Pharmacy Practice News (October 2020)

The Best-Read Pharmacist’s News Source

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Volume 47 • Number 10 • October 2020

Survival benefit seen in multiple trials CLINICAL

Pharmacists help halt risky gout therapy in ED .....................

Making off-label feeding safer in younger patients .............

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5 stewardship tips for rapid diagnostic testing ........... 9 POLICY

Meeting Medicare’s new payment rules for COVID-19 ....................

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REVIEW ARTICLE

Biosimilars in Oncology Information Technology Integration: Part 2 of 3 See page 22.

Steroids Offer ‘Umbrella’ For COVID Cytokine Storm

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articipants in the 340B drug pricing program scrambled to respond to a flurry of new audit demands from drug manufacturers on the number of contract pharmacies that participants are allowed to use under 340B. The covered entities have been seeking intervention from the Department of Health and Human Services and the Health Resources and Services Administration (HRSA), which administers 340B, but as of the end of September, no action had been taken, experts said at the National Association of Specialty Pharmacy (NASP) 2020 Annual Meeting & Expo Virtual Experience.

340B covered entities began receiving letters from manufacturers outlining new requirements in late July. The demands fell into two broad categories: 1. Submissions by covered entities of all 340B claims data to

teroids appear to improve the survival of the sickest COVID-19 patients, by dampening the cytokine storm, according to three recent reports in JAMA—one of them a meta-analysis.

As a result, the World Health Organization issued a new guideline recommending systemic corticosteroids for the treatment of patients with severe and critical COVID-19. However, the guideline suggested that corticosteroids not be used for those with mild disease. The WHO said steroid treatment in mild COVID-19 cases brought no benefits, and could even prove harmful (bit.ly/32Bt2O5).

Steroids appear to work by calming the inflammatory response, which occurs when the body’s immune system overreacts, damaging the lungs and surrounding tissue in seriously ill COVID-19 patients. “There is now strong evidence to suggest that the blockade of inflammation in COVID-19 is effective in severely ill patients,” said C. Michael White, PharmD,

Continued on page 18

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TECHNOLOGY

Guidelines-based AUC vancomycin dosing: one way to get there .....................

340B: Scrambling To Meet New Requirements

The Bottom Line: IV-WMS and Cost Savings

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ost is often cited as one of the barriers to a hospital’s adoption of IV workflow management systems (IV-WMS). But what if the technology actually saves money—to the tune of more than $500,000 annually?

That’s the savings accrued at Cincinnati Children’s Hospital, where Alex C. Lin, PhD, and his colleagues at the James L. Winkle College of Pharmacy at the University of Cincinnati found that the adoption of IV-WMS reduced the amount of wasted and missing IV doses by 14,176 and 2,268 doses, Continued on page 21

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Poor feeding linked to big mortality spike

Universal Nutrition Screening Urged for COVID-19 Patients

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utrition experts are urging providers to screen all COVID-19 patients for malnutrition, based on new data showing that infected patients’ mortality rates spike significantly in the presence of suboptimal feeding.

The interplay between COVID-19 and nutrition shouldn’t come as a surprise, Leah Gramlich, MD, FRCP, a nutrition specialist based out of the Royal Alexandra Hospital in Edmonton, Alberta, noted during a recent webinar hosted by the American Society for Parenteral and Enteral Nutrition (ASPEN).

She explained that patients infected with the coronavirus often have a poor appetite and gastrointestinal symptoms, such as diarrhea,

Oncology Roundup: Updates in oncogeriatric care, metastatic CRC, trophoblastic tumors and more.

See pages 12 and 13.

both of which can affect their nutritional status (Gastroenterology 2020;159[2]:775-777).

Such patients’ survival literally is at stake, she stressed, citing the new data, which included hundreds of COVID-19 patients in Wuhan, China. The researchers screened patients for nutritional deficiencies using the Nutrition Risk Screening (NRS) score, and found that the vast majority (92%) were at risk for poor nutrition (NRS score ≥3), with 16% at high risk (NRS score ≥5).

Patients remained in the hospital for an average of 30 days, but those with NRS scores of at least 5 needed nearly an additional week Continued on page 6

Smart Labels

Clinical

Pharmacy Practice News • October 2020

3

Pain Medicine

ED Patients With Gout Flares Too Often Receive Opioids

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atients with gout flares presenting to the emergency department (ED) are often given opioids or discharged with opioids, even though the pain relievers are not recommended in treatment guidelines, New Jersey researchers report.

Reviewing 214 patient records from the ED with gout at Robert Wood Johnson University Hospital in Somerset, investigators found that 51 patients (24%) were discharged on opioids, and that about 82% of patients had their first encounter with opioids due to this visit.

In the ED, opioids (28%) were used second only to nonsteroidal anti-inflammatory drugs (NSAIDs; 41.6%). At discharge, opioids (23.9%) were the third most common medication prescribed, after NSAIDs (37%) and steroids (34.6%), the investigators reported at the American College of Clinical Pharmacy’s 2020 virtual poster symposium (poster 348).

Best practices for gout flare management in the ED are urgently needed, said senior author Luigi Brunetti, PharmD, an associate professor of pharmacy practice and administration at Rutgers University’s Ernest Mario School of Pharmacy, in New Brunswick.

Dr. Brunetti said he had been collaborating with rheumatologist Naomi Schlesinger, MD, on a few gout-related projects when they noted patients being discharged from the ED on opioids and decided to study it further. “That’s when

we identified these trends in drug use that had us scratching our heads,” Dr. Brunetti said. “It’s one thing if you have a patient coming in on an opioid, perhaps for another indication. But we had a significant percentage of patients that were sent home on an opioid who previously were not prescribed one.”

The study pulled records from all patients visiting the ED with a primary diagnosis of gout from Jan. 1, 2016, through July 1, 2019. They used a comparative analysis to determine differences between patients who were or were not discharged on opioids, and multivariable logistic regression to identify factors associated with an opioid prescription upon discharge from the hospital.

Moreover, 12% of patients were discharged on opioids without anti-inflammatory drugs, and a history of opioid use (odds ratio [OR], 3.3; 95% CI, 1.3-8.6; P=0.14) and gastroesophageal reflux disease (OR, 3.5; 95% CI, 1.09-10.9; P=0.035) was associated with opioid prescription upon discharge. Medications prescribed in the ED and upon discharge were NSAIDs, corticosteroids, opioids, acetaminophen and colchicine.

“There’s a good frequency of inappropriate prescribing of opioids for gout flares, and it’s good the authors have statistics to make a case for better education of gout management,” commented Cortney Mospan, PharmD, an assistant

professor of pharmacy at Wingate University Levine College of Health Sciences, in Wingate, N.C. Dr. Mospan co-authored a recent continuing education article on the pharmacist’s role in managing gout and hyperuricemia (bit.ly/2UD554C).

What the Guidelines Say This spring, the American College of Rheumatology released the 2020 Guideline for the Management of Gout, Dr. Mospan said. There are three foundational drugs recommended for flares: NSAIDs, corticosteroids and colchicine.

A gout flare indicates that uric acid has elevated to the point that it exceeds the ability to be absorbed, and crystals start to form, she noted. The body recognizes these crystals as foreign substances, which activates the immune system to attack and eliminate them.

“When you look at treatment options recommended by the guidelines, those are all anti-inflammatory medications as opposed to a pain medication like opioids, because what we need to be doing in that acute gout flare—even though there is a tremendous amount of pain—is to decrease that inflammatory response,” Dr. Mospan said. “That will result in pain relief and subside that acute gout flare.”

There’s another reason to treat that inflammation, she added. Studies have shown a connection between elevated uric acid and cardiovascular disease,

EDITORIAL BOARD

including hypertension ion and diabetes (N Engl ngl J Med 2008;359[17]: 7]: 1811-1821).

Prescribing opi-oids is problematic not only because the drugs do noth-ing for the underlying ng inflammation; opioids ds also can introduce ce patients—who haven’t n’t been exposed before— e— to the addictive painnkillers, Dr. Mospan an said. Moreover, leftover pills could be diverted by the patient or a visitor to the home, increasing the supply of illicit opioids in the community.

Pharmacists can play a key role in gout treatment, Dr. Mospan said, including educating patients on medication benefits and side effects and the importance of adherence. They also can help prescribers adhere to treatment recommendations.

Based on the Rutgers study, such help is sorely needed. Aside from the high percentage of opioid prescriptions, the investigators also found that about 30% of patients were prescribed acetaminophen, which is not recommended and will not help with pain.

—Karen Blum The sources reported no relevant financial relationships.

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

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4 Clinical

Pharmacy Practice News • October 2020

COVID-19 Pandemic Fixed-dose hydrocortisone led to a

Steroids Calm Storm

93%

continued from page 1

the department head and a professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs. Dr. White, a member of the Pharmacy Practice News editorial advisory board, was not part of the studies but has conducted systematic reviews into other treatment options for COVID-19 and was asked to comment.

