Pharmacy Practice News - February 2022

The Best-Read Pharmacist’s News Source

pharmacypracticenews.com

CLINICAL

Helping providers do a better job treating resistant UTIs .....................

Real-world evidence: It’s worth switching to rituximab biosimilar ......

3

By David Wild

4

POLICY

Reimbursement Matters: Pay tips for COVID mAbs, other injectables ................ 17 ASHP forecast 2022: challenges, opportunities amid ongoing pandemic ......

Pharmacist-Led Programs Boost Rapid ART Starts

18

TECHNOLOGY

Thwarting drug diversion through ADCs and readyto-use syringes .............. 24 REVIEW ARTICLE

D

espite the benefits of quickly starting antiretroviral therapy (ART) in people living with HIV, the time between diagnosis and initiation can be dangerously long.

Pharmacists can help shorten this gap as part of a multidisciplinary care team that meets with patients as soon as possible after diagnosis— sometimes on the same day, said Amy Brotherton, PharmD, an assistant professor of medicine at Alpert Medical School of Brown University, in Providence, R.I. Dr. Brotherton helped develop a care model at the hospital’s outpatient HIV clinic, in which a multidisciplinary team that includes pharmacists, nurses, social workers and outreach workers meets with a patient on the day of diagnosis.

The Particulars of Filtering Particulates See page 14.

REVIEW ARTICLE

Medication Errors: The Year in Revew See insert after page 14.

Time to Switch To Race-Free eGFR Renal Test?

By David Wild

U

sing a race-free version of the estimated glomerular filtration rate (eGFR) Chronic Kidney Disease Epidemiology Collaboration serum creatinine (CKD-EPIcr 2021) equation to assess kidney function will help reduce racial and ethnic inequalities in kidney disease management, nephrology pharmacists said during the 2021 annual meeting of the American College of Clinical Pharmacy (ACCP), held virtually.

Continued on page 6

Recent varenicline recall spurs debate

Nitrosamine Risk: Where Are We Now?

By Bruce Buckley

T

he threat of nitrosamine contamination has mostly receded in the past year, as the FDA strengthened its industry guidance for detecting hazardous levels of the carcinogen, and USP followed suit with General Chapter <1469> “Nitrosamine Impurities” (bit.ly/3qGn625).

But the risk hasn’t disappeared. As a result, health systems and other stakeholders are responding with a variety of strategies, including a proposed new evidence-based scoring system that could be used to assess contamination risk and other factors affecting drug safety.

Continued on page 12

Task force pushing for more balanced equations

Volume 49 • Number 2 • February 2022

Continued on page 10

Surveillance Software Spots Elusive Signs of Drug Diversion

By Gina Shaw

A

data analytics program offers pharmacists a powerful new tool for spotting the signs of drug diversion—along with the opportunity for intervening and protecting against repeat offenders, a team reported at the ASHP 2021 Midyear Clinical Meeting and Exhibition, held virtually.

The stakes for preventing diversion are high, noted Jennifer Cimoch, PharmD, an inpatient regulatory clinical pharmacy specialist at the Hospital of the University of Pennsylvania, in Philadelphia, who helped roll out the system at her facility. “There are legal ramifications and liability risks for your hospital, regulatory concerns of fraudulent billing due to inaccurate documentation, and concerns about patient

safety due to inadequate pain relief and/or receiving care from an impaired healthcare worker,” Dr. Cimoch said. Beyond that, “there also is harm to the diverter, and there is negative publicity to your organization.”

In 2020, Dr. Cimoch and her colleagues began to use drug diversion surveillance software developed by Invistics, a company that has received funding from the HEAL (Helping to End Addiction Long-Term) Initiative of the National Institutes of Health.

The software leverages machine learning and advanced analytics to detect opioid and drug theft across nursing and pharmacy departments in hospitals and health systems.

“It monitors drug utilization and disposition

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Continued on page 26

The Best-Read Pharmacist’s News Source

pharmacypracticenews.com

As COVID-19 cases soar …

CLINICAL

Stewardship efforts help reduce AEs during anticoagulation ...............

4

Muscle relaxants and pain a dangerous mix ...

7

F

POLICY

Standardization spurs better system-wide compounding .................

10

OPERATIONS & MGMT

Drug diversion: yet another pandemic challenge ..........................

ISMP survey reveals gaps in compounding compliance ......................

14

16

TECHNOLOGY

Harnessing big data key to ADC-driven inventory control ..........

Health Systems Stay Vigilant To Rx Shortages

24

ro m the be g i n n i n g o f the COVID-19 pandemic, there has been a scramble to meet the soaring demand for critical medications, as infection rates, hospitalizations and deaths surged in hot spots around the country. “There were so many moving parts,” said Meryl Biksacky, PharmD, a drug information specialist at Intermountain Healthcare, in Salt Lake City. “It took a constantly vigilant team approach, with a lot of heads in the mix and a lot of ingenuity.”

Those early efforts at drug shortage team building and troubleshooting at Intermountain and other health systems helped ease the impact of drug supply disruptions, even as infections began to peak again in the fall and winter.

Volume 48 • Number 2 • February 2021

Pharmacist-led Initiatives Save Millions

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Clinical

Pharmacy Practice News • February 2022

3

Infectious Disease

As UTI Drug Resistance Increases, Treatment Choices Critical

By David Wild

W

ith recent data indicating that roughly 60% of antibiotics prescribed for urinary tract infections (UTIs) in the outpatient setting do not conform with clinical guidelines, and some UTI drug resistance rates markedly rising, one expert urged pharmacists to carefully review the appropriateness of UTI prescriptions.

“With a lot of UTI infections comes a lot of antibiotic prescribing, and sometimes our providers don’t do the greatest job [with stewardship],” said Ryan Moenster, PharmD, a clinical pharmacy specialist in infectious diseases, VA St. Louis Health Care System, during the 2021 annual meeting of the American College of Clinical Pharmacy (ACCP), held virtually.

One recent analysis included 44.9 million female outpatient visits for uncomplicated UTIs from 2015 to 2019 and found that only 58.4% of prescriptions for these infections were concordant with treatment guidelines (Am J Obstet Gynecol 2021;225[3]:272. e1-272.e11). “That’s not fanstastic data,” Dr. Moenster said.

Coinciding with those prescribing patterns has been a rise in the prevalence of extended-spectrum cephalosporinresistant urinary Escherichia coli, which increased from 14% to 19% of UTI isolates between 2013 and 2017, he noted (Clin Infect Dis 2021;73[11]:e4552-e4559).

Dr. Moenster urged attendees to review their “go-to stable” of outpatient antibiotics for this indication. “We all know about the unacceptably high rates of fluoroquinolone resistance and the limitations of using that as empiric antibiotic therapy, but less is discussed about trimethoprimsulfamethoxazole [TMP-SMX], nitrofurantoin and fosfomycin,” he said.

Regarding TMP-SMX, a hospital study conducted in South Carolina revealed that roughly 20% of 351 patients with community-onset UTIs had Enterobacterales isolates with resistance to the agent (J Glob Antimicrob Resist 2020;21:218-222). Use of TMPSMX in the prior 12 months was associated with a 2.58-fold increased risk for Enterobacterales resistance to the drug, the researchers found (P=0.02).

A randomized controlled trial shed light on the efficacy of nitrofurantoin and fosfomycin for the treatment of lower UTIs (JAMA 2018;319[17]:1781-1789). Specifically, 70% of patients who received a five-day course of nitrofurantoin and 58% given a single dose of fosfomycin experienced a clinical response at 28 days (P=0.004), while 74% and 63%, respectively, experienced a microbiological response (P=0.04).

However, “we can’t talk about these agents without talking about some of their notable limitations,” Dr. Moenster stressed. For example, some patients have an allergy to TMP-SMX, while there is a

14% ➡ 19% The increase in prevalence of extended-spectrum cephalosporin-resistant urinary Escherichia coli between 2013 and 2017 Source: Clin Infect Dis 2021;73(11):e4552-e4559.

risk for renal dysfunction with the drug, he said. As for nitrofurantoin, one limitation is its “relatively high” creatinine clearance cutoff (<60 mL per minute), as indicated in the package insert. Additionally, nitrofurantoin and fosfomycin are not recommended for pyelonephritis, Dr. Moenster noted. Furthermore, only the single-dose regimen of fosfomycin is FDA approved, “although clinicians do use alternative dosing recommendations for certain patients,” he said.

Dr. Moenster also urged attendees to consider their own local resistance rates when choosing an outpatient UTI treatment. For example, in 2020, the VA St. Louis Health Care System identified high levels of E. coli susceptibility to nitrofurantoin (92%) but lower levels of susceptibility to TMP-SMX (72%).

“This is one of the best examples I can think about in terms of basing your decisions on your local antibiogram,” Dr. Moenster said.

EDITORIAL BOARD ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

Lisa Dumkow, PharmD, the antimicrobial stewardship program director at Mercy Health Saint Mary’s, in Grand Rapids, Mich., echoed the importance of selecting outpatient UTI treatments based on local antibiograms.

“We try to avoid treating asymptomatic bacteriuria and stress the importance of using nitrofurantoin as first-line therapy whenever possible, limiting the use of cephalosporin agents to patients who do not qualify for nitrofurantoin,” she said.

“It’s a delicate balance with our firstgeneration cephalosporins, because while their empiric chance of targeting our urinary pathogens is high—based on our local antibiogram—there is also a big risk of increasing ESBL [extended-spectrum beta-lactamase] rates with overuse.”

Dr. Dumkow reported no relevant financial disclosures. Dr. Moenster reported financial relationships with Allergan-AbbVie and Shionogi.

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4 Clinical

Finance

The Case for Switching to Rituximab Biosimilar

By David Wild

S

witching from originator rituximab (Rituxan, Genentech) to rituximab-abbs (Truxima, Teva) can save an institution up to $13,000 annually per patient while maintaining efficacy and safety, according to two studies presented at the 2021 virtual annual meeting of the American Society of Clinical Oncology (ASCO).

“The findings provide important realworld evidence and should help physicians build confidence in the clinical equivalence of biosimilar rituximab,” said Sandra Cuellar, PharmD, a clinical ambulatory pharmacist and clinical associate professor of pharmacy practice at the University of Illinois Chicago, who was not involved in the research.

In one study, Elizabeth James, PharmD, the director of health economics and outcomes research at Aventine Consulting, in Marblehead, Mass., and her co-investigators estimated the

annual cost savings if rituximab-abbs uptake increased from the 17.5% rituximab market share it had in 2020 to 22%, which Teva forecast it would achieve in 2021 (abstract e18820).

Using a model that included a hypothetical population of 1 million Medicare-insured patients and used existing prevalence rates of various disease states treated with rituximab, the team estimated 90 patients would have non-Hodgkin lymphoma (NHL), 96 patients would have chronic lymphocytic leukemia (CLL), 461, rheumatoid arthritis, and 273, granulomatosis with polyangiitis or microscopic polyangiitis.

Their assumptions considered the 2020 average sales price (ASP) file and the Centers for Medicare & Medicaid Services Physician Fee Schedule, as well as other factors. The researchers did not factor in utilization data for rituximabpvvr (Ruxience, Pfizer), launched in January 2020, and rituximab-arrx

‘After waiting for a long time for oncology biosimilars to be launched, we now have three rituximab biosimilars in the United States, and we’ve seen them take on an increasing share of the rituximab market.’

—Sandra Cuellar, PharmD

Table 1. Annual Savings for Patients Receiving Truxima Indication

Savings, $

NHL (untreated FL with maintenance)

12,924

NHL (untreated FL without maintenance, relapsed or refractory FL, or untreated diffuse large B-cell lymphoma)

10,339

CLL

9,845

Rheumatoid arthritis

7,602

Granulomatosis with polyangiitis or microscopic polyangiitis

5,474

NHL (2-year maintenance)

15,509

CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; NHL, non-Hodgkin lymphoma Source: 2021 virtual annual meeting of the American Society of Clinical Oncology, abstract e18820.

Table 2. Efficacy of Truxima and Originator Rituximab in CLL and NHL Patients CLL

NHL

Outcome

Truxima

Rituxan

Truxima

Rituxan

Overall response rate, %

97.9

93.9

94

95.9

Complete response, %

64.6

67.3

68

73.5

Partial response, %

33.3

26.5

26

22.4

Stable disease, %

0

6.1

4

2

Progression, %

2.1

0

2

2

CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin lymphoma Source: 2021 virtual annual meeting of the American Society of Clinical Oncology, abstract e18696.

(Riabni, Amgen), approved in December 2020. However, Dr. James noted that uptake of those agents likely would have been slow initially, and, thus, she did not think they would change the results significantly.

According to their analysis, a 4.5% increase in market share of rituximababbs—equal to 41 additional patients in their study population using the biosimilar—would lead to an estimated savings of $312,379. Patient-specific savings would vary from $5,474 to $12,924, depending on the indication (Table 1).

According to Dr. James, the results demonstrate that an incremental switch to rituximab-abbs “provides the opportunity for payors and patients to reduce their drug expenditures.”

She said biosimilars reimbursed under the medical benefit will likely see additional “downward pricing pressure, since ASP pricing often decreases when ASP is calculated each quarter.”

She also predicted that “as biosimilars begin earning FDA interchangeable status—as glargine-yfgn [Semglee, Viatris] did in July—we’ll see pharmacists be able to dispense biosimilars without requesting a change,” facilitating their use.

Safety and Efficacy in U.K. Population Data from a separate study presented at the ASCO meeting documented the cost and clinical impact of rituximababbs use in the United Kingdom (abstract e18696).

