and various sedative-hypnotics.

The FDA approved oliceridine (Olinvyk), a novel centrally acting μ-opioid receptor agonist with reduced β-arrestin recruitment, on August 7, 2020, for managing moderate to severe acute pain in adults who require an intravenous (IV) opioid and for whom alternative treatment is inadequate.

 Oliceridine is a schedule II ethanamine opioid medication structurally different from natural (ie, morphine) and semisynthetic (ie, hydromorphone) opioids and other opioid classes. Conventional opioids activate the μ-opioid receptor, resulting in G protein—mediated analgesia. The receptor activation by established full agonist opioids also leads to recruitment of β-arrestin, which is associated with receptor downregulation and respiratory depression, constipation, and nausea, adverse effects (AEs) of opioids, though the latter 3 have been called into question.

Compared with conventional opioids, oliceridine stimulates G protein signaling with profoundly less β-arrestin activation. The understood receptor activity of a G protein—biased μ-opioid receptor agonism with less β-arrestin recruitment allows this agent to provide analgesia while potentially mitigating the risks of respiratory depression and gastrointestinal (GI) AEs.

Buprenorphine also stimulates the μ-opioid receptor with less β-arrestin recruitment compared with traditional opioids. However, it is more difficult to overcome receptor occupation by buprenorphine with naloxone reversal because the latter has a lower binding affinity compared with buprenorphine. Conversely, oliceridine has been shown be reversed handily by naloxone.

Onset of action for oliceridine is 1 to 3 minutes, making it optimal for managing acute pain. Oliceridine has the same boxed warnings as other opioids, including risks of abuse, addiction, life-threatening respiratory depression, misuse, neonatal opioid withdrawal syndrome if abruptly discontinued, and profound sedation with concomitant use of central nervous system depressants. There is also a risk of QT interval prolongation in doses greater than 27 mg, though studies did not find significant QT interval changes at FDA-approved doses.

Oliceridine is metabolized by cytochrome P450 (CYP) 2D6 and 3A4 to inactive metabolites, and renal dose adjustment is not required. Concomitant use of oliceridine and strong to moderate CYP2D6 (ie, fluoxetine) and CYP3A4 (ie, clarithromycin) inhibitors, along with discontinuation of CYP3A4 inducers, can result in increased plasma concentration of oliceridine, raising the risk of opioid-related AEs and exacerbated respiratory depression. Similarly, there is a greater risk of toxicity in patients expressing CYP2D6 poor metabolizer phenotypes.

 Of note, the effects of enzyme induction are delayed about 3 weeks; enzyme inhibition, about 48 hours.

 Additionally, this medication is intended for acute use in controlled settings, where patients are closely monitored, mitigating some of the risk.

Findings of pivotal trials indicated the efficacy and safety of oliceridine, ultimately leading to its FDA approval. The study results showed improved analgesia with oliceridine compared with the placebo and similar efficacy to morphine. Additionally, less potential for nausea and lower rates of respiratory risk were reported in the oliceridine group than with those receiving morphine. Notably, the trials also showed that AEs of oliceridine, though of less risk than morphine, are dose dependent. Doses greater than 27 mg/day were not evaluated. Oliceridine was not evaluated in several patient populations, including those who have sleep apnea, are obese, or were already receiving chronic opioid therapy; therefore, clinical judgment is required when considering use in these populations.

The novel approach of limiting β-arrestin recruitment has been shown to limit GI and respiratory AEs.6 Oliceridine may be used in emergency department settings or after surgery in patients who require acute pain management. Overall, oliceridine offers an alternative for patients in hospitals or other controlled settings, with moderate to severe acute pain when nonpharmacological and nonopioid options are inappropriate.

 Pharmacists can help ensure the safe use of oliceridine by identifying and appropriately managing drug-drug interactions, particularly CYP medication issues and concomitant use of corrected QT interval—elevating drugs, such as fluoroquinolones. They can also present cost considerations and a risk-versus-benefit evaluation to the team.

, PharmD is a PGY-2 pain and palliative care pharmacy resident, both at Albany Stratton VA Medical Center in New York. 

Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB

, is CEO and founder of Remitigate Therapeutics, LLC, and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts; an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in New York; and the director of the PGY-2 pain and palliative care residency at Albany Stratton VA Medical Center.

Weiner SG, Price CN, Atalay AJ, et. al. A health system-wide initiative to decrease opioid-related morbidity and mortality. 

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Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. 

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FDA approves new opioid for intravenous use in hospitals, other controlled clinical settings. News release. FDA. August 7, 2020. Accessed August 15, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-opioid-intravenous-use-hospitals-other-controlled-clinical-settings

Kliewer A, Gillis A, Hill R, et al. Morphine‐induced respiratory depression is independent of β‐arrestin2 signalling. 

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FDA advisory committee briefing document: oliceridine. FDA. October 11, 2018. Accessed September 2, 2020. https://www.fda.gov/media/121230/download

Raehal KM, Walker JKL, Bohn LM. Morphine side effects in β‐arrestin 2 knockout mice. 

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Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of pain. 

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Olinvyk (oliceridine). Prescribing information. Trevena Inc; 2020. Accessed October 15, 2020. https://www.drugs.com/pro/olinvyk.html

Gudin J, Fudin J. Peripheral opioid receptor antagonists for opioid-induced constipation: a primer on pharmacokinetic variabilities with a focus on drug interactions. 

. 2020;13:447-456. doi:10.2147/JPR.S220859

Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N. APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the μ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy. 

. 2019;12:927-943. doi:10.2147/JPR.S171013

Singla NK, Skobieranda F, Soergel D, et. al. APOLLO-2: a randomized, placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-based ligand at the μ‐opioid receptor, for management of moderate to severe acute pain following abdominoplasty. 

. 2019;19(7):715-731. doi:10.1111/papr.12801

Oliceridine (Olinvyk) expands options for managing moderate to severe acute pain, but cost, drug-drug interactions, and other factors come into play.

Pharmacists Can Help Assess New FDA-Approved IV Opioid

The number of biosimilar agents available for use in clinical practice continues to increase.

As such, institutions are replacing innovator biologics with their biosimilars, often to take advantage of the financial benefits, which can be quite significant for an organization. One analysis estimated that biosimilar approvals will reduce direct spending on biologic drugs by $54 billion between 2017 and 2026.

 When introducing biosimilars into clinical practice, key considerations include acceptance by patients, demonstration of a positive financial analysis, selection of biosimilars most suited to the organization, and buy-in from physicians.

For an organization contemplating a switch from an innovator biologic to its biosimilar, it is critical to ensure buy-in from the physicians who will be ordering the drug for their patients. A recent systematic review of 20 surveys related to aspects of biosimilar use concluded that more education is needed for physicians about biosimilars.

 Pharmacists are the ideal health care professionals to provide this education. When discussing biosimilars with physicians, several key concepts should be conveyed.

Institutions are replacing innovator biologics with their biosimilars, often to take advantage of the financial benefits.

November 2020