The meta-analysis reviewed seven randomized clinical trials from 12 countries with a total of 1,703 critically ill patients with COVID-19 comparing corticosteroids with the standard of care. The trials studied three different corticosteroids—dexamethasone, hydrocortisone and methylprednisolone—and the authors analyzed the results of the RECOVERY, REMAPCAP, CoDEX, CAPE COVID and three additional trials. The primary end point was risk for death after 28 days. Fewer people receiving any type of systemic steroid died (222/678; 33%) than those who did not receive steroids (425/1,025; 41%) (JAMA 2020 Sep 2. [Epub ahead of print]; bit.ly/32AW6Fb). Dexamethasone had the largest populations studied and was the only steroid with significant surviv-

This open-label, multicenter, randomized clinical trial of 299 patients with COVID-19 and moderate or severe acute respiratory distress syndrome compared IV dexamethasone plus standard of care with standard of care alone. They saw a statistically significant increase in the number of days patients were alive and free from mechanical ventilation. The dexamethasone group had a mean of 6.6 days off the ventilator (95% CI, 5.0-8.2) versus four days in the standard-of-care group (95% CI, 0.2-4.38; P=0.04), but there was no mortality difference between both groups (JAMA 2020 Sep 2. [Epub ahead of print]; bit.ly/3c3j378).

An international group in the REMAPCAP trial looked at whether hydrocortisone also had promising effects on critically ill patients with COVID-19 (JAMA 2020 Sep 2. [Epub ahead of print]; bit.ly/2RAacjU). In the randomized hydrocortisone study, 403 patients with suspected or confirmed COVID-19 who required respiratory or cardiovascular

‘We have learned in other disease states that steroids have a clearly demarcated role in managing systemic inflammation without worsening the underlying condition.’

—Steven J. Martin, PharmD al benefits in a subgroup analysis (36% reduction in odds), but hydrocortisone had almost the same reductions in odds (31%) and just missed significant findings. Methylprednisolone was only assessed in a single small trial, and the odds reduction was a nonsignificant 9%, but with a very large confidence interval.

The meta-analysis helped to clarify whether the benefit from steroids seen in the earlier RECOVERY trial was due to just dexamethasone, but this pooling of data seems to point to the efficacy of other steroids, according to Steven J. Martin, PharmD, BCPS, the dean and a professor of Ohio Northern University Rudolph H. Raabe College of Pharmacy, in Ada. Dr. Martin did not participate in the studies.

“I believe the RECOVERY trial’s use of dexamethasone led to the early speculation that that drug may be preferred, but the other two trials with hydrocortisone and methylprednisolone also demonstrated positive benefits. Thus, at this point, one would conclude that this is a class effect,” explained Dr. Martin, also a member of the PPN editorial advisory board.

The CoDEX trial supporting the use of dexamethasone was performed in Brazil.

organ support, such as mechanical ventilation or drugs to support their blood pressure, were enrolled between March and June 2020. The cohort included patients of mixed ethnicities in Australia, Canada, France, Ireland, the Netherlands, New Zeland, the United Kingdom and the United States. One group was treated with a fixed dose of 50 mg of hydrocortisone four times per day for seven days; another group was treated with hydrocortisone only if their blood pressure dropped; and a third group received no hydrocortisone.

The results showed that using the fixed dose of hydrocortisone led to a 93% chance of a better outcome—greater chance of survival and less need for organ support—than not using hydrocortisone. If the hydrocortisone was given only when the blood pressure was low, the chance of a better outcome was 80%.

This study stopped recruiting patients early after the RECOVERY trial published data in early June, suggesting dexamethasone boosted recovery (N Engl J Med 2020 Jul 17. [Epub ahead of print]. doi: 10.1056/NEJMoa2021436).

“The data seemed clearest for

chance of survival and less need for organ support than not using the steroid. dexamethasone, but in totality they all worked,” said Shmuel Shoham, MD, an associate professor of medicine at the Johns Hopkins University School of Medicine, in Baltimore. Dr. Shoham was not part of the studies but has been involved in other trials for COVID-19 and sits on the COVID-19 treatment guideline panel of the Infectious Diseases Society of America.

“That does not mean it is better than the other ones,” Dr. Shoham said. “If available, it might still make sense to use dexamethasone as a first option, but it looks like it is the class effect rather than individual corticosteroids that is important.”

Hydrocortisone has mineralocorticoid effects that produce a positive sodium balance and higher serum sodium concentrations, increased extracellular fluid volume, hypokalemia and alkalosis, Dr. Martin explained. “Expanded extracellular fluid is generally a good thing in shock, but alkalosis can worsen oxygenation if the pH becomes too high.

Hypokalemia can cause heart rhythm disturbances if too low. Dexamethasone doesn’t have mineralocorticoid activities, and I can’t tell whether that was a good thing or bad thing in these studies.

“There are potency differences, but the dosing of the drugs was adjusted to account for those differences,” he said.

“At this point, one would conclude this is a class effect.”

Dr. White agreed: “While dexamethasone has the strongest data set showing benefit, hydrocortisone is a very reasonable alternative. Methylprednisolone had too small a trial to make a meaningful determination of its efficacy; the 95% confidence interval was very wide. But in equipotent doses, there is reason to believe from other inflammatory diseases that methylprednisolone could also be an alternative if dexamethasone and hydrocortisone were unavailable.”

This is an important consideration because “dexamethasone was one of the drugs on back order and shortage since the initial RECOVERY trial results came out, so being able to diversify to other corticosteroids would help meet demand,” Dr. White explained.

Dosing seems to be an important consideration, according to Drs. White and

Martin, and lower doses appear to be as effective as higher ones.

“I have to believe dose is important,” Dr. Martin said. “The dosing for the trials in the meta-analysis was varied. In trials that administered low doses of corticosteroids, the overall fixed-effect OR [odds ratio] was 0.61, and the corresponding absolute risk was 29% for lowdose corticosteroids versus an assumed risk of 40% for usual care or placebo.

In trials that administered high doses of corticosteroids, the fixed-effect OR was 0.83, and the corresponding absolute risk was 36% for high-dose corticosteroids versus an assumed risk of 40% for usual care or placebo.”

Even the authors of the meta-analysis concluded that higher doses were not more beneficial than lower ones. Using lower doses could also help reserve the medication for more patients, according to Dr. White.

It’s important to advise people that all of the patients in these studies were critically ill and required some type of oxygenation, typically ventilator support, all three experts said.

There is little to support widespread use by mildly ill patients. “We have learned in other disease states that steroids have a clearly demarcated role in managing systemic inflammation without worsening the underlying condition,” Dr. Martin said. “Too much steroid can cause problems of its own.”

In its treatment recommendations, the WHO recommended against the use of steroids outside of critical patients.

“At the beginning of the year, at times, it felt almost hopeless, knowing that we had no specific treatments. It was a very worrying time. Yet less than six months later, we’ve found clear, reliable evidence in high-quality clinical trials of how we can tackle this devastating disease,” said Anthony Gordon, MD, FFICM, FRCA, the chair of anesthesia and critical care at the Imperial College London, who participated in the REMAP-CAP study.

—Marie Rosenthal Dr. Gordon reported receiving grants from the NIHR and the NIHR Research Professorship. Drs. Martin, Shoham and White reported no relevant financial relationships.

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6 Clinical

Pharmacy Practice News • October 2020

Nutrition

Feeding and COVID-19 continued from page 1

to recover. Nine percent of the patients died; among those with NRS scores of 5 or higher, the mortality rate was 43% (JPEN J Parenter Enteral Nutr [Epub Jul 1, 2020]. doi:10.1002/jpen.1953).

Hence the push for more widespread nutrition screening in COVID-19 patients. Different countries have developed a variety of screening tools, but “as long as the tool has been validated for use in your patient population and setting,” the effort should yield positive results, Dr. Gramlich said. If the tool shows the patient is at risk for nutritional deficiencies, a dietitian or nutrition care provider can conduct a formal assessment to determine whether malnutrition is present, identify barriers to intake, and develop an individualized plan, she noted. If patients develop any additional risk factors for nutritional deficiencies, such as nausea or poor food intake, they should be screened again.

Gramlich noted. Indeed, “nutrition care is a team sport,” she said. “It requires multidisciplinary, interdisciplinary care.”

Barriers to Nutrition Support As for pharmacists’ role, in addition to screening, they can help recognize barriers to food intake, such as trouble breathing or nausea, which often have pharmacologic treatment options. For instance, around-the-clock antiemetic therapy “makes a huge difference” in improving food intake, she said, adding that pharmacists also should pay attention to patients’ use of opioids during their hospital stay, which can have a major impact on gastric emptying and appetite.