Ali McBride, PharmD, the director of WW HEOR Markets, U.S. Hematology at Bristol Myers Squibb, and his coinvestigators gathered effectiveness and safety data from 46 hematologists and oncologists who had treated 201 CLL or NHL patients with either rituximababbs or originator rituximab between January 2018 and June 2019. The originator and biosimilar groups were demographically similar.

According to the researchers, both originator and biosimilar rituximab resulted in similar clinical outcomes (Table 2), and there were no significant differences in adverse events (AEs) between patients receiving the two agents. Specifically, 54% to 66% of patients in the cohorts experienced grade 3 or higher AEs during treatment, and neutropenia, fatigue, anemia and infusion reactions were the most common serious AEs with either agent, they reported.

Looking at the specific cost impact of rituximab-abbs use in the United Kingdom, Dr. McBride’s team documented a mean annual savings of roughly 1,000 pounds (roughly $1,370) per patient when rituximab-abbs was used instead of the originator product.

4.5% 4 5% increase in market share of rituximab-abbs would lead to an annual estimated savings of

$312,379 Source: 2021 virtual annual meeting of the American Society of Clinical Oncology, abstract e18820.

Dr. Cuellar noted that Dr. McBride’s team did not look at survival data, which “may be the most important clinical outcome for physicians.” However, she noted that this outcome is not a required end point for FDA approval.

Dr. Cuellar said she is optimistic that biosimilar-related savings will continue to grow. “I’m encouraged that after waiting for a long time for oncology biosimilars to be launched, we now have three rituximab biosimilars in the United States, and we’ve seen them take on an increasing share of the rituximab market,” she said.

Dr. Cuellar pointed to research she and her co-investigators conducted, in which they looked at overall U.S. rituximab sales data from 2020 and found that biosimilars of the agent in that year accounted for 18.3% of rituximab used in the clinic setting and 16.5% of rituximab used in non–Veterans Affairs community and private hospitals (Am J Health Syst Pharm 2021;78[14]:1294-1308).

The team, led by Eric Tichy, PharmD, MBA, the vice chair of pharmacy supply solutions at Mayo Clinic in Rochester, Minn., did not parse the data by specific biosimilars.

She predicted that “we’ll continue to see more hospitals and health systems integrate oncology biosimilars into their operations.”

Dr. Cuellar reported a financial relationship with Pfizer. Dr. James reported a financial relationship with Aventine Consulting. Dr. McBride is an employee of Bristol Myers Squibb.

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6 Clinical

Pharmacy Practice News • February 2022

Nephrology

A Race-Free Equation continued from page 1

A joint task force of the American Society of Nephrology and National Kidney Foundation recommended the equation as the most balanced race-free calculation, the pharmacists said. The task force also recommended adding cystatin C as a variable in the equation when testing for the biomarker is available.

“It’s really important for us as pharmacists to advocate for these task force recommendations and facilitate implementation of the recommended equations in our clinical labs, incorporating cystatin C when possible,” said Wendy St. Peter, PharmD, a professor at the University of Minnesota College of Pharmacy in Minneapolis.

said. “Race is a social construct, and there’s no evidence that shows that, for instance, Black people have different physiology around kidney elimination than others do.”

Rather than biological differences, racial disparities in kidney health likely reflect other factors, such as a higher prevalence of hypertension and diabetes among Blacks, she noted (NCHS Data Brief No. 289, October 2017; bit. ly/3fY6k8w). Nevertheless, including race in the CKD-EPIcr 2009 and MDRD (modification of diet in renal disease) eGFR equations historically improved the performance of these equations in Blacks in the United States, largely because

average by 3.7 mL/minute/1.73 m2 in Blacks, compared with an average overestimation of 0.5 mL/minute/1.73 m2 in non-Blacks—potentially leading to disparities in CKD care, Dr. St. Peter noted (N Engl J Med 2021;385[19]:1737-1749).

Removal Not a Perfect Solution Although including race in these equations has been problematic, simply removing the race modifier from eGFR equations has been a less than perfect solution, said Linda Awdishu, PharmD, a professor of clinical pharmacy at the University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, in La Jolla.

“Removal of the race coefficient from GFR-estimating equations has usually resulted in underestimation of the measured value,” she said, cit-

among Blacks, with 90.5% of all eGFR values falling within the acceptable range of 30% of their measured GFR (N Engl J Med 2021;385[19]:1737-1749).

The task force recommended the equation after reviewing 26 eGFR equations. However, because cystatin C is not available to all labs, the task force recommended providers use the race-free CKD-EPIcr 2021 equation and measure cystatin C when available.

“The task force’s recommended 2021 CKD-EPIcr equation is an improvement in that it is formulated without race, is almost as accurate as the CKD-EPIcr 2009 equation and is not more biased in Blacks compared with non-Blacks,” Dr. St. Peter said.

However, the performance of the new CKD-EPIcr-cys 2021 equation is “even better,” she stressed, and including both

‘Race is a social construct, and there’s no evidence that shows that, for instance, Black people have different physiology around kidney elimination than others do.’

—Wendy St. Peter, PharmD creatinine and cystatin C improves the accuracy of the equation, defined as the proportion of eGFR values within 30% of measured GFR, and is associated with less bias, defined as the median difference between estimated and measured GFR, among Blacks and non-Blacks.

When it comes to making “critical medication-related decision making,” including both serum creatinine and cystatin C “may be a better choice,” Dr. St. Peter said.

Role of Pharmacists Racial and ethnic disparities “abound in chronic kidney disease,” she said, pointing to a 3.4-fold higher prevalence of end-stage kidney disease among Black people documented in a United States Renal Data System annual report (bit.ly/33y5rAX). Self-identified Blacks with kidney disease also experience earlier and steeper declines in kidney function, compared with whites, “even though they start out at a higher eGFR than whites,” Dr. St. Peter said (Am J Kidney Dis 2013;62[2]:261-266).

“Blacks are also less likely to see their nephrologist before requiring dialysis, less likely to be treated with home dialysis, and less likely to be wait-listed and receive a kidney transplant,” she added (J Am Soc Nephrol 2016;27[7]:2123-2134).

Environment or Biology?

These disparities are more a product of environment than biological differences, which the medical community is increasingly recognizing, Dr. St. Peter

serum creatinine levels are higher in this population relative to the same measured GFR in non-Blacks in the United States.

“While it’s not clear why that is, serum creatinine levels are impacted by nonGFR determinants such as muscle mass, age, sex, protein or creatine ingestion, and some medications,” Dr. St. Peter noted.

A Race Modifier for eGFR Equations According to Dr. St. Peter, the problem of race in kidney disease evaluation goes back for decades. The first eGFR equation—the Cockcroft-Gault equation—was developed in 1973 using a homogeneously white population, leading the equation to underestimate measured GFR in Blacks.

Subsequent eGFR equations, such as the CKD-EPIcr 2009, tried to account for increased serum creatinine values among the Black population, including race as a coefficient. But that equation overestimated measured GFR on

ing data such as an analysis of the large National Health and Nutrition Examination Survey database. According to the analysis, eGFR among Black adults was a median 14.1 mL/minute/ 1.73 m2 lower when race was excluded from an equation than when it was included. This potentially increases the prevalence of CKD in Blacks from 14.9% to 18.4%, and reclassifies 29% of Blacks with kidney disease to more severe kidney disease stages—potentially affecting the choice of medications (JAMA 2021;325[19]:2018-2019).

Cystatin C Recent studies on the accuracy of several new race-free eGFR equations found that including both serum creatinine and cystatin C in a race-free eGFR equation was substantially more accurate than using either serum creatinine or cystatin C alone, Dr. St. Peter said.

Specifically, this equation underestimated GFR by only 0.1 mL/minute/1.73 m2

Rebecca Maxson, PharmD, an associate clinical professor at Auburn University Harrison School of Pharmacy, in Alabama, echoed the need to include cystatin C when assessing kidney function.

“Pharmacists need to be on the forefront of educating other healthcare providers about the importance of adding cystatin C into the equation, whether through grand rounds presentations, in the classroom, or on P&T [pharmacy and therapeutics] and lab committees,” Dr. Maxson said.

“Better GFR estimates lead to improved direct patient care through better dosing,” she stressed during the ACCP presentation.

The sources reported no relevant financial disclosures. This article was reviewed by Stacey McCoy, PharmD, MS, BCPS, the pharmacy clinical program manager for Clinical Surveillance & Compliance, Wolters Kluwer Health; and Rachel Eyler, PharmD, BCPS, the nephrology senior content specialist for Clinical Effectiveness, Wolters Kluwer Health.

UNANIMOUSLY RECOMMENDED BY THE ACIP1

PROTECTING YOUR ADULT PATIENTS FROM HEPATITIS B

IS AS EASY AS

HEPLISAV-B IS THE ONLY 2-DOSE, 1-MONTH HEPATITIS B VACCINE FOR ADULTS2,3 INDICATION HEPLISAV-B is indicated for prevention of infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

IMPORTANT SAFETY INFORMATION Do not administer HEPLISAV-B to individuals with a history of severe allergic reaction (e.g., anaphylaxis) after a previous dose of any hepatitis B vaccine or to any component of HEPLISAV-B, including yeast.

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of HEPLISAV-B. Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to HEPLISAV-B. Hepatitis B has a long incubation period. HEPLISAV-B may not prevent hepatitis B infection in individuals who have an unrecognized hepatitis B infection at the time of vaccine administration.

The most common patient-reported adverse reactions reported within 7 days of vaccination were injection site pain (23%-39%), fatigue (11%-17%), and headache (8%-17%).

Please see Brief Summary of full Prescribing Information on the following pages.

heplisavb.com

2 DOSES. 1 MONTH. DONE.2

Abbreviation: ACIP, Advisory Committee on Immunization Practices.

REFERENCES: 1. Schillie S, Harris A, Link-Gelles R, Romero J, Ward J, Nelson N. Recommendations of the Advisory Committee on Immunization Practices for use of a hepatitis B vaccine with a novel adjuvant. MMWR Morb Mortal Wkly Rep. 2018;67(15):455-458. 2. HEPLISAV-B [package insert]. Emeryville, CA: Dynavax Technologies Corporation; 2020. 3. Freedman M, Kroger A, Hunter P, Ault KA. Recommended Adult Immunization Schedule, United States, 2020. Ann Intern Med. 2020;172(5):337-347.

© 2022 Dynavax Technologies Corporation.

All rights reserved. January 2022 US-21-00-00225

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION

Table 1 Study 1: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination

HEPLISAV-B [Hepatitis B Vaccine (Recombinant), Adjuvanted] Solution for Intramuscular Injection 1 INDICATIONS AND USAGE HEPLISAV-B is indicated for prevention of infection caused by all known subtypes of hepatitis B virus. HEPLISAV-B is approved for use in adults 18 years of age and older.

2 DOSAGE AND ADMINISTRATION For intramuscular administration.

2.1 Dose and Regimen Administer two doses (0.5 mL each) of HEPLISAV-B one month apart.

2.2 Administration HEPLISAV-B is a clear to slightly opalescent, colorless to slightly yellow solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.

Administer HEPLISAV-B by intramuscular injection in the deltoid region using a sterile needle and syringe.

3 DOSAGE FORMS AND STRENGTHS HEPLISAV-B is a sterile solution for injection available in 0.5 mL single-dose prefilled syringes. [see How Supplied/Storage and Handling (16.1)].

4 CONTRAINDICATIONS Do not administer HEPLISAV-B to individuals with a history of severe allergic reaction (e.g. anaphylaxis) after a previous dose of any hepatitis B vaccine or to any component of HEPLISAV-B, including yeast [see Description (11)].

5 WARNINGS AND PRECAUTIONS 5.1 Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of HEPLISAV-B. 5.2 Immunocompromised Individuals Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to HEPLISAV-B. 5.3 Limitations of Vaccine Effectiveness Hepatitis B has a long incubation period. HEPLISAV-B may not prevent hepatitis B infection in individuals who have an unrecognized hepatitis B infection at the time of vaccine administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

A total of 9597 individuals 18 through 70 years of age received at least 1 dose of HEPLISAV-B in 5 clinical trials conducted in the United States, Canada, and Germany. Data from 3 of these trials are provided below.

Study 1 in Subjects 18 through 55 Years of Age Study 1 was a randomized, observer-blind, active-controlled, multicenter study in Canada and Germany in which 1810 subjects received at least 1 dose of HEPLISAV-B and 605 subjects received at least 1 dose of Engerix-B® [Hepatitis B Vaccine (Recombinant)].

Enrolled subjects had no history of hepatitis B vaccination or infection. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months.

Engerix-B was given at 0, 1, and 6 months. In the total study population, the mean age was 40 years; 46% of the subjects were men; 93% were white, 2% black, 3% Asian and 3% Hispanic; 26% were obese, 10% had hypertension, 8% had dyslipidemia, and 2% had diabetes mellitus. These demographic and baseline characteristics were similar in both vaccine groups.

Solicited Local and Systemic Adverse Reactions Subjects were monitored for local and systemic adverse reactions using diary cards for a 7-day period starting on the day of vaccination. The percentages of subjects who reported local and systemic reactions are shown in Table 1.

Table 1 Study 1: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination

Reaction Local

Engerix-B %

Post-Dose*

Post-Dose*

1

2

1

2

3

Headache

16.9

12.8

19.2

12.3

9.5

Malaise

9.2

7.6

8.9

6.5

6.4

N=1784

N=1764

N=596

N=590

N=561

1.1

1.5

1.8

1.7

1.8

Reaction

Fever‡

Note: only subjects having data are included. Clinical trial number: NCT00435812 *HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Engerix-B was given at 0, 1, and 6 months † Redness and swelling ≥ 2.5 cm. ‡ Oral temperature ≥ 100.4°F (38.0°C).