What’s more, as medication experts, pharmacists can provide information about drug–nutrient interactions or medication metabolic complications to the health care team, noted Phil Ayers, PharmD, BCNSP, the chief of clinical

6 Tips for Improving Nutrition In Hospitalized COVID-19 Patients Consider around-the-clock antiemetics in patients with nausea; don’t settle for as-needed therapy if nausea is an issue.

support their potentially long recovery.

“They can’t go to the store, and their family members, if exposed, may not be able to go to the store,” she explained.

If hospitalized, patients may have to contend with personal protective equipment (PPE), nausea, breathing difficulties and other issues that can impede food intake. There also can be difficulties in providing care: Hospital pharmacists and dietitians may, for example, have to deal with shortages in PPE and recommendations to minimize exposure, Dr. Ayers said. Indeed, having a patient be readily accessible for a complete nutrition assessment “is a major challenge for all involved in the treatment of COVID-19 patients,” he told Pharmacy Practice News. As a result, “many institutions are using other means to collect this information, such as calling patients, family members, using telehealth, electronic health record review and discussing with the nurse at bedside.”

Taken together, all of these interventions underscore how invaluable the nutrition care team can be, not only for COVID-19 patients, but for those hospitalized with any condition, Dr. Gramlich noted. That’s why she called nutrition experts the “unsung heroes” of health care. When a patient is struggling with maintaining adequate feed-

Source: ASPEN.

No prolonged fasting.

Avoid immobilization by getting patients up and out of bed.

Involve patients in their care; explain their nutritional deficiencies and what they could mean to their recovery.

Consider alternatives to opioids.

Consider nutritional requirements for COVID-19 patients. Fluid: approximately 3 quarts/L per day; calories: 2,000-2,500 per day; protein: 75-100 g per day.

Source: American Society for Parenteral and Enteral Nutrition (bit.ly/3hzj3Ne).

“Screening is not a one-and-done process,” stressed Dr. Gramlich, who is also a professor of medicine in the Division of Gastroenterology at the University of Alberta, in Edmonton.

Jay Mirtallo, MS, RPh, BCNSP, a clinical practice specialist at ASPEN who did not participate in the webinar, echoed the importance of widespread screening, and agreed that using a validated screening tool is important. However, if pharmacists and other providers don’t have access to such a tool, he noted, simply asking whether patients experienced recent unexplained weight loss, or have food insecurity—such as trouble accessing or preparing food for themselves— could help identify people at risk.

“You need to screen them, and then you have to act on it right away, because malnourishment can happen really quickly,” Mr. Mirtallo told Pharmacy Practice News.

Given that urgency, a collaborative approach to nutrition support is key, Dr.

pharmacy services and a nutrition support service pharmacist at Mississippi Baptist Medical Center, in Jackson, who did not participate in the ASPEN webinar.

Pharmacists also “need to be able to advocate for patients,” Dr. Gramlich said.

This may include protecting meal times, such as making sure patients aren’t taken for scans or other testing during lunch or dinner hours. Dietitians often can’t make rounds in hospitals every day, but pharmacists can; if they see something, they should say something, Mr. Mirtallo said, adding, “If nutrition care isn’t being considered on a daily basis, pharmacists need to speak up.”

Pharmacists also can help identify and address the barriers that can prevent COVID-19 patients from meeting their nutritional needs, Dr. Gramlich said. For instance, once patients are discharged or recovering at home, they have to socially isolate, which makes it more difficult to get enough healthy foods to

ing, nutrition experts may not always be the first providers we turn to, “but they are a key aspect of recovery,” given how poorly hospitalized patients fare when malnourished, she noted (Lancet 2019;393[10188]:2312-2321).

Inflammation May Be the Key Mr. Mirtallo said he suspects that once researchers learn more about COVID-19, they will discover that its effect on nutritional status “will be as big or bigger than it is for other diseases.”

As for possible mechanisms of action, “it’s still too early to know for sure,” he said. “It’s just too new.” But there is definitely a relationship between COVID-19 and nutrition, he stressed, because the virus creates widespread inflammation, which malnutrition can exacerbate (SN Compr Clin Med 2020;1-5. doi: 10.1007/ s42399-020-00410-0).

Regardless of how future studies on COVID-19 and nutrition pan out, there’s

no doubt that nutrition care often is neglected, Mr. Mirtallo noted. “It slips through the cracks, because you’re focused on the disease and treatment for the disease, which is mostly drugs,” he said. But as Mr. Mirtallo has been reminding his students for 40 years, nutrition is a key aspect of pharmacologic management. “So you can’t really separate the two.”

Dr. Gramlich echoed the need for a more inclusive view of nutrition, particularly during the pandemic. “I actually see nutrition care in COVID-19 as a pillar of overall care,” she said. “That pillar of care should be applied to all patients.

In the time of COVID-19, it’s even more important.”

—Alison McCook Dr. Gramlich reported financial relationships with Abbott, Baxter, Fresenius Kabi and Takeda; Dr. Ayers with American Regent and Fresenius Kabi; and Mr. Mirtallo with Fresenius Kabi.

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8 Clinical

Pharmacy Practice News • October 2020

Nutrition

Making Off-Label Feeding Safer in Pediatrics A

close look at the off-label use of Smoflipid in neonates and pediatric patients has led one hospital to change its treatment algorithm—most critically, administering the alternative lipid injectable emulsion (ILE) earlier to improve the chances of preventing or resolving cholestasis.

“We’re now trying to treat children sooner rather than waiting for cholestasis to develop,” said Charles Vanderpool, MD, CNSC, the medical director of the Nutrition Support and Intestinal Rehabilitation Program at Indiana University School of Medicine, in Indianapolis, and a co-author of a new study detailing their findings (JPEN J Parenter Enteral Nutr 2020 May 26. [Epub ahead of print]. doi: 10.1002/jpen.1929).

Resolving cholestasis is critical for optimal outcomes. The condition, in which the flow of bile from the liver stops or slows, can lead to intestinal failure–associated liver disease (IFALD), which occurs in 25% to 50% of neonates receiving prolonged parenteral nutrition (Neoreviews 2020;21[9]:e591-e599). Smoflipid (Fresenius Kabi), a lipid emulsion made up of soy, medium-chain triglycerides, and olive and fish oils, has been suggested as a possible treatment for IFALD. However, lipid therapies also have raised concerns given their lower levels of essential fatty acids (EFAs), which increases the risk for EFA deficiency (EFAD).

To identify which patient characteristics might best predict responses, the team conducted a retrospective chart review over two years of all

neonates who received Smoflipid therapy at Riley Hospital for Children, in Indianapolis. Among those started on Smoflipid, 42 (89%) had cholestasis. The team compared these patients based on response to the therapy. Sixteen patients (38%) with cholestasis had resolution during Smoflipid therapy. Older age at treatment appeared to improve the chances of resolving cholestasis (58 vs.

33.5 days; P=0.01). Longer treatment with Smoflipid (85.5 vs. 41 days; P=0.001) and lower direct bilirubin at the start of

the therapy (3.7 vs. 5.2 mg/dL; P=0.035) also increased the chances of resolution.

The findings led their center to consider Smoflipid therapy for children at risk for cholestasis or who have shown even a modest increase in direct bilirubin, Dr. Vanderpool explained.

His team found that EFAD was present in 54% of patients on Smoflipid.

However, none of the patients exhibited clinical symptoms of EFAD, such as a dry scaly rash, hair loss or reduced gr ggrowth owth rate. “II think it is a

‘Given that [Smoflipid] is a relatively new lipid emulsion within the United States pediatric medical community, it is important to monitor patients for appropriate dosing, adverse events and safety concerns when used off-label.’

—Charles Vanderpool, MD, CNSC

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safe lipid, but Smoflipid is currently FDA approved for use in adults only,” Dr. Vanderpool said. “Given that it is a relatively new lipid emulsion within the United States pediatric medical community, it is important to monitor patients for appropriate dosing, adverse events and safety concerns when used off-label.”

Gordon S. Sacks, PharmD, BCNSP, the senior director of medical affairs for Fresenius Kabi USA, noted that the Mayo Clinic Laboratory fatty acid profile (T:T ratio) reference range of no more than 0.05, used in the study to diagnose EFAD, is much lower than the more traditional Holman Index of no more than 0.2.

No patients met the latter definition, Dr. Sacks noted. “Adequate EFA provision is vital in this population to maintain growth and support brain and retinal development,” he added. “We agree with the study authors that use of new products, such as alternative ILEs, warrant close monitoring by a multidisciplinary team that is knowledgeable about interpreting the fatty acid profile (T:T ratio) to establish a diagnosis of EFAD.” Historically, the only ILEs available in the United States were 100% soybean oil.

Although effective in preventing EFAD and providing a balance of nutrient sources, these ILEs also have been associated with liver disease in neonates and patients on long-term nutrition therapy (J Parenter Enteral Nutr 2017;41[1 suppl]:3S13S). Over the last few years, pharmacists and dietitians have welcomed additional options, including Smoflipid and Omegaven, also from Fresenius Kabi, as well as Baxter’s Clinolipid.

Although Smoflipid is not yet FDA approved for use in children, it is frequently used off-label. Omegaven, on the other hand, is FDA approved for nutrition-associated cholestasis, “and currently has more data to support its use,” said Joseph Ybarra, PharmD, the director of corporate clinical pharmacy for Christus Health, in Irving, Texas.

Although Dr. Vanderpool’s study is limited by being retrospective and lacking a protocol for dosing lipids, it provides useful information, Dr. Ybarra said. “Eventually, these therapies will be FDA approved [for children],” he said. “If not dosed properly, Smoflipid will lead to EFAD. With the old products, we never worried about that. Still, while EFAD should be looked at and monitored, it wouldn’t dissuade me from using this in practice.

“As we always say, more studies are needed. And this is no exception.”

—Lynne Peeples The sources reported no relevant financial relationships other than their stated employment.

Clinical

Pharmacy Practice News • October 2020

9

Infectious Disease

5 Tips for Making Rapid Diagnostic Testing a Success

R

apid diagnostic tests (RDTs) play an important role in treating infections.

Antibiotics are changed, de-escalated or stopped based on the results. The process, when it works, can save patients from taking unnecessary drugs, speed up their recovery and decrease health care costs (Clin Infect Dis 2013;57[9]:1237-1245).

Pharmacists are an important part of this effort, serving as the interface among the physician, microbiology laboratory and antimicrobial stewardship team, to improve antimicrobial use and patient outcomes. Their role is essential, explained Timothy P. Gauthier, PharmD, BCPS, the manager of the antimicrobial stewardship clinical program at Baptist Health South Florida. “These technologies enable us to get people on the right medications faster,” he said. “Pharmacists can really help to make sure these tools are used, and they’re used correctly.”

Here’s how to get the most out of RDTs: Make sure the test is ordered.

When pharmacists learn there is a positive blood culture, the first question they should ask is whether an RDT is available, Dr. Gauthier said. “The physician may not even know RDTs exist [for that particular infection],” he said.

Not every infection requires an RDT, he noted, but for many it is useful.

Make friends. Teamwork makes a dream work, and that’s definitely true with RDTs. Pharmacists work closely with the antimicrobial stewardship team, and it’s also beneficial to have a good working relationship with the lab, Dr. Gauthier noted. “Medical laboratory staff bring tremendous value to clinical pharmacists, and they’re highly underrecognized,” he said.

Show their worth. Although RDTs are quite common, facilities may balk at widespread implementation due to cost. If an administrator doubts the benefit of these tools, share data that show they make a difference. One study looked at RDTs’ effect on therapy for gram-positive bacterial infections, using pharmacists to notify prescribers of results and make treatment recommendations. They found the process cut time to optimal antibiotic therapy (8.4 vs. 15.4 hours using traditional culture; P=0.0095), and enabled more providers to change antibiotics within two hours (28% vs. 10.5% without the RDT and pharmacist intervention; P=0.0002) (Hosp Pharm 2016;51[10]:815-822).

Pharmacists can point to other research, too, such as a 2013 paper that showed an RDT with an antimicrobial stewardship program enabled providers to identify organisms more quickly (55.9 hours with the intervention vs. 84.0; P<0.001) and start optimal antibiotic therapy faster (47.3 hours with the intervention vs. 90.3;

P<0.001). Patients who received the intervention also had lower mortality (14.5% vs. 20.3%), spent less time in intensive care (8.3 vs. 14.9 days), and experienced a lower rate of recurrent bacteremia (2.0% vs. 5.9%) (Clin Infect Dis 2013;57[9]:12371245).

Even using a rapid polymerase chain reaction test that scanned for only methicillin-resistant Staphylococcus aureus was associated with $21,000 less in hospital

costs per patient, on average (P=0.02) (Clin Infect Dis 2010;51[9]:1074-1080).

Stay up-to-date. Often, the challenge of RDTs is interpreting the results, Dr. Gauthier said. This step can be a particular concern for generalists, who may not be familiar with how the data should be applied to a given patient.

RDT technology is continually evolving and pharmacists have to stay current, he said. Read the literature and look to your

RDT provider: Some offer education to facilities that adopt the technology.

Don’t rely only on RDTs. Medicine isn’t only about test results.

Although RDTs are a valuable tool for making treatment decisions, the most important thing to consider is the patient’s response.

—Alison McCook

DISCOVER FOR YOURSELF at

bridion.com Copyright © 2020 Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc. All rights reserved. US-XBR-00693 02/20

Dr. Gauthier reported serving as a consultant to Pattern Bioscience.

10 Clinical

Pharmacy Practice News • October 2020

Infectious Disease

Emerging Drug-Resistant Candida a Challenge T

en years since the first report of Candida auris—found in a patient with an ear infection in Japan—the highly drug-resistant fungus has taken a foothold in many parts of the world, including the United States. Infectious disease experts are responding with pleas for greater efforts to control and contain the spreading public health threat.

“It’s really hard to kill. I think it’s caught all of us a little off guard,” said Tom Chiller, MD, the chief of the Mycotic Diseases Branch at the CDC. Historically, there were only a handful of Candida fungi that caused human disease. For drug resistance to develop, people needed to use the antifungals for long periods, such as would occur in immunocompromised patients with HIV who may be infected repeatedly, noted Jeffrey Rybak, PharmD, an infectious disease pharmacist and mycologist at the University of Tennessee College of Pharmacy, in Memphis. Over the last three decades, less common species began to emerge with higher baseline rates of resistance, such as Candida glabrata and Candida tropicalis. Still, multidrug resistance was relatively rare.

Then, in 2009, along came C. auris, and everything changed.

The CDC has confirmed approximately 800 domestic cases of C. auris.

Much like carbapenem-resistant Enterobacteriaceae and other drugresistant bacteria, the yeast is readily transmitted in health care settings and has often been found to be either drug resistant at the outset of infection or has acquired resistance.

“C. auris is not necessarily hypervirulent or more deadly than other Candida species,” said Dr. Rybak, noting that mortality rates are about the same as other Candida infections: 30% to 60%.

“But if we don’t use the right drug for it, patients don’t do well.”

From Colonization to Infection Nearly all of those approximately 800 confirmed cases—likely an underestimate given that many cases may go unidentified—have been in three states: Illinois, New Jersey and New York. The CDC also has identified more than 1,600 cases of colonization.

A unique characteristic of C. auris is its ability to colonize the skin for prolonged periods, making it much more easily spread. Once colonized with the organism, a patient today is considered always colonized, Dr. Chiller said.

Between 5% and 10% of colonization cases become infections.

Of particular concern are long-term care facilities, where the fungus can spread and persist on surfaces such as bedrails, floors or shared equipment for

weeks, even months. Effective sterilization and handwashing are critical to keep the organism at bay. “If it goes unidentified, it can establish a foothold in that institution and then begin this cascading effect of colonizing and later infecting more and more patients,” Dr. Rybak said.

At that point, eradication is difficult.

Quaternary ammonium compounds

said, is that it requires skin swabs to identify carriers, because “this Candida likes salty parts of the body, not the gut like most other Candida species.”

What’s more, most hospitals are not well-equipped to distinguish different Candida species from a skin swab or clinical isolates. “Even if they sent a culture to a regional hospital, the most common readily available clinical plat-

1 in 3

Number of unnecessary antibiotic prescriptions written annually.

Trouble With Treatments

Source: CDC.

‘If [Candida auris] goes unidentified [in health care facilities], it can establish a foothold … and then begin this cascading effect of colonizing and later infecting more and more patients.’

—Jeffrey Rybak, PharmD are among common agents that frequently fail against the species. David W. Denning, MB BS, FRCP, a professor of infectious diseases in global health at the University of Manchester, in England, co-authored a paper that outlined infection prevention and control measures (Int J Antimicrob Agents 2019;54[4]:400-406). The authors recommended at least twice-daily cleaning of all high-touch surfaces with cleaners such as sodium hypochlorite, peracetic acid and vaporized hydrogen peroxide—while being careful of the products’ toxicities.

Among the factors that make C. auris “challenging to identify,” Dr. Denning

antimicrobial-resistant labs: Applied Biosystems 7500 Fast Real-Time PCR platform. The labs, however, are not necessarily meant to be used for clinical care.

Drs. Chiller and Rybak highlighted the need for more robust screening protocols and the identification of patients who have been through care facilities or parts of the world where the species is prevalent. One strategy may be to put these at-risk patients in contact isolation until confirmation is attained. “If tests come back negative, then you can take them out,” Dr. Chiller said.

“We have to be vigilant and aggressive if we want to control and contain this organism,” he added. “We don’t want the organism to set up shop in lots of our hospitals.”

forms were not designed to identify this organism,” said Dr. Rybak, noting that even the updated versions of these platforms are only correct about half the time (J Clin Microbiol 2019 Aug 14.