Unsolicited Adverse Events: Unsolicited adverse events within 28 days following any injection, including placebo, were reported by 42.0% of HEPLISAV-B recipients and 41.3% of Engerix-B recipients.

Serious Adverse Events (SAEs) Subjects were monitored for serious adverse events for 7 months after the first dose of vaccine. The percentage of subjects reporting serious adverse events was 1.5% in the HEPLISAV-B group and 2.1% in the Engerix-B group. No acute myocardial infarctions were reported. No deaths were reported.

Potentially Immune-mediated Adverse Events Potentially immune-mediated adverse events that occurred within 7 months of the first dose of vaccine were reported in 0.2% (n = 4) of HEPLISAV-B recipients and 0.7% (n = 4) of Engerix-B recipients. The following events were reported in the HEPLISAV-B group in one subject each: granulomatosis with polyangiitis, lichen planus, Guillain-Barré syndrome, and Grave’s disease. The following events were reported in the Engerix-B group in one subject each: Bell’s palsy, Raynaud’s phenomenon, and Grave’s disease. One additional Engerix-B recipient with a history of mixed connective tissue disease had p-ANCA-positive vasculitis.

Study 2 in Subjects 40 through 70 Years of Age Study 2 was a randomized, observer-blind, active-controlled, multicenter study in Canada and the United States in which 1968 subjects received at least 1 dose of HEPLISAV-B and 481 subjects received at least 1 dose of Engerix-B. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Enrolled subjects had no history of hepatitis B vaccination or infection. Engerix-B was given at 0, 1, and 6 months. In the total population, the mean age was 54 years; 48% of subjects were men; 82% were white, 15% black, 1% Asian and 6% Hispanic; 44% were obese, 30% had hypertension, 30% had dyslipidemia, and 8% had diabetes mellitus. These demographic and baseline characteristics were similar in both vaccine groups.

Solicited Local and Systemic Adverse Reactions Subjects were monitored for local and systemic adverse reactions using diary cards for a 7-day period starting on the day of vaccination. The percentages of subjects who experienced local and systemic reactions are shown in Table 2.

Table 2 Study 2: Percent of Subjects Who Reported Local or Systemic Reactions Within 7 Days of Vaccination HEPLISAV-B %

Engerix-B %

Post-Dose*

Post-Dose*

1

2

1

2

3

N=1952

N=1905

N=477

N=464

N=448

Injection Site Pain

23.7

22.8

18.4

15.9

13.8

Injection Site Redness†

0.9

0.7

0.6

0.2

0.2

Injection Site Swelling†

0.9

0.6

0.6

0.6

0.2

Reaction Local

Systemic

HEPLISAV-B %

Engerix-B %

Fatigue

12.6

10.8

12.8

12.1

9.4

Post-Dose*

Post-Dose*

Headache

11.8

8.1

11.9

9.5

8.5

3

Malaise

7.7

7.0

8.6

7.1

5.1

Myalgia

8.5

6.4

9.6

8.0

4.5

N=1923

N=1887

N=472

N=459

N=438

1

2

1

2

N=1810

N=1798

N=605

N=603

N=598

Injection Site Pain

38.5

34.8

33.6

24.7

20.2

Injection Site Redness†

4.1

2.9

0.5

1.0

0.7

Injection Site Swelling†

2.3

1.5

0.7

0.5

0.5

17.4

13.8

16.7

11.9

10.0

Systemic Fatigue

HEPLISAV-B %

Fever‡ 0.6 0.6 0.6 0.9 0.7 Note: only subjects having data are included. Clinical Trial Number: NCT01005407 *HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Engerix-B was given at 0, 1, and 6 months † Redness and swelling ≥2.5 cm. ‡ Oral temperature ≥ 100.4°F (38.0°C).

Unsolicited Adverse Events Unsolicited adverse events within 28 days following any injection, including placebo, were reported by 35.4% of HEPLISAV-B recipients and 36.2% of Engerix-B recipients.

Serious Adverse Events Subjects were monitored for serious adverse events for 12 months after the first dose of vaccine. The percentage of subjects reporting serious adverse events was 3.9% in the HEPLISAV-B group and 4.8% in the Engerix-B group. Acute myocardial infarction occurred in 0.1% (n=2) of HEPLISAV-B recipients and 0.2% (n=1) of Engerix-B recipients.

Autoimmune Adverse Events Subjects were monitored for the occurrence of new-onset potentially immune-mediated adverse events for 12 months after the first dose of vaccine. Events were adjudicated as to whether they were autoimmune by an external group of experts blinded to treatment assignment. As determined by the adjudicators, new-onset autoimmune adverse events were reported in 0.2% (n=3) of HEPLISAV-B recipients: two subjects with hypothyroidism and one subject with vitiligo. None of these events was considered related to vaccination by the expert group. No new-onset autoimmune adverse events were reported in the Engerix-B group. Although not referred to the external group of experts, one HEPLISAV-B recipient was determined to have Tolosa-Hunt syndrome which is presumed to have an immune-mediated etiology. This event was not considered related to vaccination.

Deaths One subject (0.05%) died of a pulmonary embolism in the HEPLISAV-B group and 1 subject (0.2%) died of heart failure in the Engerix-B group. Neither death was considered related to vaccination.

Study 3 in Subjects 18 through 70 Years of Age Study 3 was a randomized, observer-blind, active-controlled, multicenter study in the United States in which 5587 subjects received at least 1 dose of HEPLISAV-B and 2781 subjects received at least 1 dose of Engerix-B. Enrolled subjects had no history of hepatitis B vaccination or infection. HEPLISAV-B was given as a 2-dose regimen at 0 and 1 month followed by saline placebo at 6 months. Engerix-B was given at 0, 1, and 6 months. In the total study population, the mean age was 50 years; 51% were men; 71% were white, 26% black, 1% Asian, and 9% Hispanic; 48% were obese, 36% had hypertension, 32% had dyslipidemia, and 14% had type 2 diabetes mellitus. These demographic and baseline characteristics were similar in both vaccine groups.

Unsolicited Medically-Attended Adverse Events Subjects were monitored for unsolicited medically-attended adverse events, those for which a subject sought medical care, for 13 months after the first dose of vaccine. Overall, medically-attended adverse events were reported in 46.0% of HEPLISAV-B recipients and 46.2% of Engerix-B recipients. Herpes zoster was reported in 0.7% of HEPLISAV-B recipients and 0.3% of Engerix-B recipients. Unsolicited medically-attended adverse events within 28 days following any injection, including placebo, were reported by 20.1% of both HEPLISAV-B and Engerix-B recipients.

Serious Adverse Events Subjects were monitored for serious adverse events for 13 months after the first dose of vaccine. The percentage of subjects who reported serious adverse events was 6.2% in the HEPLISAV-B group and 5.3% in the Engerix-B group. Acute myocardial infarction (AMI) was reported in 0.25% (n=14) of HEPLISAV B recipients and 0.04% (n=1) of Engerix-B recipients. An analysis of serious adverse events likely representing myocardial infarction (MI) was conducted using the standard Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) for MI. This analysis identified a total of 19 HEPLISAV-B subjects (0.3%) and 3 Engerix-B subjects (0.1%) with events included in the SMQ for MI (these events include the 15 reports of AMI). Additional evidence, including information on temporal relationship and baseline risk factors, does not support a causal relationship between HEPLISAV-B administration and AMI. Among the 19 events identified as MI in HEPLISAV-B recipients, three occurred within 14 days, nine occurred within 53-180 days, and seven occurred more than 180 days following any dose of HEPLISAV-B. Among the three events identified as MI in Engerix-B recipients, one each occurred 13, 115, and 203 days following any dose. All 19 HEPLISAV-B recipients and 3 Engerix-B recipients reported one or more baseline risk factors for cardiovascular disease.

Autoimmune Adverse Events Subjects were monitored for the occurrence of new-onset potentially immune-mediated adverse events for 13 months after the first dose of vaccine. Events were adjudicated as to whether they were autoimmune by an external group of experts who were blinded to treatment assignment. As determined by the adjudicators, new-onset autoimmune adverse events were reported in 0.1% (n=4) of HEPLISAV-B recipients [one each of: alopecia areata, polymyalgia rheumatica, ulcerative colitis, and autoimmune thyroiditis (with concurrent diagnosis of papillary thyroid carcinoma)]. None of these events was considered to be related to vaccination by the external experts. No new-onset autoimmune adverse events were reported in the Engerix-B group.

Deaths During the study death was reported in 25 subjects (0.4%) in the HEPLISAV-B group and 7 subjects (0.3%) in the Engerix-B group. No death was considered related to vaccination.

7 DRUG INTERACTIONS 7.1 Use with Immune Globulin There are no data to assess the concomitant use of HEPLISAV-B with immune globulin.

When concomitant administration of HEPLISAV-B and immune globulin is required, they should be given with different syringes at different injection sites.

7.2 Interference with Laboratory Tests Hepatitis B surface antigen (HBsAg) derived from hepatitis B vaccines has been transiently detected in blood samples following vaccination. Serum HBsAg detection may not have diagnostic value within 28 days after receipt of HEPLISAV-B.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to HEPLISAV-B during pregnancy. Women who receive HEPLISAV-B during pregnancy are encouraged to contact 1-844-443-7734.

Risk Summary All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In clinically recognized pregnancies in the US general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20%.

There are no clinical studies of HEPLISAV-B in pregnant women. Available human data on HEPLISAV-B administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

In a developmental toxicity study, 0.3 mL of a vaccine formulation containing 2.5 mcg HBsAg and 3000 mcg cytosine phosphoguanine (CpG) 1018 adjuvant was administered to female rats prior to mating and during gestation. These animal studies revealed no evidence of harm to the fetus due to this vaccine formulation [see Data].

Data Animal data Developmental toxicity studies were conducted in female rats. Animals were administered 0.3 mL of a vaccine formulation containing 2.5 mcg HBsAg and 3000 mcg CpG 1018 adjuvant twice prior to mating, and on gestation days 6 and 18 (a single human dose of HEPLISAV-B contains 20 mcg HBsAg and 3000 mcg CpG 1018 adjuvant). No adverse effects on pre-natal and post-natal development up to the time of weaning were observed.

There were no vaccine-related fetal malformations or variations observed.

8.2 Lactation Risk Summary It is not known whether HEPLISAV-B is excreted in human milk. Data are not available to assess the effects of HEPLISAV-B on the breastfed infant or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HEPLISAV-B and any potential adverse effects on the breastfed child from HEPLISAV-B or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use Safety and effectiveness of HEPLISAV-B have not been established in individuals less than 18 years of age.

8.5 Geriatric Use Clinical trials included 909 adults 65 through 70 years of age who received HEPLISAV-B. Among subjects who received HEPLISAV-B, a seroprotective level of antibody to HBsAg was achieved in 90% of those 65 through 70 years of age compared to 96% of those aged 18 through 64 years of age.

Safety and effectiveness of HEPLISAV-B in adults older than 70 years of age were extrapolated from findings in subjects younger than 70 years of age.

8.6 Adults on Hemodialysis Safety and effectiveness of HEPLISAV-B have not been established in adults on hemodialysis.

17. PATIENT COUNSELING INFORMATION • Inform vaccine recipient of the potential benefits and risks associated with vaccination, as well as the importance of completing the immunization series.

• Emphasize that HEPLISAV-B contains non-infectious purified HBsAg and cannot cause hepatitis B infection.

• Advise vaccine recipient to report any adverse events to their healthcare provider or to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967 and www.vaers.hhs.gov.

• Provide the Vaccine Information Statements, which are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Manufactured by: Dynavax Technologies Corporation Emeryville, CA 94608 USA © 2020, Dynavax Technologies Corporation. All rights reserved.

US-20-00-00172

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10 Clinical

Pharmacy Practice News • February 2022

Supply Chain

Nitrosamine Risk continued from page 1

Concerns over nitrosamine came to a head in 2019, when Valisure, a New Haven, Conn.–based independent pharmaceutical testing laboratory, exposed unsafe levels of the contaminant in ranitidine and later metformin in a 2019 Citizen’s Petition to the FDA (bit.ly/ 3IeupUE). Since that time, the situation has improved in some specific areas, noted David Light, the company’s CEO. However, “the drug supply chain as a whole continues to lack this real-

an “excellent case study” of proactive company engagement, but questioned whether hypothetical generic Chantix manufacturers “would all have found that issue” if generic varenicline had been approved as a brand substitute, which it hadn’t.

Monitoring the quality and safety of the generic drug supply chain from active pharmaceutical ingredients to finished dosage forms has been a challenge, especially during the COVID-19

‘All hospitals and pharmacies can do is ensure we remove recalled drugs. Without quality ratings and transparency, it’s impossible to purchase for quality.’

—Erin Fox, PharmD ly critical component of independent quality assurance testing,” Mr. Light told Pharmacy Practice News. “That’s a critical missing piece in general.”

And now, he added, “with the COVID-19 pandemic and the scramble to meet supply, I can only imagine that those quality problems are getting worse, and that will likely affect us for some years down the road.”

In June, the issue surfaced anew when Pfizer stopped production of Chantix (varenicline) after batch tests revealed unacceptable levels of a new form of the contaminant: nitrosaminevarenicline. Three months later, the company recalled all lots of the popular smoking cessation medication. Pfizer, together with the FDA, acted swiftly, and the prescription-only drug disappeared from pharmacy shelves.

Mr. Light said Pfizer’s response was

Web Exclusive

pandemic, when overseas and even domestic travel became problematic for FDA inspectors. In March 2020, the agency suspended most foreign and domestic inspections due to the virus, except for “mission-critical inspectional work.” As the omicron variant drove COVID-19 caseloads higher across the country and globally, an FDA spokesperson told Pharmacy Practice News that “we are actively working on an approach for addressing all outstanding inspections.”