[Epub ahead of print]).

A less common platform, matrixassisted laser desorption/ionization– time-of-flight mass spectrometry, is nearly 100% accurate in detecting C. auris. So far, however, few hospitals are able to purchase the platform due to its high cost (J Clin Microbiol 2018;56[4]:e01700-17).

Meanwhile, the CDC has rolled out another accurate tool for screening patients for C. auris in its seven

C. auris is far more resistant to antifungals than other species of Candida.

The yeast is resistant to fluconazole 90% of the time. Fluconazole represents about 80% of all antifungal use in the United States, partly due to its low price and ease of IV or oral administration.

Approximately 40% of C. auris infections are resistant to amphotericin B, which is only available intravenously, and carries a high price and high adverse event profile. The antibiotic is particularly nephrotoxic (Ann Intern Med 2019 Jul 30. [Epub ahead of print]).

Still, the drug has the broadest spectrum of activity against fungal infections and is commonly relied upon as the last line of defense.

The last major class of antifungals, echinocandins, is recommended as first-line treatment for C. auris infections due to a relatively low resistance rate of about 2%. However, three cases were reported in 2019 in which the organism was susceptible to the drugs when initiated but then developed resistance during treatment, according to the CDC. If a patient does not appear to be improving on echinocandins, Dr. Rybak recommended obtaining a confirmatory culture and considering the addition of a secondary agent. However, the use of multiple antifungals is not routinely recommended, he said.

Dr. Rybak emphasized that C. auris need not be a cause for panic. “The better we are at looking out for it,” he said, “the better we can make sure we are appropriately identifying and treating it, and the less of a problem it will become.”

—Lynne Peeples The sources reported no relevant financial relationships.

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12 Clinical

Pharmacy Practice News • October 2020

Oncology

Benefits of Integrated Oncogeriatric Care Are Robust G eriatric assessment and integrated oncology care improve quality of life and decrease unplanned hospitalization and early treatment discontinuation due to adverse events in older people with cancer who are receiving chemotherapy, immunotherapy or targeted therapy, according to findings presented at the 2020 virtual annual meeting of the American Society of Clinical Oncology.

“Our findings suggest that all older people 70 years and above with cancer should receive a comprehensive geriatric assessment to optimize clinical care and health outcomes,” said investigator Wee-Kheng Soo, MBBS, a geriatrician and medical oncologist at Eastern Health, in Victoria, Australia. A comprehensive geriatric assessment focuses on vulnerabilities commonly seen in older people, including difficulty with functional activities, medical issues, polypharmacy, poor nutrition, memory problems, depression and social isolation. “By recognizing these problems early on, you can then apply practical interventions to support them.

In essence, we are staging the aging to enable appropriate care,” Dr. Soo said.

The study—called INTEGERATE (Integrated Geriatric Assessment and Treatment in Older People with Cancer Planned for Systemic Anti-Cancer Therapy)—is the first randomized controlled trial to show the effectiveness of comprehensive geriatric assessment with geriatricians and oncologists working in partnership (abstract 12011). The trial involved 154 patients older than 70 years with cancer, who were going to receive chemotherapy, immunotherapy or targeted therapy. The patients were randomly assigned to receive integrated oncogeriatric care, consisting of a

Table. Elderly Functional Index Score

By Treatment Group

comprehensive geriatric assessment and geriatrician-led management (n=76), or usual care (n=78).

During follow-up, patients in the integrated oncogeriatric care group reported significantly better quality-oflife outcomes on the Elderly Functional Index (ELFI) score at 12, 18 and 24 weeks compared with the group receiving usual care (Table). “The greatest difference was seen at week 18, with an estimated marginal mean ELFI score of 72.0 in the intervention group and 58.7 in the usual care group,” Dr. Soo said. In addition, results from the European Organisation for Research and Treatment of Cancer Quality of Life questionnaires showed that the intervention group had significant improvements in other qualityof-life measures, including functioning, mobility, perception of burden of illness, and worries about the future.

Benefits also were seen at the systems

Follow-up Week

Marginal Mean Score: Intervention Group

Marginal Mean Score: Usual Care Group

12

71.4

60.3

11.1 (3.5-18.7)

0.004

18

72.0

58.7

13.3 (5.5-21.2)

0.001

24

73.1

64.6

8.5 (0.5-16.5)

0.037

level. The intervention resulted in 1.3 fewer visits to the emergency department per person annually, a 39% decrease, and 1.2 fewer unplanned hospital admissions per person annually, a reduction of 43%.

The number of overnight hospital stays also decreased by seven days per person per year (24%). In addition, the proportion of patients discontinuing treatment early due to adverse events was significantly lower in the intervention group (32.9% vs. 53.2%; P=0.01).

Noting that integrated oncogeriatric care resulted in “significant improvements in health outcomes” on patient and systems levels, Dr. Soo pointed out that the trial was one of several studies supporting the role of such assessment presented at the ASCO meeting (additional abstracts 12029, 12009 and 12010).

Ginah Nightingale, PharmD, an

Difference (95% CI)

P Value

associate professor in the Department of Pharmacy Practice at Thomas Jefferson University College of Pharmacy, in Philadelphia, called Dr. Soo’s study important and predicted increased application of geriatric assessment in clinical practice. “I would expect further adoption of the geriatric assessment for all cancer patients over the age of 65, as recommended in an ASCO guideline,” Dr. Nightingale said. “The study further emphasizes the importance of individualizing the recommendations for these complex patients by utilizing the findings from a geriatric assessment and how this relates to improved outcomes.”

—Kate O’Rourke Drs. Soo and Nightingale reported no relevant financial relationships.

Paradigm-Changing Study Results for MSI-H Metastatic CRC

F

ront-line therapy with pembrolirolizumab doubled progression-free survival (PFS) compared with chemotherapy in patients with microsatellite instability– high (MSI-H) mismatch repair– deficient (dMMR) metastatic colorectal cancer (mCRC) during g the KEYNOTE-177 trial, according g to results presented at the 2020 virtual annual meeting of the American Society of Clinical Oncology (abstract LBA4).

The Merck-funded study involved 307 patients with MSI-H or dMMR mCRC who were e randomly assigned 1:1 to receive standard-of-care chemotherapy or pembrolizumab (Keytruda, Merck). Standard-of-care regimens consisted of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) with or without bevacizumab or cetuximab.

Investigators led by Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine, in Paris, reported that median PFS was 16.5 months in the pembrolizumab group and 8.2 months in patients receiving standard of care (hazard ratio, 0.60; P=0.0002). At 12 and 24 months of follow-up, PFS was 55.3% and 48.3%, respectively, with pembrolizumab versus 37.3% and

18.6%, respectively, with standard of care.

Of patients receiving pembrolizumab, 11% experienced a complete response (CR), 32.7% had a partial response (PR) and 20.9% had stable disease. In comparison, 3.9%, 29.2% and 42.2% of patients receiving standard of care had a CR, PR and stable disease, respectively.

In addition, response was more durable with pembrolizumab, with 83% of patients having a response lasting longer than two years, compared with 35% of patients receiving chemotherapy.

Grade 3 or greater treatment-related adverse events (AEs) were less common with pembrolizumab than chemotherapy (22% vs. 66%). Immune-mediated AEs (colitis and hepatitis) were more common with pembrolizumab, whereas the most frequent chemotherapy-related AEs in the standard-of-care group were diarrhea, neutropenia, fatigue, nausea and vomiting, stomatitis, alopecia and neurotoxicity.

“This is a paradigm-changing study,” said Cindy L. O’Bryant, PharmD, a professor in the Department of Clinical Pharmacy at the University of Colorado

Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora. “For our MSI-H metastatic colorectal patients, this provides a potential first-line treatment option that doesn’t contain chemotherapy.

That is huge because the side effects of standard-ofcare colorectal cancer chemotherapy regimens can be debilitating and impactful on patient quality of life and tolerability.”

According to Dr. O’Bryant, based on the results of the trial, if a patient has MSI-H mCRC, a good performance status, right-sided disease and is KRAS wild type, pembrolizumab should be strongly considered as first-line treatment. “For patients who don’t meet that criteria, the advantages of pembrolizumab in this setting are less clear,” said Dr. O’Bryant, a member of the Pharmacy Practice News editorial advisory board.

“Despite the significant increase in PFS and durable responses, the benefit of pembrolizumab in this study was not seen until after six months,” she added. “Until we know more, it is important that patients be individually assessed to determine optimum front-line therapy.”

—Kate O’Rourke Dr. André reported financial relationships with Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Clovis Oncology, GIC Advice, Gristone Oncology, GSK/Tesaro, HalioDx, MSD Oncology, Pierre Fabre, Roche, Sanofi, Servier and Ventana. Dr. O’Bryant reported financial relationships with GSK/Tesaro and Pfizer.

Clinical

Pharmacy Practice News • October 2020

13

Oncology

Think Twice Before Dose-Reducing Gemcitabine Plus Nab-Paclitaxel SAN FRANCISCO—Clinicians should carefully consider reducing the doses of gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel in older patients with metastatic pancreatic cancer. In a large real-world cohort study, patients receiving modified dosing had worse outcomes.

For the treatment of metastatic pancreatic cancer, the dosing of front-line gemcitabine plus nab-paclitaxel is frequently altered from the traditional dosing schedule of days 1, 8 and 15 of a 28-day cycle to a modified dosing schedule of two doses per cycle. The modification often is used in elderly patients as a means of preventing or ameliorating toxicities. This practice may be harmful, according to a series of 1,317 older patients in which a modified schedule did not meet the criteria for noninferiority with respect to time on treatment or overall survival (OS), investigators from Fox Chase Cancer Center, in Philadelphia, reported at the 2020 GI Cancers Symposium (abstract 655).

“With the caveats of potential confounding that exist in a de-identified retrospective database, these results suggest that dose intensity may be important in patients with metastatic pancreatic cancer,” said lead investigator Arthur Winer, MD. Previous research conducted by Dr. Winer and his colleagues showed that OS was similar between patients treated with the modified and the traditional schedules, but the population size was small (2019 GI Cancers Symposium, abstract 358).

“We sought to analyze a larger real-world database to assess these trends, so we retrospectively analyzed patients aged 65 and older in the Flatiron Health nationwide database,” Dr. Winer said.

Study Population The 1,317 patients were separated into groups starting with either the traditional (n=842) or modified (n=475)

Table. Outcomes With Modified and Traditional Dosing of Gemcitabine Plus Nab-Paclitaxel Traditional Dosing

End Point

Modified Dosing P Value

schedule. The only Median time on treatment, first line, 3.68 1.55 <0.001 baseline difference in months the groups was that the median age of the modMedian time on treatment, second 2.99 2.30 0.4 ified cohort was one line, months year older (73 vs. 72 years in the traditional Median overall survival, first line, months 8.82 4.67 <0.0001 group; P<0.001). GemMedian overall survival, second line, 6.78 5.82 0.05 citabine plus nab-paclimonths taxel was given in the first-line setting to 1,237 patients, 60% of whom pancreatic cancer. Clinicians should think whether received standard dosing and 40% modified dosing. they really need to start with lower dosing or whether The researchers analyzed time on treatment and OS, they could try the full dose, understanding that many testing noninferiority of the modified schedule after patients cannot tolerate it,” he cautioned. adjusting for age, sex, race, performance status and “The data reported in this study is intriguing with line of therapy. regard to the reasons why some patients started with More patients in the modified dosing arm were likely dose-reduced regimens and the potential reduced to start treatment with a reduced dose of gemcitabine survival in dose-reduced patients,” commented (32% vs. 20%; P<0.001), but over the course of treatAndrew Orr-Skirvin, PharmD, the chair of the Department, dose reductions for the two drugs became ment of Pharmacy and Health Systems Sciences at more common in the three-dose cohort (32% vs. 23%; Northeastern University Bouvé College of Health SciP=0.004). “You’re giving more drug and getting more ences, in Boston. He suggested that an appropriately toxicity,” Dr. Winer said. powered prospective study might better answer the However, in both the first and second lines of treatquestion of whether dose reductions lead to reduced ment, the conventional three-dose regimen resulted survival versus whether survival is reduced in patients in longer OS and in the first-line setting, time on treatwho were given reduced doses because of comorbidment was longer with conventional dosing than with ities or performance status. Dr. Orr Skirvin stressed the modified two-dose schedule (Table). The results that “data in other disease states does indicate that were consistent when patients were stratified by perage alone is not a good indicator of poor chemotherformance status. apy tolerance, and may lead to undertreatment in “It’s unclear why patients started with a modipatients with curable malignancies.” fied dosing schedule. Their various comorbidities may have independently influenced their survival,” Dr. Winer said. “However, with some caveats, these results suggest that modified dosing should be used with some caution in patients with metastatic

—Caroline Helwick Dr. Winer reported no relevant financial relationships.

ICI Found Beneficial for Gestational Trophoblastic Tumors

A

velumab showed efficacy against gestational trophoblastic tumors (GTTs), normalizing human chorionic gonadotropin (hCG) levels and allowing for a successful pregnancy in one patient, according to results of the TROPHIMMUN trial presented at the 2020 virtual annual meeting of the American Society of Clinical Oncology.

“Avelumab in GTT patients resistant to single-agent chemotherapy [led] to about 50% hCG normalization without any relapse after treatment discontinuation, with 29 months of follow-up, meaning these patients are likely to be cured,” said lead study author Benoit You, MD, PhD, an oncologist with Lyon University Hospital and Lyon Investigational Center for Treatments in Oncology and Hematology.

As rare placental tumors associated with high levels of hCG, GTTs affect an estimated one in every 1,500 pregnancies (www.ncbi.nlm.nih.gov/books/ NBK470267/). Standard single-agent or polychemotherapy treatments are associated with high cure rates but significant toxicity, Dr. You said, noting that, thus, “there is a strong need for innovative

treatments.”

He and his coinvestigators conducted the phase 2 TROPHIMMUN trial to assess the ability of avelumab (Bavencio, EMD Serono) to normalize blood hCG levels in patients with GTTs. At the ASCO meeting, they presented results from cohort A, which included patients with resistance to single-agent chemotherapy (abstract LBA6008).

Of 17 enrolled patients, 15 were treated and assessable. Normalization of hCG was achieved in eight patients (53%), enabling avelumab discontinuation. “There was no subsequent relapse despite the discontinuation of avelumab,” Dr. You said.

Resistance to avelumab developed in the remaining seven patients (47%), and they were managed using chemotherapy with or without surgery.

One patient in the group with normalization of blood hCG had a normal pregnancy after avelumab treatment and delivered a healthy infant. “This is the first report of a normal pregnancy in a patient cured from her tumor with an immunotherapy, and this provides reassuring data regarding the impact of immunotherapy

on fertility,” Dr. You said.

Patients treated with avelumab experienced mild or moderate adverse events (AEs) including fatigue, nausea/vomiting, infusion-related reactions, dry eye and diarrhea. Three patients developed thyroid disorders.

Commenting on the results, Cindy L. O’Bryant, PharmD, a professor in the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora, said there are case reports on another immunotherapy agent that show benefit in this setting, but this is the first time an immunotherapy has been looked at in a clinical trial.

However, she pointed out that the cure rate with second-line chemotherapy is about 96%, so at this time avelumab should not be used in this setting for all patients with GTTs. “We need to understand more about biomarkers as well as disease factors of patients that would predict response to avelumab before it can be recommended as an initial second-line treatment,” said Dr. O’Bryant, a member of the Pharmacy

Practice News editorial advisory board.

“This is a small study and we need more data in a larger patient population, but this could be considered as a treatment option for patients who can’t tolerate more chemotherapy or patients who are thinking about fertility moving forward.”

—Kate O’Rourke Dr. You reported financial relationships with Amgen, AstraZeneca, Bayer, Clovis Oncology, ECS Progastrin, GlaxoSmithKline, GSK/Tesaro, Novartis and Roche/ Genentech. Dr. O’Bryant reported financial relationships with GSK/Tesaro and Pfizer.

14 Clinical

Pharmacy Practice News • October 2020

In Brief

Dex Beats Propofol for Timed Outcomes After Cardiac Surgery ORLANDO, FLA.—Dexmedetomidine proved superior to propofol with respect to all time-dependent outcomes, a meta-analysis has shown.

Enrico M. Camporesi, MD, a professor emeritus of surgery at the University of South Florida, in Tampa, and his colleagues screened 804 studies, of which 11 were included in the final analysis (1,184 patients). Patients who received dexmedetomidine demonstrated a significant reduction in time to extubation (standardized mean difference, 0.231±0.053; P=0.008). ICU length of stay (LOS) also was analyzed in eight studies, again demonstrating significant benefit in patients who received dexmedetomidine (standardized mean difference,

–0.703±0.143; P<0.0001).

“The difference was approximately five hours,” Dr. Camporesi said.

Mechanical ventilation time also favored dexmedetomidine, although the difference was not significant (standardized mean difference, –0.722±0.446; P=0.105). “It was getting close to significance,” he explained. “The difference would have been significant if we included retrospective data, but we wanted to only include prospective clinical data in the meta-analysis.”

A similar trend was found with respect to hospital

Tracking Diversion During COVID-19 NEW ORLEANS— Drug diversion may be an unrecognized offshoot of the ongoing COVID-19 pandemic.

Security experts cite several high-profile examples, including a pharmacy technician who was charged with the theft of more than 700 hydroxychloroquine tablets and azithromycin from Harbor-UCLA Medical Center in West Carson, Calif., and several other cases of diverted morphine, ventilators, personal protective equipment (PPE) and other key items that are crucial to patient care during the pandemic.