The spokesperson added: “In the spirit of transparency, we released a ‘Resiliency Roadmap for FDA Inspectional Oversight’ report detailing not only the effect of the COVID-19 pandemic on our inspectional activities for each regulated commodity in FDA’s portfolio, but also our detailed plan for a more consistent state of operations and our priorities going forward. At this time, we are currently conducting all foreign, preapproval inspection work determined to be Mission Critical, Tier 1, as well as limited Tier 2 inspections on a case-by-case basis.”

Public Confidence at Risk

Reestablishing trust in nitrosaminecontaining products was a major motivation in USP’s decision to implement General Chapter <1469> “Nitrosamine Impurities” in the aftermath of the nitrosamine recalls.

For an exclusive Q&A with Edwin L. Gump, PhD, the group’s lead on the initiative, see expanded version at www.pharmacypracticenews.com.

One potential casualty of widely publicized drug quality issues and recalls may be the public’s confidence in the medicines they take, said Edwin L. Gump, PhD, USP’s vice president, Small Molecules. “With each news headline about the drugs affected by nitrosamine impurities, the public’s trust in the safety of their medicines deteriorated,” Dr. Gump said. “Patients debated whether they were in more danger by taking their medicines than they would be if they stopped.”

He added that although trust in medicine is difficult to measure, “the

impact of a lack of trust has been seen time and again around the world. The length and quality of people’s lives are diminished because, out of fear, they choose to forgo potentially lifesaving treatments.”

Batch Testing Not Feasible For health systems, the volume and diversity of medications they order have made individual batch testing largely infeasible. Eric Tichy, PharmD, MBA, the division chair at Mayo Clinic in Rochester, Minn., said it was “not really practical” for all of the nation’s 5,000 hospitals to be performing their own tests. “The FDA is responsible for making sure these drugs are safe.

That’s their core mission,” he said.

“And if the FDA isn’t doing it,” he added, it should be up to the distributors. “We’re not buying these products from manufacturers. We’re part of a GPO [group purchasing organization].

And there are wholesalers we’re buying these products from. The distributors have the aggregate power” to ensure the quality and safety of the medications they order and ship to customers.

(Except for Steven Lucio, PharmD, of Vizient—see sidebar—distributors and GPOs contacted by Pharmacy Practice News declined to comment or did not respond to requests for interviews.)

Erin Fox, PharmD, BCPS, the senior

director of drug information and support services at the University of Utah Health, in Salt Lake City, stressed the futility that health systems often experience in trying to ensure the quality of medications purchased from multiple sources, many of them overseas.

“With the labeling laws, the drug companies don’t even have to tell us who made the drugs,” Dr. Fox told Pharmacy Practice News. “This is on the drug companies to do their job and FDA to ensure they are compliant. All hospitals and pharmacies can do is ensure we remove recalled drugs. Without quality ratings and transparency, it’s impossible to purchase for quality.”

An Evidence-Based Scoring System That’s not to say, however, that efforts to push for more quality shouldn’t be made. To that end, eight healthcare thought leaders, including Dr. Fox and C. Michael White, PharmD, FCP, FCCP, proposed a system of evidence-based drug quality scores that health systems could rely on to ensure the safety of pharmaceuticals selected for their formularies (bit.ly/3fBPpsh).

Although scrupulous testing at the manufacturer level could ensure the safety of products being shipped, for some drugs, such efforts won’t end the potential for nitrosamine contamination,

Another Call for More Transparency In Manufacturing

S

ince the disclosures of nitrosamine impurities, has regulatory oversight and greater stakeholder awareness improved the safety and quality of the medication supply chain?

Steven Lucio, PharmD, a senior principal for Pharmacy Solutions at Vizient Inc., a healthcare management consulting firm, said the answer is something of a mixed bag.

“The additional awareness across the industry and the increased communication by regulators have helped the overall efforts towards a higher quality supply chain for pharmaceuticals, which is great,” Dr. Lucio told Pharmacy Practice News. “We have had to endure two decades of drug shortages, many of which were presumably attributable to quality manufacturing issues. The attention to supply chain quality, resiliency and the origination point of active pharmaceutical ingredients has been even further heightened during the pandemic. We must continue these efforts to improve quality.”

However, he continued, “even though there is greater awareness of these challenges to medication quality, there still is limited transparency. While FDA may publish certain quality ratings in aggregate,” he added, referring to Figure 4 on page 7 of the FDA’s Office of Pharmaceutical Quality 2019 Annual Report (bit.ly/3tE5C8v), “such information is not available at a manufacturer or product-specific level.”

Vizient is doing its part, he said, by launching the End Drug Shortages Alliance (bit.ly/3FIo8is), which “brings together stakeholders from all aspects of the supply chain to foster collaboration on the transparency, quality and redundancy of supply of pharmaceuticals.”

—B.B.

Clinical

Pharmacy Practice News • February 2022

11

Supply Chain noted Dr. White, the Distinguished Professor of Pharmacy Practice and head, Department of Pharmacy Practice, at the University of Connecticut School of Pharmacy, in Storrs. “One residual risk,” he said, “lies with active ingredients with dimethylamine groups that can break down to form NDMA as they sit on the shelf,” he noted.

“Ranitidine was the first example of drugs with this propensity,” he continued. “The extent to which other drugs with dimethylamine groups have the same risk is not fully known, and more research is needed. This is because a product can leave the manufacturer under the limit, but then exceed it where it cannot be tested before use.

“The main thing health-system pharmacists can do is to ensure that the drugs they have on hand are being stored according to USP standards, and that patients understand the need to abide by expiration dates and store their medication in a cool, dry place in their home,” Dr. White said. “This is especially true of drugs like doxylamine, chlorpheniramine, sumatriptan, nizatidine, diltiazem and tetracycline that have dimethylamine groups in their active ingredients.”

‘The main thing health-system pharmacists can do is to ensure that the drugs they have on hand are being stored according to USP standards, and that patients understand the need to abide by expiration dates and store their medication in a cool, dry place in their home.’

polypharmacy who has several drugs that are near the upper level of acceptable nitrosamine dosage individually but in aggregate exceed this limit considerably.”

He noted that “the upper limit is a single threshold per product and its regular dosing, and is not predicated on the ingestion of several drugs a day, even though for today’s seniors that is just what is occurring.”

The sources reported no relevant financial disclosures.

—C. Michael White, PharmD

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12 Clinical

Pharmacy Practice News • February 2022

Infectious Disease

Pharm-Led ART Starts continued from page 1

When Dr. Brotherton arrived at the clinic, patients were meeting with a provider and starting ART as late as two weeks after diagnosis, she said during a presentation at the 2021 annual meeting of the American College of Clinical Pharmacy (ACCP), held virtually.

“There was minimal pharmacist involvement in the care of patients newly diagnosed with HIV, and I felt there

was potential to leverage pharmacists’ skills to help shorten the time to ART initiation,” said Dr. Brotherton, who is also a clinical pharmacist specialist in infectious diseases at the Miriam Hospital, in Providence.

Under the new model of care, which was implemented in 2019, pharmacists now serve important clinical functions, such as identifying candidates for rapid

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

WARNING: DEATH IN PRETERM INFANTS • Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature.

• Autopsy findings included intravascular fat accumulation in the lungs.

• Preterm infants and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion.

INDICATIONS AND USAGE SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated.

Limitations of Use The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions.

DOSAGE AND ADMINISTRATION The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk Package for admixing only and is not for direct infusion. Prior to administration, transfer to a separate PN container.

CONTRAINDICATIONS Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients.

Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL. WARNINGS AND PRECAUTIONS • Death in Preterm Infants: (see BLACK BOX WARNING) • Hypersensitivity Reactions: SMOFlipid contains soybean oil, fish oil, and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut oil. Signs or symptoms of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and undertake appropriate treatment and supportive measures.

• Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can support microbial growth and is an independent risk factor for the development of catheter-related bloodstream infections. The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions or drugs.

• Fat Overload Syndrome: This is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, fatty liver infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma).

• Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop.

ART, evaluating symptoms, performing physical exams, and assessing risk for treatment-related adverse events and opportunistic infections. Pharmacists also evaluate a patient’s readiness to start treatment, provide counseling and education, and address potential psychosocial barriers to adherence, Dr. Brotherton said.

An important aspect of allowing pharmacists to provide services at the top of their license was adding a collaborative practice agreement and establishing a defined clinical protocol in tandem with the clinic’s physicians, she said.

• Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum.

During prolonged PN administration in patients with renal impairment, the aluminum levels in the patient may reach toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, including preterm infants, who receive parenteral intakes of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products.

• Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction.

• Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome.

• Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment.

Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended.

• Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream.

ADVERSE REACTIONS Most common adverse drug reactions >1% of patients who received SMOFlipid from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device-related infection.

Less common adverse reactions in ) 1% of patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis.

The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Infections and Infestations: infection.

Respiratory, Thoracic and Mediastinal Disorders: dyspnea.

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

DRUG INTERACTIONS Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters.

USE IN SPECIFIC POPULATIONS • Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women.

• Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients.

• Hepatic Impairment: Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure.

OVERDOSE In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid infusion until triglyceride levels have normalized. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum.

REFERENCE: 1. Deckelbaum RJ, et al. Biochemistry (Mosc). 1990;29(5):1136-1142.

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

©2021, Fresenius Kabi USA, LLC. | All rights reserved. | 1252-SMF-05-12/20

“Now, pharmacists can select and initiate ART on the day of the initial clinic visit, and they can order baseline laboratory tests.”

During followup telehealth visits, pharmacists review abnormal lab results with patients, assess treatment tolerability and medication adherence, and when necessary, make treatment recommendations to providers based on their patient encounters.

“Our pharmacists also work with our retail pharmacy and pharmacy technicians to gather financial information and ensure patients have access to medication, whether that is through a manufacturer or through patient assistance programs,” Dr. Brotherton added.

Starting ART as soon as possible for all HIV patients regardless of CD4 count is increasingly being recognized for its benefits, including both reduced time to viral suppression and sustained viral suppression, along with better patient retention in care, according to a meta-analysis co-authored by Sarah M. Michienzi, PharmD, a visiting clinical assistant professor in the Department of Pharmacy Practice at the University of Illinois at Chicago (Curr Infect Dis Rep 2021;23[5]:7). Data on viral suppression were particularly consistent across studies, with one representative trial included in the meta-analysis showing that viral suppression (<400 copies/ mL) at 10 months occurred in 97% of patients given rapid ART within 90 days, versus 72% in patients treated with standard care (relative risk, 1.36; 95% CI, 1.24-1.49) (PLoS Med 2016;13[5]:e1002015).

Dr. Brotherton’s own experience suggests that ART can be successfully incorporated into clinical practice. In a retrospective analysis originally presented at the CROI 2020 (Conference on Retroviruses and Opportunistic Infections) (abstract 498), she detailed outcomes from 55 patients seen at the clinic before the new model and 33 seen after the program was rolled out.

Her team found that all patients seen under the new program had ART initiated on the day of their first clinic visit, compared with an average of 17 days prior to the program’s implementation (P<0.001). Moreover, all of the pharmacists’ recommendations regarding ART regimens were accepted by physicians;

Clinical

Pharmacy Practice News • February 2022

13

Infectious Disease Viral suppression (<400 copies/mL) at 10 months occurred in

97% of patients given rapid ART within 90 days, versus

72% of patients treated with standard care (relative risk, 1.36; 95% CI, 1.24-1.49).

Source: PLoS Med 2016;13(5):e1002015.

pharmacists addressed d medicadii tion access issues for 61% of patients; and the time from clinic intake to viral suppression fell from 81 to 34 days (P=0.001).

Other interventions focused on cost issues, Dr. Brotherton noted. For uninsured or underinsured individuals, for example, pharmacists obtained 30-day manufacturer-provided free trials and also pursued long-term coverage through manufacturers, patient assistance grants or through AIDS drug assistance program/HIV state funding.

“Regardless of method of payment/ coverage, all patients who started ART left the appointment with medication in hand filled at our on-site pharmacy,” she said. “By helping patients access medications, we helped them avoid a total of nearly $500,000 in out-of-pocket costs.”

an appointment for a clinic i f li i visit i i quickly after diagnosis, their providers added space in their schedules

have resources like an on-site 340B pharmacy, but especially if they don’t have case management resources available at their clinic, pharmacists should be familiar with the strategies available to them for accessing ART,” he stressed. Those strategies, he added, can be implemented “through foundation or manufacturer-based patient assistance programs, copay assistance, or statebased HIV drug assistance programs.”

The sources reported no relevant financial disclosures.

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University of Toledo Approach Eric Sahloff, PharmD, helped implement a rapid ART start program in 2017 at the University of Toledo Medical Center’s Ryan White Clinic, where he is a clinical pharmacist. His group also uses pharmacists’ skills, specifically in choosing the optimal ART regimen with the clinic’s medical director, Dr. Sahloff told Pharmacy Practice News. Pharmacists also address insurance issues and enroll patients in assistance programs, he said.

The clinic’s interdisciplinary approach has significantly reduced the time to viral suppression, from a median of 137 days to a median of 76.5 days, according to a comparison of treatment before and after the program’s implementation (Am J Health Syst Pharm 2021;78[suppl 4]:S95-S100).

Moreover, all patients eligible for ART initiated treatment on the day of their first clinic visit, instead of an average of 15 days prior to the program’s implementation, according to the analysis.

Although the outcomes in both clinics were similar, Dr. Sahloff said the Ohio clinic had unique barriers to rapid ART initiation. “One challenge we faced was that many of our patients are diagnosed through the local health department or emergency rooms outside of our clinic, which initially made it difficult to get people into care promptly, and ideally on the same day as they were notified of their HIV diagnosis,” said Dr. Sahloff, who was not involved in the ACCP presentation.

To ensure all patients would have

to accommodate new patients within the 24- to 72-hour window, he said.

Additionally, the clinic contacted local HIV testing partners to emphasize the clinical importance of rapid referral to their clinic and prompt treatment, Dr. Sahloff said.

Getting newly diagnosed patients into care as soon as possible is essential to optimizing ART outcomes, but it has been equally important to ensure all patients have same-day access to medication supplies, Dr. Sahloff said.

“Luckily, as a Ryan White Clinic, we

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14 Clinical

Pharmacy Practice News • February 2022

Review Article

The Particulars of Filtering Particulates

I

n 2016, the Institute for Safe Medication Practices notified clinicians of a change in labeling for lipid injectable emulsions (ILEs) indicating that a 1.2-micron

filter should be used for ILEs infused alone or as part of a parenteral nutrition (PN) admixture.1 Previously, standard practice did not require filtering when an ILE was administered as a sole infusion; however, for more than 2 decades, guidelines required a 1.2-micron filter for total nutrient admixtures (also called TNAs or 3-in-1 admixtures) in which the dextrose/amino acid component and ILE are compounded together in the same container.

In cases where the ILE and dextrose/amino acid components are administered separately, also known as 2-in-1 PN, recommendations varied, with some experts suggesting that the dextrose/amino acid solution be filtered through a 0.22-micron filter and a second 1.2-micron filter be used to infuse the ILE component.2 In other cases, only the dextrose/ amino acid solution was filtered with a 0.22-micron filter, leaving the ILE unfiltered, whereas some placed only a 1.2-micron filter below the Y-site where the dextrose/amino acid solutions and ILE were comingled. The only thing in common in these approaches was that they were driven by consensus.

The manufacturer-issued 2016 directive added to the debate, along with variation—and confusion—in practice that has long been associated with use of filters for PN administration.1 In-line filtration for PN admixtures was initially proposed more than 50 years ago as a strategy for reducing infectious complications associated with PN.3 However, researchers subsequently learned that contaminated PN fluid is rarely the source of infectious complications. Instead, most catheter-related

bloodstream infections (CRBSIs) stem from touch contamination that occurs after the fluid has passed through the filter.4,5 Based on this information, the CDC issued guidelines in 2002 that stated, “Do not use filters routinely for infection-control purposes.”4 By highlighting the limited role that in-line filters play in reducing CRBSIs, the CDC guidelines may have inadvertently created the false impression that in-line filters serve no purpose for PN administration.5,6 However, filters remain important in PN administration. Even as it became clear that filters do not significantly affect infectious complications, the ability of these devices to remove particulate matter emerged as a critically important benefit of filtering PN admixtures.2 Among the first to sound the alarm about the danger of particulate matter in PN admixtures was Puntis et al, who described the unexpected death of an infant who had received a prolonged course of PN.7 In that case report, granulomatous pulmonary arteritis due to particulate matter was thought to contribute to the child’s death. Upon subsequent analysis, the PN formulation was found

PATRICIA WORTHINGTON, MSN, RN Retired Nutrition Support Clinical Nurse Specialist Department of Nursing Thomas Jefferson University Hospital Philadelphia, Pennsylvania

PEGGI GUENTER, PHD, RN, FAAN, FASPEN Special Projects Consultant American Society for Parenteral and Enteral Nutrition

KATHLEEN M. GURA, PHARMD, BCNSP, FASHP, FASPEN, FPPA, FMSHP Manager, Pharmacy Clinical Research Program/Clinical Specialist GI/Nutrition Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

ALLISON BLACKMER, PHARMD, BCPS, BCPPS, FCCP, FASPEN Director, Clinical Practice, Quality, and Advocacy American Society for Parenteral and Enteral Nutrition

to contain approximately 37,000 particles between 2 and 100 micron in size, of which 80% were from the ILE. Then in 1994, the FDA issued a

safety alert to clinicians after receiving a report of 2 deaths and at least 2 cases of respiratory distress related to calcium phosphate precipitation

Table 1. Evolution of Recommendations for Filter Use for PN and ILE Administration 1969: Wilmore and Dudrick recommend filtration for infection control purposes.3 1992: Puntis et al report infant dying due to particulate matter in PN and recommends in-line filtration of PN and lipids.7 1994: The FDA advises use of filters to reduce the hazards of precipitation associated with PN by using a 0.22-micron filter for dextrose/amino acid solutions and 1.2-micron filter for TNA admixtures.2 2002: The CDC recommends against using filters solely for infection control purposes.4 2004: ASPEN Safe Practices for Parenteral Nutrition recommends using 2 filters, but also suggests that when considering particulate and micro-precipitate contamination, a 1.2-micron filter can be used for all PN with or without ILE; 0.22-micron filters could continue to be used for dextrose/ amino acid solutions.9 2016: ILE manufacturers update labeling, requiring filtering all ILE products with 1.2-micron filters.1 2021: ASPEN recommends using a single 1.2-micon in-line filter for all PN administration, both for TNAs and in situations where the dextrose/amino acid component and ILE are administered as separate infusions. PN should never be infused without a filter.10 ASPEN, American Society for Parenteral and Enteral Nutrition; ILE, lipid injectable emulsion; PN, parenteral nutrition; TNA, total nutrient admixture

Clinical

Pharmacy Practice News • February 2022

Review Article

Table 2. Best Practices for Using Filters for PN Administration10 • Prior to compounding, a pharmacist must verify the stability and compatibility of the PN formulation.

• Perform visual inspection of the PN container for evidence of particulate matter or admixture instability, including emulsion cracking for TNAs. • When administering the dextrose/amino acid component of the PN and ILE as separate infusions, the first infusion must be completely set up and the pump programmed for that fluid before setting up the second infusion.

• Avoid coadministration of medications with PN admixtures. When no other option exists, use appropriate flushing techniques before and after the medication is administered.

• When coadministration of medications with PN cannot be avoided, the medication tubing should be attached at a Y-site above the filter.

Medications that should not be filtered should not be administered with PN. • Select a 1.2-micron filter for all PN regimens including TNAs, dextrose/ amino acid admixtures, and ILE. • Observe the manufacturer’s directions for priming the filter before connecting to the patient’s VAD. • Follow the manufacturer’s instructions included with the filter or administration set with in-line filter for priming. Many filters require holding the filter vertically while priming.

• To avoid clogging the filter during setup, consider allowing a small volume of ILE through the administration tubing allowing the ILE to enter the filter. Close the clamp on the ILE administration set (optional).

• Prime the dextrose/amino acid admixture through the administration tubing completely filling the tubing and filter to the distal end of the tubing. This will dilute the ILE present in the filter to avoid clogging.

• Connect the filter to the hub of the patient’s VAD. When administering the dextrose/amino acid component of the PN and the ILE as separate infusions, attach the filter below the Y-site where the infusions meet.

Figure 1. Setup for use of 1.2-micron filter with dextrose/amino acid PN (2-in-1) with ILE as 2 infusions via a Y-site connector.

ASPEN, American Society for Parenteral and Enteral Nutrition; ILE, lipid injectable emulsion; PN, parenteral nutrition Reprinted with permission from ASPEN. Copyright 2021. Worthington P, Gura KM, Kraft MD, et al. Update on the use of filters for parenteral and enteral nutrition: an ASPEN position paper. Nutr Clin Pract.

2021;36(1):29-39.

• Release all clamps and initiate the infusion.

• Schedule filter changes to coincide with the initiation of a new PN admixture.

ASPEN, American Society for Parenteral and Enteral Nutrition; ILE, lipid injectable emulsion; PN, parenteral nutrition; TNAs, total nutrient admixtures; VAD, vascular access device

(CaHPO4 [calcium monohydrogen phosphate]) in peripherally infused, unfiltered TNA solutions.2 Autopsies revealed diffuse microvascular pulmonary emboli containing calcium phosphate, a finding that was subsequently reproduced upon laboratory investigation.8 These findings led the researchers to acknowledge that using a 1.2-micron filter during PN administration could potentially prevent further morbidity and mortality related to particulate matter in PN admixtures. Table 1 provides more information regarding the time line of filter use for PN administration.

Following the 1994 FDA safety alert, guidelines for using filters for PN were issued by a number of professional organizations and manufacturers of PN components.10 Despite this guidance, filter use—regardless of pore size—remains an inconsistent, nonstandardized practice. A survey and gap analysis on ILE administration conducted in 2017 revealed that 10% to 20% of respondents did not adhere to practice guidelines

for filtering ILE.11 The gap analysis revealed far more confusion and considerable variation regarding how in-line filters were used than expected, especially outside of the United States. This suggests that clinicians continue to hold the view that the primary purpose of in-line filters is to protect against infectious complications, while the danger posed by particulate matter is not widely appreciated and often overlooked.

Particulate Load: Size Matters Regardless of fluid type, all IV infusions have the potential for delivering particulate matter into the bloodstream. Calcium–phosphate precipitates, lipid aggregates, silicon fragments, glass shards (from ampules), and other unintended foreign materials can be infused along with the fluid, resulting in complications such as catheter occlusion and phlebitis.5 Endothelial damage also can occur resulting in inflammation and thrombus formation.12 Of the see FILTERING, page 16

Figure 2. Setup for use of 1.2-micron filter with TNA solutions and/or ILE infusions.

ASPEN, American Society for Parenteral and Enteral Nutrition; ILE, lipid injectable emulsion; TNA, total nutrient admixture Adapted from and reprinted with permission from ASPEN. Copyright 2021. Worthington P, Gura KM, Kraft MD, et al. Update on the use of filters for parenteral and enteral nutrition: an ASPEN position paper.

Nutr Clin Pract. 2021;36(1):29-39.

15

16 Clinical

Pharmacy Practice News • February 2022

Review Article

FILTERING continued from page 15

particulates present in IV solutions, more than 50% are between 5 and 15 micron in size and undetectable without magnification.13 Particulates greater than 10 microns may potentially obstruct tissue and lung capillaries; particulates greater than 12 microns cannot be phagocytosed by pulmonary macrophages or reticuloendothelial cells. Only 5% of particles in IV fluids are greater than 50 microns and

visible to the naked eye. Perez et al demonstrated that in-line filters were effective in decreasing particulate load, especially particulates measuring 10 to 25 micron in size.14 Concerns that in-line filters disrupt infusion therapy by becoming clogged are misguided, since such blockages illustrate that the device is working as intended, preventing the infusion of particulates into the patient. Rather than simply removing the occluded filter, it should be removed and replaced with a new filter before resuming the infusion.10

Addressing the Problem: Call For a Practice Change Alarmed by the degree of misinformation surrounding filter use and the potential for error created by the new requirement to filter ILE, the American Society for Parenteral and Enteral Nutrition (ASPEN) convened a task force to review past guidance regarding the filtration of PN, examine the clinical consequences of infusing particulate matter, discuss the challenges and issues related to filtration, and clarify ASPEN’s

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recommendations for the use of filters for PN administration.

The ASPEN task force developed a position paper underscoring the critical importance of using a filter for all PN, at all times.10 The paper outlines best practices for using filters for PN administration, as shown in Table 2. Most important, to alleviate the confusion and errors associated with using 2 filters with different pore sizes, ASPEN recommends using a 1.2-micron in-line filter for administration of all PN infusions: TNAs, dextrose/amino acid solutions, and ILE. For TNAs, place the filter as close to the catheter hub as possible. For dextrose/amino acid solutions, the filter is inserted below the Y-site where the dextrose/amino acid solutions and ILE coinfuse, as shown in Figures 1 and 2. The safety of using a single 1.2-micron filter for PN administration is supported by decades of experience in hospital and home care settings. Simplifying filtering practices in this way also may improve compliance with IV inline filter use overall. The full ASPEN position paper can be accessed at: https://aspenjournals.onlinelibrary. wiley.com/doi/10.1002/ncp.10587.

Key Points

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This activity is jointly provided by Global Education Group and Applied Clinical Education.

CHAIR Charles E. Argoff, MD

FACULTY These activities are supported by an independent educational grant from the Opioid Analgesic REMS Program Companies.

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The ASPEN position paper underscores the important role of inline filters in promoting the safety of PN therapy.10 The core elements identified in the paper include the following: • In-line IV filters serve a critical purpose in reducing exposure to particulate matter during PN therapy.

• Particles greater than 2 micron, which are retained by 1.2-micron filters, appear to pose the most serious risk for adverse consequences.

• Based on the best available evidence and guidance from scientific and regulatory agencies, ASPEN recommends using a 1.2-micron in-line filter for administration of TNAs, dextrose/amino acid solutions, and ILEs. For TNAs, place the filter as close to the catheter hub as possible. For dextrose/amino acid solutions, place the filter below the Y-site where the dextrose/amino acid solutions and ILE coinfuse.

• The safety of using a single 1.2-micron filter for PN administration is supported by decades of experience in hospital and home care settings. This approach alleviates the confusion and errors associated with using 2 filters with different pore sizes. Simplifying filtering practices could potentially increase

Policy

Pharmacy Practice News • February 2022

17

Reimbursement Matters

2022 Payment Updates

COVID-19 Vaccine and mAbs: Billing for Part A A

n often-neglected revenue source are the fees that are available for adminisering an injectable medication or biologic, regardless of whether it was purchased by the provider or obtained at zero cost. If this is unfamiliar territory for you, it’s covered in Module 5 of our Reimbursement Tool Kit (bit.ly/3rS8xI7).