The uptick in diversion can be traced to the pressures of caring for patients during a pandemic, according to Charlie Cichon, the executive director of the National Association of Drug Diversion

Investigators (NADDI), which trains law enforcement, state licensing board members and hospital staff each year. Indeed, hospitals spending more energy on COVID-19 instead of diversion are more vulnerable, Mr. Cichon noted.

“Has diversion stopped? Absolutely not,” he said. “Until a hospital sets up a team diversion program involving pharmacy, nursing, physicians, human resources and a team investigator, they’ll unfortunately find there’s more going on.”

At Upstate University Hospital, in Syracuse, N.Y., the 800-bed health system tracks opioids, COVID-19 medications and PPE, and “treats them all as controlled substances,” said clinical informatics pharmacist Derek Empey, RPh. “We review

LOS, which was examined in four studies. “Once again we were getting close to significance with dexmedetomidine, but not quite,” Dr. Camporesi said. “Some of these studies were 16 years old, so I imagine if a contemporary study was performed, this would likely reach significance.” The standardized mean difference in hospital LOS was –1.133±0.239 (P=0.087).

Nevertheless, these benefits were not without their drawbacks. Indeed, patients who received dexmedetomidine experienced significantly more bradycardia than their counterparts who received propofol (odds ratio [OR], 3.397; P=0.02). Similarly, significantly more dexmedetomidine patients were found to experience hypotension (OR, 1.682; P=0.017).

However, neither medication resulted in serious morbidity or mortality.

electronic documentation and fluctuations in patients’ pain scores [an indication of possible painkiller diversion], and speak with nurses about what they’ve seen.”

Mr. Empey urged alertness to “even minor blips on your diversion radar for proper vetting and followup” because COVID-19 can lower a hospital’s daily census by up to 40% due to lack of elective surgeries. By default, he added, “this will lower total removals of controlled substances and potentially mask diversion patterns that would otherwise be more apparent via reporting and analytics.”

—Michael Vlessides

Security teams have another tool for keeping one step ahead of diverters—reporting them to HealthcareDiversion.org, headed by chairman Tom Knight, who said the site is reviewing dozens of COVID-19–related diversion claims to date.

He said the reports will be posted to the site in the next few months, after he verifies them with public information from law enforcement and other sources. Health care facilities will be able to learn about diversion details from the posts and avoid similar thefts at their own institutions.

FDA Solicits Comments mments On Pediatric Codeine deine Use

New SCD Pain Recs s Call For Individualized Care

T

P

he FDA is asking for physician and d other stakeholder input on the potential al use of cytochrome P450 2D6 (CYP2D6) D6) genotyping in children under the age e of 12 years prior to potentially treating them with analgesic products that include codeine.

The agency, which currently contraindicates codeine use in children under 12 years, is considering modifying this designation in those deemed through genotyping to have normal CYP2D6, a drugmetabolizing enzyme.

“Concerns have been raised in a citizen petition that children under 12 years of age in acute pain may not be able to access appropriate opioid analgesic drugs, and [the] FDA is interested in understanding the scope and impact of any potential access issues,” according to the agency. Specifically, the FDA is interested in feedback regarding the potential role of codeine for pain management in this population, access to and clinical usefulness of CYP2D6 genotype testing, and the availability of e-prescribing in cases where access to opioids is urgently needed.

Codeine-containing analgesics consist of the active ingredient alone or in combination with other active ingredients such as acetaminophen, as in cough and cold remedies. The FDA removed indications for codeine in pediatric patients in January 2018.

The medication’s primary analgesic effect comes from its partial metabolism to morphine through the CYP2D6 pathway. A high level of metabolic variation, however, can result in an insufficient therapeutic effect in poor metabolizers or toxicity in ultra-rapid metabolizers. The risk for potentially fatal respiratory depression in children has long been a concern related to codeine use.

Comments can be submitted to regulations.gov.

—Al Heller

eople living with chronic pain due to sickle ckle cell disease (SCD) should be managed with a variety of pharmacologic and nonpharmacologic strategies, egies, according to new guidelines released by the e American Society of Hematology.

However, many modalities do not have strong evidence in the literature, according to the guidelines, and some common therapies, such as chronic monthly transfusion therapy, are not endorsed as a first-line treatment due to lack of evidence.

A dearth in the medical literature is not new to those treating SCD. The guidelines’ authors noted that while an estimated 30% to 40% of patients with SCD suffer from chronic pain, management remains a “major clinical challenge” due to “the complex and poorly understood pathophysiology that drives both acute and chronic pain” in affected patients. Mechanisms may include hypoxia-reperfusion injury, inflammation, increased red blood cell adhesion, and both central and peripheral nervous system sensitization.

The guidelines stress nonopioid pharmacologic interventions, indicating that some evidence supports the use of serotonin–norepinephrine reuptake inhibitor medications, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants and gabapentinoids. Chronic opioid therapy is not suggested, unless “pain is refractory to multiple other treatment modalities,” the authors wrote, and potential risk for misuse or other adverse effects is low.

Two categories of nonpharmacologic therapies are also recommended with the same level of evidence as the medications: cognitive-behavioral pain management strategies and “provider-delivered integrative approaches (e.g., massage therapy or acupuncture).” Physical exercise, such as yoga, was advised against to treat SCD pain, along with chronic monthly transfusion therapy.

If other treatments fail, transfusion can be an option as long as the patient understands the uncertainty in benefit from the therapy and the possible adverse effects of transfusion, the authors wrote.

The guidelines were published in the journal Blood Advances (2020;4[12]:2656-2701).

—PPN Staff The sources reported no relevant financial relationships.

—PPN Staff

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16 Policy

Pharmacy Practice News • October 2020

Reimbursement Matters

Meeting Medicare’s new rules for COVID-19

Fulfilling the Payor’s Requirements T

here’s just no getting around the issue: You absolutely must know who the payor is and what the requirements are for documentation and subsequent submission if your facility intends to get paid for an admission, clinic visit, service, medication or product. We say this over and over again, yet there seems to be

a reluctance for health care facilities and their various departments to tackle the inherent problems that prevent this from happening seamlessly.

This column walks through some of the new regulations that you’ll need to navigate to ensure proper payment, including rules that apply to COVID-19–related care.

The Coronavirus Aid, Relief and Economic Security Act The Coronavirus Aid, Relief and Economic Security Act increased the weighting factor of the assigned diagnosis-related group (DRG) by 20% for an individual diagnosed with COVID-19 discharged during the COVID-19 pandemic. This 20% payment boost applies to patients

Free CME/CE now available!

CASE DISCUSSIONS ON IMPROVING OUTCOMES OF AMBULATORY SURGERY

“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

with the following ICD-10 (International Classification of Diseases, 10th Revision) diagnosis codes: • B97.29 (other coronavirus as the cause of diseases classified elsewhere) for discharges occurring on or after Jan. 27, 2020, and on or before March 31, 2020.

• U07.1 (COVID-19) for discharges occurring on or after April 1, 2020, through the duration of COVID-19.

Medicare has a responsibility to address any potential integrity risks to the program. To that end, a new rule requires that with admissions occurring on or after Sept. 1, claims eligible for the 20%

Neuromuscular Blockade and Its Reversal RELEASE DATE: FEBRUARY 1, 2020

EXPIRATION DATE: FEBRUARY 1, 2021

Faculty Curtis Choice, MD (Chair) Assistant Professor Department of Anesthesiology Albert Einstein College of Medicine Director, Division of Ambulatory Anesthesia Director of Anesthesiology Montefiore Hutch Ambulatory Surgery Center Clinical Director, Preoperative Services for Hutch Tower II PAT Clinic Montefiore Medical Center Bronx, New York

This activity is jointly provided by Postgraduate Institute for Medicine (www.pimed.com) and MedEdicus LLC. This activity is supported by an independent educational grant from Merck & Co., Inc. Distributed via Anesthesiology News and CMEZone

increase in the MS-DRG weighting factor also will be required to have a positive COVID-19 laboratory test documented in the patient’s medical record. Positive tests must be demonstrated using only the results of viral testing (i.e., molecular or antigen), consistent with CDC guidelines. The test may be performed prior to or during the hospital admission. The concept is simple: If your facility wants to be eligible for payment with the 20% boost, it needs to document that the patient did indeed have a laboratory test completed. The pushback has been fierce, leaving many to wonder, why is it so difficult to have an accurate record of what was done? What changes need to be made to tell the patient’s story accurately, completely, intraoperatively and in a codeable fashion? (For more guidance, visit go.cms.gov/33JrwJb.)