The newly announced ability to bill for the administration of monoclonal antibody (mAb) infusions is a perfect example of how to tap into this underappreciated revenue source—injectable drug administration in the outpatient setting.

A recent article by Novitas Solutions (bit.ly/3KCTGdx) offers useful guidance on how to bill for administering mAbs and COVID-19 vaccines. According to this MAC, beneficiary coinsurance and deductibles for the mAbs will be waived.

When COVID-19 vaccine and mAb doses are provided by the government without charge, be sure to only bill for the administration, with the billed amount at $0.01, or whatever minimum charge your billing system allows.

The authors also say that if the patient

compliance with recommendations for filter use with PN administration.

• Although 1.2-micron filters are not recommended for use as a routine infection control measure, these devices are effective in preventing Candida albicans, a pathogen frequently associated with PN administration, from reaching the patient.

• ASPEN recommends that healthcare organizations that do not filter PN admixtures or ILE reevaluate these decisions and consider the small price of filters compared with increased morbidity and mortality that may result from not filtering ILEs or PN.

References 1.

Cohen MR, Smetzer JL. Selected medication safety risks to manage in 2016– Part I intravenous fat emulsion needs a filter. Hosp Pharm. 2016;51(5):353-357.

2. Lumpkin MM. Safety alert: hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm.

1994;51(11):1427-1428.

3. Wilmore DW, Dudrick SJ. An in-line filter for intravenous solutions. Arch Surg.

1969;99(4):462-463.

4. O’Grady N, Dellinger EP, Gerberding JL, et al. Guidelines for the prevention of intravascular-catheter related infections.

MMWR Recomm Rep. 2002;51(RR-10):1-29.

5. Ball PA. Intravenous in-line filters: filtering the evidence. Curr Opin Clin Nutr Metab Care. 2003;6(3):319-325.

6. Oie S, Kamiya A. Particulate and microbial contamination in in-use admixed

was enrolled in a Medicare Advantage plan in 2020 and 2021, submit the infusion claims to original Medicare, effective Jan. 1, 2022. CMS also offers a useful guidance at go.cms.gov/3C9lzF5.

Keep a Handle on Bundled Payments Here are a few more basics to keep in mind when billing for injectable drugs in the outpatient setting. Although under OPPS, reimbursement for the drug products may be decreasing or be

incorporated into a bundled or packaged payment or even be provided free of charge, payments for injectable drug administration. These new rulings on mAb administration bring the importance of understanding this revenue source to light. Private insurers may offer these add-on payments, too. The CMS definition of ”drug administration,” for the purposes of reimbursement, is a bundle that involves both nursing and pharmacy, and includes: • use of local anesthesia; • starting the IV; • access to IV, catheter or port; • routine tubing, syringe and supplies; • drug preparation; • flushing at completion; and • hydration fluid.

To recoup these charges, there must be a well-oiled mechanism for capturing the data related to drug administration, with the requisite charting being done to substantiate the charges.

Mechanisms for billing drug administration fees for zero-priced drugs need to be a priority.

“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

Revenue cycle functions and IT systems must be built to support this billing. What are the quirks of your computerized billing system? You may need to price the product at anywhere between $0.01 and $1.01 to prevent the system from automatically throwing out the charge. Remember, if drug data are missing, payors will assume that no drug was administered—and that, of course, means no payment.

The entire flow of medication order processing from a reimbursement perspective is shown in the Figure. see mAb BILLING, page 23

parenteral nutrition solutions. Biol Pharm Bull. 2005;28(12):2268-2270.

7. Puntis JW, Wilkins KM, Ball PA, et al. Hazards of parenteral treatment: do particles count? Arch Dis Child.

1992;67(12):1475-1477.

INNOVATION IN

8. Hill SE, Heldman LS, Goo ED, et al. Fatal microvascular pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN J Parenter Enteral Nutr.

1996;20(1):81-87.

SECURE DRUG DELIVERY PREP-LOCK™ TAMPER EVIDENT CAPS

9. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70

Help ensure the safe delivery of your compounds, comply with growing regulations, and enhance patient care.

10. Worthington P, Gura KM, Kraft MD, et al.

Update on the use of filters for parenteral nutrition: an ASPEN position paper. Nutr Clin Pract. 2021;36(1):29-39.

11. Christensen ML, Ayers P, Boullata JI, et al.

Lipid injectable emulsion survey with gap analysis. Nutr Clin Pract. 2017;32(5):694-702.

Strengthen <797> compliance

Ensure the integrity of your compounds with Prep-Lock™ Tamper Evident Caps.

12. Woodhouse CR. Infusion thrombophlebitis: the histological and clinical features. Ann R Coll Surg Engl. 1980;62(5):364-368.

13. Van Boxtel T, Pittiruti M, Arkema A, et al. WoCoVA consensus on the clinical use of in-line filtration during intravenous infusions: current evidence and recommendations for future research. J Vasc Access. 2021 Jan 28. doi:10.1177/1129729821989165

Maintain Sterility

Evidence of access indicates the potential compromise of content sterility.

14. Perez M, Decaudin B, Abou Chahla W, et al.

Effectiveness of in-line filters to completely remove particulate contamination during a pediatric multidrug infusion protocol. Sci Rep. 2018;8(1):7714.

Mitigate Diversion

Serves as an active deterrent to potential diversion and misuse.

Additional Resources •

ASPEN Parenteral Nutrition Resources: https://www.nutritioncare.org/ PNResources/

•

ASPEN Update on the Use of Filters for Parenteral Nutrition: nutritioncare.org/ pnfilters

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18 Policy

Pharmacy Practice News • February 2022

Pharmacy Practice

ASHP Foundation’s Pharmacy Forecast 2022:

Challenges, Opportunities Amid Ongoing Pandemic

By Karen Blum

P

Positive responses, %

100 harmacists will have 81 plenty of opportuni80 67 ties to expand their scope 55 60 of practice by pushing for 40 provider status, assessing patients for social deter20 minants of health (SDOH), 0 helping in emergency preAdapt speCollaborate with Make the develcialty/other manufacturers on opment of new paredness, managing drug new pod demand contractcare models a shortages and demonstratstructures ing, regional wareperformance housing and other expectation ing value through new supply-chain surge strategies. service lines or business ventures, according to the Figure. Key responses on agility ASHP Foundation’s Pharand resilience. macy Forecast for 2022.

The 10th edition of the 87% of panelists predicted health systems forecast, presented at the ASHP 2021 Midyear Clinical Meeting will partner with community organizaand Exhibition, held virtually, and pub- tions to address healthcare disparities in lished in the American Journal of Health- their communities.

Regarding the use of technology, 73% System Pharmacy (2022;79[2]:23-51), surof panelists said advanced data analytics veyed 311 pharmacy leaders nationwide.

The 2022 report focused on five will be used by health systems to address domains: delivering value to stakehold- healthcare disparities, and 62% indicated ers; addressing access, disparities and that virtual assistant devices or healthequity; reimagining health systems for care mobile apps will allow patients to agility and resilience; building work- have access to a pharmacist for medicaforce capability; and honing pharmacy tion education and counseling. Meanwhile, 84% of panelists said the U.S. public preparedness. health infrastructure would expand roles Access, Disparities and Equity for pharmacists in preparedness planThe COVID-19 pandemic pushed the ning, vaccine administration, screening need to address healthcare disparities for diseases and health coaching; and 78% and equity to the forefront, the authors said innovative scheduling and remote said, with limited access to care high- work solutions will be required to recruit lighted by the initial rollout of vaccines. and retain pharmacy team members.

As part of new legislation limiting Pharmacists and pharmacy technicians are skilled and positioned to address surprise medical bills for patients, 63% SDOH and their effect on care access, of panelists said pharmacists will be and can work to improve population required to advise patients on medica-

demic be made a permanent part of the scope of pharmacy practice; • including pharmacists in transitions of care medication services; • allocating pharmacy labor resources to lead medication assistance program access and assist patients with medication affordability and adherence; and • collaborating with health plans and state agencies to continue establishing value-based care initiatives that include pharmacist-led comprehensive medication management services.

Agility and Resilience “In our lifetime, the healthcare system has not faced this amount or duration of stress and challenges as we have over the last 22 months from the COVID-19 pandemic,” said Michelle Wiest, PharmD, BCPS, the vice president of pharmacy services for UC Health, in Cincinnati, while introducing the agility and resilience section.

“Agility and resilience are paramount for health systems to be successful and to respond to patient care needs.”

Pharmacists demonstrated these capabilities during the public health emergency through methods such as evaluating emerging COVID-19 drug therapies to rapidly make patient care decisions, adjusting workflows to protect staff and preserve personal protective equipment, and managing numerous drug shortages. As such, 87% of panelists said health-system pharmacists will be essential providers in regional and national emergency preparedness response evaluation and planning.

‘We need to continue pushing institutions to invest in technologies. COVID-19 showed us ways in which we can provide care and medication management service without necessarily being at the bedside.’

—Vivian Johnson, PharmD, MBA health. However, policy changes, such as adopting new payment models, are required to optimize pharmacists’ roles.

Pharmacists have had a long-standing role in public health, but only half of surveyed panelists indicated that pharmacists and pharmacy technicians will systematically screen patients for SDOH, said committee member Leyner Martinez, PharmD, MHA, the director of pharmacy services at Baptist Hospital of Miami. Adequate training is needed to expand services around these efforts, Dr. Martinez said.

However, 64% of panelists expect that standard measures will be developed and widely used to assess equity of care, and

tion affordability and mediation assistance programs. In addition, 71% said payors will link value-based savings to improving health equity measures— another area where pharmacists can help lead initiatives, Dr. Martinez noted.

Overall, Dr. Martinez and her colleagues recommended that practice leaders support efforts for pharmacists to receive advanced independent provider status, and adopt analytical programs to assess and screen for SDOH to enhance medication management.

Other recommendations include: • advocating that state and federal policy changes made during the pan-

Right-sizing staff based on unpredictable patient acuity loads and managing staff shortages and burnout also will play a role, panelists said, with 70% agreeing that pharmacy departments will maintain such contingency plans in at least 50% of hospitals.

In addition, most panelists said developing new models of care and services will be a performance expectation of health-system pharmacy leaders (Figure). Dr. Wiest and her colleagues recommend that pharmacy leaders urge health-system pharmacists to: • participate in local and national interdisciplinary public health teams;

• integrate technology and workforce data to develop patient care models that optimize patient outcomes; and • engage in distribution relationships that encourage a stable pharmacy supply chain.

They also said that pharmacists should become competent in the use of wearable health metric devices and invest in new models of patient care with pharmacists as key providers of health services.

Delivering Value Pharmacists will be called upon to demonstrate value to stakeholders, including health systems, provider networks and payors, said Vivian Johnson, PharmD, MBA, the senior vice president of clinical services for Parkland Health and Hospital System, in Dallas. “Right now, we’re viewed as one of the most accessible professionals, because we are in the community,” she said.

Some 92% of panelists said pharmacy leaders will add new service lines or business ventures to increase revenues, and 79% said the pharmacy department will significantly contribute to revenues.

This could include greater pharmacist involvement in integrated practices, transitions of care, ambulatory care settings, hospital at-home programs or population health programs.

Health-system pharmacies will be recognized as preferred sites of care for delivery of new complex therapies, according to 77% of panelists, and 94% said pharmacy departments will lead strategies to manage the financial impact of high-cost medications in 50% of health systems. Although 71% said health systems will invest in digital health solutions and artificial intelligence technology to improve medication management, Dr. Johnson said that number needs to be higher. “We need to continue pushing institutions to invest in technologies,” she said.

“COVID-19 showed us ways in which we can provide care and medication management service without necessarily being at the bedside.”

A copy of the full report is available at www.ashpfoundation.org/research/ pharmacy-forecast.

The sources reported no relevant financial disclosures.

Watch our video interviews about the forecast at https://www.pharmacy practicenews.com/ Multimedia

Minimize risk by reducing diversion opportunities.

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Learn more at www.simplist-us.com INDICATIONS AND USE

Fentanyl Citrate Injection is contraindicated in patients with a hypersensitivity to fentanyl.

Fentanyl Citrate Injection, for intravenous or intramuscular use, is indicated for: • Analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance and in the immediate postoperative period (recovery room) as the need arises.

• Use as an opioid analgesic supplement in general or regional anesthesia.

• Administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.

• Use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

Risks of Skeletal Muscle Rigidity and Skeletal Muscle Movement: Manage with neuromuscular blocking agent.

See full prescribing information for more detail on managing these risks.

Fentanyl Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids. Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available.

IMPORTANT SAFETY INFORMATION WARNING: RISK OF ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning.

• Fentanyl Citrate 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.

Severe Cardiovascular Depression: Monitor during dosage initiation and titration.

Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.

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

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury: Monitor for sedation and respiratory depression.

The most common serious adverse reactions were respiratory depression, apnea, rigidity, and bradycardia.

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.

Concomitant Use of CNS Depressants: May decrease pulmonary arterial pressure and may cause hypotension. See full prescribing information for management instructions. For post-operative pain, start with the lowest effective dosage and monitor for potentiation of CNS depressant effects.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Fentanyl Citrate Injection because they may reduce the analgesic effect of Fentanyl Citrate Injection or precipitate withdrawal symptoms.

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

Pregnancy: May cause fetal harm.

• Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl.

Lactation: Infants exposed to Fentanyl Citrate Injection through breast milk should be monitored for excess sedation and respiratory depression.

• 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.

Geriatric Patients: Titrate slowly and monitor for CNS and respiratory depression.

This Important Safety Information does not include all the information needed to use Fentanyl Citrate Injection, safely and effectively. Please see full prescribing information, including Boxed Warning, for Fentanyl Citrate Injection at www.fresenius-kabi.com/us.

Please see Brief Summary of Prescribing Information including full boxed warning on the following page(s).

To place an order, contact your Sales Representative or call Customer Service at 1.888.386.1300 | www.fresenius-kabi.com/us

©2021 Fresenius Kabi USA, LLC. All Rights Reserved. 1271-SIM-05-12/21 Omnicell and the Omnicell brandmark are registered trademarks of Omnicell, Inc. in the United States and internationally.

Fentanyl Citrate Injection, USP CII for intravenous or intramuscular use.

BRIEF SUMMARY OF PRESCRIBING INFORMATION

WARNINGS AND PRECAUTIONS [Also see Boxed Warning]

This brief summary does not include all the information needed to use Fentanyl Citrate Injection safely and effectively. Please see full prescribing information including BOXED WARNING, for Fentanyl Citrate Injection, at www. fresenius-kabi.com/us.

Addiction, Abuse, and Misuse Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance. As an opioid, Fentanyl Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence].

Fentanyl Citrate Injection, for intravenous or intramuscular use, CII

Opioids are sought by drug users and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling Fentanyl Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

WARNING: RISK OF ADDICTION, ABUSE, AND MISUSE; LIFETHREATENINGRESPIRATORY DEPRESSION; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Fentanyl Citrate 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 Fentanyl Citrate Injection, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions].

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Fentanyl Citrate Injection. Monitor for respiratory depression, especially during initiation of Fentanyl Citrate Injection or following a dose increase [see Warnings and Precautions].

Cytochrome P450 3A4 Interaction The concomitant use of Fentanyl Citrate Injection with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration.

Monitor patients receiving Fentanyl Citrate Injection and any CYP3A4 inhibitor or inducer [see Warnings and Precautions, Drug Interactions, Clinical Pharmacology] 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 [see Warnings and Precautions, Drug Interactions].

• Reserve concomitant prescribing of Fentanyl Citrate Injection 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 Fentanyl Citrate Injection is indicated for: • analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises.

• use as a narcotic analgesic supplement in general or regional anesthesia.

• administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.

• use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

Important Dosage and Administration Instructions Fentanyl Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

• Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available.

• Individualize dosage based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

• Monitor vital signs routinely.

CONTRAINDICATIONS Fentanyl Citrate Injection is contraindicated in patients with: • Hypersensitivity to fentanyl (e.g., anaphylaxis) [See Adverse Reactions]

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal; respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Fentanyl Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage]. Carbon dioxide (CO2) retention from opioidinduced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential. As with other potent opioids, the respiratory depressant effect of Fentanyl Citrate Injection may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves. Through other mechanisms [see Clinical Pharmacology)] Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl Citrate Injection is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients selected for these forms of anesthesia.

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Fentanyl Citrate Injection. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.

Monitor patients closely including vital signs, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration].

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 [see Dosage and Administration].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Fentanyl Citrate Injection with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may exacerbate respiratory depression [see Warnings and Precautions], particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fentanyl Citrate Injectiontreated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Fentanyl

Citrate Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentanyl Citrate Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Fentanyl Citrate Injection [see Dosage and Administration, Drug Interactions].

Concomitant use of Fentanyl Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor, could result in lower than expected fentanyl plasma concentrations and, decrease efficacy. When using Fentanyl Citrate Injection with CYP3A4 inducers, or discontinuation of a CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the fentanyl Citrate Injection dosage [see Dosage and Administration, Drug Interactions].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants When benzodiazepines or other CNS depressants are used with Fentanyl Citrate Injection, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Fentanyl Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Fentanyl Citrate Injection is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Fentanyl Citrate Injection with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). If the decision is made to manage postoperative pain with Fentanyl Citrate Injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions].

Risks of Muscle Rigidity and Skeletal Muscle Movement Fentanyl Citrate Injection may cause muscle rigidity, particularly involving the muscles of respiration. The incidence and severity of muscle rigidity is dose related. These effects are related to the dose and speed of injection. Skeletal muscle rigidity also has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration. In addition, skeletal muscle movements of various groups in the extremities, neck, and external eye have been reported during induction of anesthesia with Fentanyl Citrate Injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.

These effects are related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Fentanyl Citrate Injection; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when Fentanyl Citrate Injection is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of Fentanyl Citrate Injection and a full paralyzing dose of a neuromuscular blocking agent when Fentanyl Citrate Injection is used in rapidly administered anesthetic dosages.

The neuromuscular blocking agent used should be compatible with the patient’s cardiovascular status.

Severe Cardiovascular Depression Fentanyl Citrate Injection may cause severe bradycardia, severe hypotension including orthostatic hypotension, and syncope.

There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions]. In patients with circulatory shock,

Brief Summary continued on next page

Fentanyl Citrate Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Fentanyl Citrate Injection.

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazadone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions]. This may occur within the recommended dosage range.

When fentanyl Citrate Injection is used with a neuroleptic and an EEG is used for postoperative monitoring, the EEG pattern may return to normal slowly.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Fentanyl Citrate Injection may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of increasing intracranial pressure.

Risks of Use in Patients with Gastrointestinal Conditions Fentanyl 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 Risks of Seizures in Patients with Seizure Disorders Fentanyl may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Fentanyl Citrate Injection therapy.

Risks of Driving and Operating Machinery Fentanyl Citrate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery after Fentanyl Citrate Injection administration.

Risks due to Interaction with Neuroleptic Agents Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest. Administer neuroleptic agents with extreme caution in the presence of risk factors for development of prolonged QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, including baseline prolonged QT interval, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s), 5) concomitant treatment with other drug products known to prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g. diuretics) that may cause electrolyte imbalance.

Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions] • Life-Threatening Respiratory Depression [see Warnings and Precautions] • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions] • Serotonin Syndrome [see Warnings and Precautions] • Severe Cardiovascular Depression [see Warnings and Precautions] • Gastrointestinal Adverse Reactions [see Warnings and Precautions] • Seizures [see Warnings and Precautions] The following adverse reactions associated with the use of fentanyl were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

As with other opioid agonists, the most common serious adverse reactions reported to occur with fentanyl are respiratory depression, apnea, rigidity and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm, diaphoresis, serotonin syndrome, adrenal insufficiency, and anaphylaxis.

It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. When a tranquilizer is used with Fentanyl Citrate Injection, the following adverse reactions can occur: chills and/or shivering, restlessness and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents.

Postoperative drowsiness is also frequently reported following the use of neuroleptics with fentanyl citrate.

Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of fentanyl citrate with a neuroleptic agent.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Fentanyl Citrate Injection Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology].

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

DRUG INTERACTIONS Clinically Significant Drug Interactions with Fentanyl Citrate Injection Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved [see Warnings and Precautions].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.

Intervention:

Examples:

If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved [see Dosage and Administration]. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice

CYP3A4 Inducers Clinical Impact: The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Intervention: If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression.

Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: The concomitant use of Fentanyl Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection. As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Warnings and Precautions].

Examples: Benzodiazepines and other sedatives/ hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions].

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.

Brief Summary continued on next page

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions] Intervention: The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine.

Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Fentanyl Citrate Injection and/or the muscle relaxant as necessary.

Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs.

Neuroleptics Clinical Impact: Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic [see Warnings and Precautions].

Intervention: ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

Nitrous oxide Clinical Impact: Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection.

Intervention: Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Fentanyl Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery There are insufficient data to support the use of fentanyl in labor or delivery. Therefore, such use is not recommended.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid- induced respiratory depression in the neonate. Fentanyl Citrate Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Fentanyl Citrate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data Animal Data Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m2 basis). There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/ kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 0.81 times the human dose of 100 mcg/kg on a mg/m2 basis.

Lactation Risk Summary Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.38%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fentanyl Citrate Injection and any potential adverse effects on the breastfed infant from Fentanyl Citrate Injection or from the underlying maternal condition.

Clinical Considerations Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Females and Males of Reproductive Potential Infertility 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 [see Adverse Reactions, Clinical Pharmacology, Nonclinical Toxicology].

Pediatric Use The safety and efficacy of Fentanyl Citrate Injection in pediatric patients under two years of age has not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Fentanyl Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions].

Fentanyl 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.

Hepatic Impairment Fentanyl Citrate Injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

Renal Impairment Fentanyl Citrate Injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of Fentanyl Citrate Injection and its metabolites.

Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

OVERDOSAGE Clinical Presentation Acute overdose with Fentanyl Citrate 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 [See Clinical Pharmacology].

Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measured (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to opioid overdose. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Policy

Pharmacy Practice News • February 2022

23

Reimbursement Matters

mAb BILLING continued from page 17

Beyond those tips, here are some other steps to consider: • Create a CDM number for each zeropriced drug product as a companion to the regular CDM entry. For example: Drug A 10 mg/mL, CDM number 12345; Drug A, no charge, CDM number 12346.

• Create a corresponding PDM entry for these zero-priced drug products and link it to the CDM number.

• Meet with your revenue cycle team to learn the quirks of your computerized billing system.

• Don’t panic! These billing strategies are used only for a small number of expensive specialty drugs.

• When the zero-priced drug product is used, pharmacy must use the order entry for that drug product, not for the purchased product.

• Bill for the appropriate CPT inj (injection) drug administration fee(s).

• When in doubt, consider CMS’s guidance, which notes that when the drug is zero-priced, the facility/physician should bill the HCPCS code for the drug administered with the correct quantity (according to the dose per unit specified in HCPCS) and a zero charge.

Update on Remdesivir Switching gears to another important COVID-19–related payment update, on Jan. 7, 2022, CMS released a new HCPCS code for remdesivir (Veklury, Gilead), an antiviral medication indicated for the treatment of adults and pediatric patients 12 years of age and older and weighing 40 kg and over requiring hospitalization for COVID-19. The new code, issued for billing when the antiviral is administered in an outpatient setting, can be used by all payors. The code is effective for dates of service on or after Dec. 23, 2021: • HCPCS code J0248 • Long descriptor: Injection, remdesivir, 1 mg • Short descriptor: Inj, remdesivir, 1 mg

This Year’s Updates to OPPS Receiving critical payment updates is easy when you’ve signed on to CMS’s MLN Matters distribution list (go. cms.gov/3IoH47F). Although they are electronically provide to the facility’s revenue cycle team, you too can benefit from receiving them. These articles explain national Medicare policy in an easy-to-understand format, and focus on coverage, billing and payment rules for specific provider types. The articles are prepared with help from clinicians, billing experts and CMS subject matter experts, and as we have noted so many times in past columns, are a critical reimbursement resource.

Table. Five New HCPCS Codes

a

CY 2022 HCPCS Code

CY 2022 Long Descriptor

CY 2022 SI

CY 2022 APCa

A9595

Piflufolastat f-18, diagnostic, 1 millicurie

G

9430

C9085

Injection, avalglucosidase alfa-ngpt, 4 mg

G

9433

C9086

Injection, anifrolumab-fnia, 1 mg

G

9434

C9087

Injection, cyclophosphamide, (Auromedics), 10 mg

G

9435

J9021

Injection, asparaginase, recombinant, (Rylaze), 0.1 mg

G

9437

Payment for the drug is for this APC.

APC, ambulatory payment classification; CY, calendar year; HCPCS, Healthcare Common Procedure Coding System; SI, status indicator

One of the recent updates detailed in these MLN Matters reports involves multiple changes from the Drugs, Biologicals, and Radiopharmaceuticals section.

The changes that are most pertinent to pharmacy are summarized below.

Five new HCPCS codes have been created for reporting passthrough drugs and biologicals in the hospital outpatient setting, where no specific codes were available (effective Jan. 1, 2022) (Table).

Fifteen new drug, biological and radiopharmaceutical HCPCS codes have been established.

For more information, see Table 6, Attachment A in CR 12552 (effective Jan. 1, 2022) (go.cms.gov/3Kvg8oB).

Four drug, biological and radiopharmaceutical HCPCS codes were deleted. See Table 7, Attachment A in CR 12552 (effective Jan. 1, 2022).

Certain vaccines will change retroactively from nonpayable to payable status in the January 2022 I/OCE Update. See these SI changes for drugs/biologicals in Table 8, Attachment A in CR 12552.

Drugs and biologicals with payments based on ASP. Several updated payment rates are available in the January 2022 update of the OPPS Addendum A and Addendum B (go. cms.gov/2XA4yl6).

Drugs and biologicals based on ASP methodology with restated payment rates. On a quarterly basis, CMS retroactively corrects payment rates for some drugs and biologicals paid based on ASP methodology. The list of drugs and biologicals with corrected payment rates is available on the first date of the quarter; if significant, your facility may resubmit claims that are affected by adjustments to a previous quarter’s payment files. For more information, check out MLN Matters 12552 (go.cms.gov/3GK2Oul).

Physician Fee Schedule Reminder It’s important to remember that in CY 2020, CMS finalized a policy to apply an amount equal to the site-specific PFS payment rate for

non-excepted items and services provided by a non-excepted, off-campus PBD. The agency has completed the phase-in for this payment policy. The PFS-equivalent amount paid to nonexcepted, off-campus PBDs is 40% of the OPPS payment (60% less than the OPPS rate) for CY 2022. Specifically, the total 60% payment reduction will apply in CY 2022. These departments will be paid 40% of the OPPS rate (100% of the OPPS rate minus the 60% payment reduction for the clinic visit service in CY 2022).

For more information on these payment policies, see CMS’s MLN

A Reimbursement Lexicon APC, ambulatory payment classification; ASP, average sales price; CDM, charge description master; CMS, Centers for Medicare & Medicaid; CPT, Current Procedural Terminology; CY, calendar year; HCPCS, Healthcare Common Procedure Coding System; IT, information technology; MAC, Medicare administrative contractor; OPPS, Outpatient Prospective Payment System; PBD, provider-based department; PDM, pharmacy drug master; PFS, Physician Fee Schedule

Matters MM12552 document at go.cms. gov/3GK2Oul. Any actions that you can take to mitigate revenue loss and ensure you are telling the patient’s story completely and accurately and in a codable manner will help!

■

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

A don’t-miss resource for health systems interested in specialty pharmaceuticals and services.

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24 Technology

February 2022

Informatics

Heading Off Drug Diversion Through Single-Dose Dispensing

By Gina Shaw

I

n 2019, hospital staff diverted some 148 million doses of controlled substances, according to a report released in 2020 by the data firm Protenus. As part of a comprehensive strategy to reduce drug diversion in the hospital setting, the Institute for Safe Medication Practices recommends using the smallest dosage form possible to reduce waste or medication error, consistently using the same National Drug Code and dosage form to create consistent practice, and using pre-filled, ready-to-administer syringes to reduce compounding and product manipulation after administration.

A new collaboration between medication management solutions provider Omnicell, manufacturer of the leading single-dose dispensing solution Controlled Substance Dispenser (CSD), and Fresenius Kabi, manufacturer of Simplist MicroVault pre-filled syringes, aims to help hospitals put those recommendations into practice and enhance their controlled substance management initiatives.

In November, Omnicell introduced new cassettes for its CSD that are specifically designed to accommodate Fresenius Kabi’s MicroVault packaging for a variety of low-dose narcotic medications including fentanyl, hydromorphone and morphine. In addition to reducing the potential for diversion, a study found that these ready-toadminister syringes were associated with an error rate of 2.5%, compared with 10.4% for IV push traditional practice (J Patient Saf 2018;14[1]:60-65).

Being able to dispense Simplist syringes from the CSD will help hospitals optimize both nursing and pharmacy workflows, especially in today’s environment of staffing shortages, said Mike Axelsen, Fresenius Kabi’s senior manager for medication technology and analytics.

“With single-dose dispensing of product presentations that more closely match what’s commonly ordered by healthcare providers, we can eliminate the need for waste,” he said, noting that seven Simplist SKUs are available for the CSD, including various common doses of fentanyl, hydromorphone and morphine.

Baptist Health System’s Experience Kentucky’s Baptist Health System has already placed an order for the new Fresenius Kabi cassettes for the CSD. “Our institution used to have a significant number of discrepancies in our narcotics count before we adopted with Omnicell’s CSD in high-risk areas such as the emergency department,

endoscopy, oncology, L&D [labor and delivery] and the PACU [post-anesthesia care unit],” said chief pharmacy officer Nilesh Desai, MBA, BS, RPh, CPPS. “With dispensers, you have the exact dose you need. While we have not conducted a head-to-head comparison study on diversion rates before and after adopting the CSD, we monitor for diversion on all doses dispensed, and I cannot recall a single case of diversion since we went live with the CSD.” The new cassettes further enhance the CSD’s operational efficiencies as well as prevention of discrepancies or diversion, said Michael (Brandon) McLain, PharmD, the director of pharmacy at Baptist Health’s Floyd Memorial Hospital. “You’re giving nurses a dose that’s already drawn up in a ready-to-use format and it’s the dose they need, rather than having to go through steps of pulling up the dose, wasting any excess and getting another nurse to witness the wasting. You prevent a lot of that by using a ready-to-use syringe in a dose-specific format. Really, any unit where you see a high volume of controlled substances being dispensed could have added value from single-dose dispensing.”

What happens if the dispenser fails, and accidentally drops two items rather than one? (Anyone who’s ever used a candy vending machine can imagine this happening.) “There are sensors within the device that will recognize a double drop and direct the nurse to return the second one,” Dr. McLain said. “The dispenser is hard to load incorrectly, but if that happens or there is an accidental dispense, it will recognize that and send a pop-up alert.”

Such solutions dramatically reduce the possibility of giving the patient the wrong dose of drug and of drug diversion, said Nish Parekh, Omnicell’s vice president for Point of Care Solutions.

“Nurses have so many concerns with patient care; they shouldn’t have to add to that with counting back. Here, the machine is counting for them.”

Technology

Pharmacy Practice News • February 2022

25

Informatics

Allina Health Achieves Success With Drug Diversion Software

By Karen Blum

I

n continued efforts to ensure patient safety, prevent staff harm and avoid organizational liability risk due to drug diversion, pharmacy leaders with Allina Health implemented a new drug diversion surveillance application. The efforts led to a sevenfold drop in the time to close investigations, and other improvements.

Leaders wanted to further enhance the system’s existing, robust program with comprehensive audit coverage and enhanced analytics, said JoAnne Myhre, CPhT, FMSHP, the drug diversion manager for the nonprofit health system, during a poster presentation at the ASHP 2021 Midyear Clinical Meeting and Exhibition, held virtually.

Allina Health owns or operates 12 hospitals and more than 90 clinics in Minnesota and Wisconsin.

Ms. Myhre and her colleagues were looking for a program to help with reporting capabilities, additional data points beyond automated dispensing cabinets and electronic medication administration records (eMARs), the ability to “shrink” the haystack and bring them closer to the potential diverter, and other features.

“One of the biggest factors for us was how we felt the vendor would work with us, meaning how open they were to listening to us, and how nimble/flexible/ responsive they would be to our ideas, questions and concerns,” she said.

After selecting a vendor and holding a pre–go-live process to work out any kinks, the team established weekly meetings with key stakeholders and users to assess audit workflows, make key decisions and support continuous process improvement. This included pharmacy team members as well as representatives from information technology, access management and the IT security/

Omnicell holds more than 1,500 individual doses within its CSD cassettes, now including the Simplist syringes, Ms. Parekh said. “The point is to get the right dose, to the right patient, at the right time. Removing manual actions at various checkpoints reduces the potential for error and diversion that can happen at each transition of care, such as compounding the drug in the central pharmacy’s IV room, batching drugs and sending them up to the floor, and having the nurse draw up a single dose from a larger vial. The industry is moving in the direction of reducing potential errors providers may come across by giving them exactly the dose they need.”

network team. Their work formed the basis of an internal practice guide outlining updated workflows and strategies.

A six-month post-implementation data review showed notable improvements in three key indicators. The organization’s average total percent documentation variance rate—the percentage of controlled substance automated dispensing cabinet and eMAR transaction documentation not auto-reconciled by the

new application—decreased from 6.3% to 5.8%, reflecting improvements in enduser practices. The average time to close documentation variances—the amount of time users spend reconciling open variances—decreased from four to 2.2 days, representing improved efficiency.

Lastly, the average time users take to close audits/investigations decreased from 49.4 to 7.2 days, representing improvements in time and effectiveness

afforded by collaborative tools within the application, Ms. Myhre said.

“Be patient and as nimble as you can,” Ms. Myhre advised, when selecting new programs. “There are so many tools available, and each one has different things to offer its customers. Most likely, you will not find a one-size-fits-all option.”

Ms. Myhre reported no relevant financial disclosures.

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26 Technology

Pharmacy Practice News • February 2022

Informatics

Flagging Diversion continued from page 1

consolidated across multiple sources, including our ADC [automated dispensing cabinet] data, our electronic health record [EHR], our wholesaler reports and our reverse distributor reports, as well as our timekeeping records,” Dr. Cimoch said. “It then assigns risk scores to transactions that employees perform, and highrisk transactions populate into a queue that I review and then log an assessment result into the software. This expedites my ability to assess the entire organization’s activities around controlled substances and minimizes the amount of time I need to spend using manual processes.”

If Dr. Cimoch’s investigation of a flagged transaction identifies a cause not related to diversion, such as appropriately logged waste, she documents it as a practice issue. If further investigation confirms that drug diversion was involved, that is also documented in the software. “The computer learns to recognize diversion, utilizing our data along with data from other hospitals, so that we can more accurately identify the patterns associated with drug diversion,” she said.

with a crime, lost or restricted medical licenses and multiple drug relapses (JAMA 2013;310[21]:2289-2296).

Although the study did not specify whether the residents who developed SUD obtained their illicit drugs through diversion, “that’s given in these studies,” Scott Falk, MD, an associate professor of clinical anesthesiology and critical care at Penn, told Pharmacy Practice News.

Given those risks, “it’s critical to monitor the possibility of diversion closely to identify opportunities to intervene and help before this becomes a bigger problem,” Dr. Cimoch said.

The diversion software she and Dr. Falk have been using shows alerts for each problematic transaction, including missing administration, missing waste, missing returns, late administration and late waste. Each flagged transaction has a risk score. “So, if we have a transaction where there is no administration, waste or return at all, and the drug is totally unaccounted for, that has a higher risk score than one with a late waste or a late return,” Dr. Cimoch said.

Table. Evaluation of Countermeasures

‘You can use the reports to compare employees to their peers based on a variety of factors such as excessive dispenses, excessive waste, and the quantity and types of alerts and whether those resolve. You can also see … charts of risk by time range, showing whether someone is escalating in behavior.’

—Jennifer Cimoch, PharmD diversion. “You can use the reports to compare employees to their peers based on a variety of factors such as excessive dispenses, excessive waste, and the quantity and types of alerts and whether those resolve,” Dr. Cimoch explained. “You can also see missing drug alerts and charts of risk by time range, showing whether someone is escalating in behavior. The darker the red on the heat map, the greater the risk that the person is escalating in potential diversion behaviors.”

Targeting Perioperative Settings

Degree of Impact

Low Effort

High Effort

High

“Waste Quick” action on Epic

Integration of Epic and Omnicell

Low

Periodic refresher training Emphasize importance of proper controlled substances

Addressing/correcting discrepancies after-the-fact

Source: Jennifer Cimoch, PharmD, and Scott Falk, MD.

After a March to June 2020 data validation phase to ensure the software was adequately displaying transactions and drawing appropriate conclusions, the hospital went live with the program in June, and Dr. Cimoch began to review high-risk alerts for the pharmacy and purchasing departments. In August 2020, her team piloted the program for the anesthesia department, followed by a nursing pilot in September. “Since fall of 2020, we have used this program to evaluate practice with controlled substances for all disciplines.”

Anesthesia at Risk The hospital’s first departmental pilot was in anesthesia, given the high propensity for diversion in the specialty, as well as the potential harm posed to providers.

Consider one oft-cited study of substance use disorder (SUD) among anesthesiology residents, by Warner et al: Over a nearly 35-year period, 28 residents died from SUD during their training. And of those with SUD who survived, negative consequences included being charged

After reviewing each alert, the administrator enters a conclusion. One option is an inaccurate alert, such as a false positive. “If the route of administration of fentanyl was not properly reflected in the data, yet I see it charted appropriately in the EHR, I will mark it as inaccurate,” she said.

Another option is “accurate alert, do not investigate”—used, for example, when a worker wasted a drug but forgot to document it. However, currently in the Department of Anesthesia, the hospital is not using that option. “We have established that we will investigate every single accurate alert [generated by] the software, to make sure that everything is reconciled appropriately, the controlled substance is accounted for, and we provide feedback to the provider involved,” Dr. Cimoch said.

A heat map on the software dashboard draws administrators’ attention to employees with the highest risk scores, with larger red boxes indicating employees of greater concern and smaller blue boxes denoting those whose transaction history indicates a lower risk for

Penn’s Department of Anesthesia is engaged in an ongoing effort to reduce incidents of controlled substances going unaccounted for during the perioperative period, focused on anesthesia residents in the main operating rooms. The software identified multiple root causes of these discrepancies, Dr. Falk noted.

“These included failures to document administration and failures to document waste; or sometimes medication was removed under one patient’s name and used for another patient, such as if a case was canceled. Sometimes there is variability in the order of cases in operating rooms. There also is a lack of ability to transfer and document the transfer of opioids and controlled substances among providers, such as if you took over a case from someone as you came on shift. The final root cause, of course, is diversion—something we are obviously very concerned about.”

The group assessed possible solutions to these issues and determined that the highest-impact, lowest-effort countermeasure was to create a “waste quick” action within the Epic EHR (Table).

“That gives you, at the end of the case, the amount of opioids that were used during the case, and asks you to reconcile and waste opioids,” Dr. Falk said. “That’s something we put at the end of the case in our macro. Everyone has to click through that to get through a case in the EHR.” After the quick waste action reminder

was added to the Epic workflow in November 2020, monthly discrepancies among residents were relatively low, ranging from 10 in December 2020 to 15 in January and March 2021, and only a single discrepancy in February. Then they started to increase, reaching more than 40 in April and over 50 in May. Waste not being documented was one of the biggest root causes of controlledsubstance discrepancies among residents before the intervention project, at about 90% of reports, compared with about 5% each for medications administered but not reported and incorrect waste amounts.

New Discrepancies Discovered “One of the interesting things is that this type of discrepancy we were working on really improved,” Dr. Falk said.

“After the intervention, the waste not being documented was only the third most common cause of discrepancies.

But now there are brand-new types of discrepancies we started to have in high numbers, such as incorrect waste amount and medication administered but not documented. That last factor is probably our current greatest root cause.”

In June 2021, the hospital upgraded its Omnicell software to a version that allows for transfer of controlled substances between providers. After that implementation, discrepancies declined again, to less than 40 in June and July 2021.

“We learned that the process is highly dependent on human factors,” Dr. Falk said. “We are looking at some solutions to try and automate some of those factors, looking at the EHR and the ADC for further integration. Two-way communication between those two software programs is, hopefully, in our future. There’s just too many data points out there for people to be able to address these issues manually, especially within a large hospital system.”

The sources reported no relevant financial disclosures.

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