Michael Guertin, MD, MBA, CPE, FASA

The Proposed 2021 OPPS Rules

Director, Leadership and Business Anesthesia Fellowship Director, Faculty Leadership Institute The Ohio State University Wexner Medical Center Columbus, Ohio

In this case, let’s look at the segments of this rule set that address payments for drug administration services, which are effective Jan. 1, 2021. Under the proposed 2021 Outpatient Prospective Payment System (OPPS) rules, virtually all of the codes for drug administration services have increased with the bump in payment ranging from 2.04% to 11.78%. For example, Chemotherapy IV infusion 1 hr will be paid $315.93 (CPT [Current Procedural Terminology] code 95413), with additional payment for longer infusions.

Stan Lando, CRNA Montefiore Medical Center Bronx, New York 1.0 AMA PRA Category 1 Credit™ 1.0 ANCC contact hour (0.2 contact hour of pharmacotherapy credit)

Access today at www.cmezone.com/CU202

Policy

Pharmacy Practice News • October 2020

17

Reimbursement Matters Drug administration is a bundled payment that can yield easy income, yet is often overlooked! Services included in the CPT administration codes include: • use of local anesthesia • starting the IV • access to the IV, catheter or port • routine tubing, syringe and supplies • preparation of drug • flushing at completion • hydration fluid Knowing the above services, however, is just the beginning; proper documentation also must occur to indicate several key components, such as the drug that was given and the time up and the time down for the infusion, so that the correct code or sequence of codes can be applied. The payment rules allow for the drug administration services to be paid for separately regardless of whether or not the drug actually was paid for separately. This means that whether the drug is status indicator (SI) G (pass-through)

or SI K (separately payable), or even SI N (paid as part of the bundle), it must be included on the claim. Remember that the payor might mandate the use of a prepaid specialty drug or a prepaid distributor, which means the drug being administered is considered a $0 priced product in the same manner that a patient assistance drug is $0 priced. Both of these types of products also are eligible for the payment of drug administration fees. This is where more documentation once again is critical, as is a discussion with the revenue cycle team as to how they should be built into the pharmacy information technology system and chargemaster so as not to be confused with the purchased product.

Of course, the person entering the order for these two types of $0 priced drugs also must be aware so that the correct dug build is used.

Now here comes the confusing part: “Chemo” does not really mean “just chemo.” CMS guidance regarding the use of “chemo” versus “non chemo” administrations can be found in the Medicare Claims Processing Manual, Chapter 12, Section 30.5. The following excerpt adds some details, including the caveat that local carriers may have further details (i.e., preferences): • Chemotherapy administration codes apply to parenteral administration of nonradionuclide antineoplastic drugs; to antineoplastic agents for

treatment of noncancer diagnoses (e.g., cyclophosphamide for autoimmune conditions) or to monoclonal antibody agents, and other biologic response modifiers.

• The category of monoclonal antibodies includes infliximab, rituximab, alemtuzumab, gemtuzumab (Mylotarg, Pfizer) and trastuzumab.

• The category of hormonal antineoplastics includes leuprolide acetate and goserelin acetate (Zoladex, TerSera).

My advice is to have pharmacy prepare a list of outpatient IV-administered

drugs and biologics in the formulary and differentiate them for the revenue cycle team as to which CPT codes apply to the administration of which drugs. All too often I have heard the sad tale of leaving this to the discretion of the revenue cycle team. If they implement a hard stop for all drugs that end in “mab,” for example, this prevents the appropriate drug administration codes from being assigned and processed, resulting in a loss of revenue.

Another revenue cycle ploy is to use the hazardous chemical (NIOSH) list as the guide. This once again eliminates the use

of the appropriate code for products that qualify but are not hazardous. Both of these actions are very bad work-arounds that cost the facility precious revenue.

For more guidance from CMS on these issues, visit go.cms.gov/3lPCQLL. Being paid for drug administration fees is a source of revenue, and as you all well know, every contribution to financial stability is essential. Just think, if you missed 1,000 chemo 1 hr codes, you missed $315,930 of pharmacy revenue. That certainly would help the staffing pay pool!

■

online: Catch us binutrition.com

seniu www.fre

ska

Be S.U.R.E. about your lipid injectable emulsion (ILE) SMOFlipid follows expert recommendations to the letter.

Supplement parenteral nutrition with lipids1 Use alternative ILEs as a source of energy and essential fatty acids2 Reduce the load of soybean oil3 EPA- and DHA-containing ILEs should be considered4,5

SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. Contraindications: Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients.

Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL.

>(9505.! +,(;/ 05 79,;,94 05-(5;: +LH[OZ PU WYL[LYT PUMHU[Z HM[LY PUM\ZPVU VM PU[YH]LUV\Z SPWPK LT\SZPVUZ OH]L ILLU YLWVY[LK PU [OL TLKPJHS SP[LYH[\YL (\[VWZ` Ä UKPUNZ PUJS\KLK PU[YH]HZJ\SHY MH[ HJJ\T\SH[PVU PU [OL S\UNZ 7YL[LYT PUMHU[Z HUK SV^ IPY[O ^LPNO[ PUMHU[Z OH]L WVVY JSLHYHUJL VM PU[YH]LUV\Z SPWPK LT\SZPVU HUK PUJYLHZLK MYLL MH[[` HJPK WSHZTH SL]LSZ MVSSV^PUN SPWPK LT\SZPVU PUM\ZPVU

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

18 Policy

Pharmacy Practice News â&#x20AC;˘ October 2020

Reimbursement

340B Deadline Scramble continued from page 1

an external auditing entity. These submissions are required to continue receiving 340B reimbursements.

Manufacturers that have issued this requirement include Merck, Novartis and Sanofi-Aventis.

2. Restrictions on the use of contract pharmacies. Eli Lilly issued restrictions, as of July 1, on three formulations of tadalafil (Cialis), allowing

their distribution at 340B covered entities and their off-site clinics only, a limited-distribution plan approved

by HRSA. In August, AstraZeneca sent covered entities a more restrictive plan: The manufacturer would no longer honor 340B chargebacks for any drugs shipped to contract pharmacies on behalf of covered entities that maintain their own on-site dispensing pharmacy.

Institutions that do not have an on-site dispensing pharmacy will be restricted to a single contract pharmacy. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s the broadest challenge to the contract pharmacy model to date,â&#x20AC;? said Peggy Tighe, JD, a principal at Powers, Pyles, Sutter and Verville, and legislative counsel to the Ryan White Clinics for 340B Access.

These new requirements are causing a lot of confusion, said Neil Minkoff, MD, the chief medical officer for Coeus Healthcare. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s like 340B is half a dozen different programs depending on

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.

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. â&#x20AC;˘ 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 plantderived 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. â&#x20AC;˘ Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. â&#x20AC;˘ 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. â&#x20AC;˘ 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.

Limitations of Use:

ADVERSE REACTIONS

SMOFLIPID (lipid injectable emulsion), for intravenous use BRIEF SUMMARY OF PRESCRIBING INFORMATION 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/products/smoflipid.

>(9505.! +,(;/ 05 79,;,94 05-(5;: Â&#x2039; +LH[OZ PU WYL[LYT PUMHU[Z HM[LY PUM\ZPVU VM PU[YH]LUV\Z SPWPK LT\SZPVUZ OH]L ILLU YLWVY[LK PU [OL TLKPJHS SP[LYH[\YL Â&#x2039; (\[VWZ` Ă&#x201E;UKPUNZ PUJS\KLK PU[YH]HZJ\SHY MH[ HJJ\T\SH[PVU PU [OL S\UNZ Â&#x2039; 7YL[LYT PUMHU[Z HUK SV^ IPY[O ^LPNO[ PUMHU[Z OH]L WVVY JSLHYHUJL VM PU[YH]LUV\Z SPWPK LT\SZPVU HUK PUJYLHZLK MYLL MH[[` HJPK WSHZTH SL]LSZ MVSSV^PUN SPWPK LT\SZPVU PUM\ZPVU INDICATIONS AND USAGE

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 â&#x20AC;˘ Death in Preterm Infants: (see BLACK BOX WARNING) â&#x20AC;˘ 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. â&#x20AC;˘ Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can support microbial growth and is an independent risk factor for the development of catheterrelated 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. â&#x20AC;˘ 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 patientâ&#x20AC;&#x2122;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). â&#x20AC;˘ 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. â&#x20AC;˘ 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

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 â&#x20AC;˘ Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women. â&#x20AC;˘ Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients. â&#x20AC;˘ 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.

9,-,9,5*,:! Singer P, Berger MM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition intensive care. Clin Nutr. 2009; 28(4):387-400. Vanek VW, et al. A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. Nutr Clin Pract. 2012;27(2):150-192. 2015 Canadian Critical Care Nutrition Clinical Practice Guidelines. https://www.criticalcarenutrition.com/resources/cpgs/pastguidelines/2015. Weimann A, Braga M, Carl F, et al. ESPEN guideline: clinical nutrition in surgery. Clin Nutr. 2017;36(3):623-650. McClave, S.A., et al. (2016). â&#x20AC;&#x153;Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).â&#x20AC;? JPEN J Parenter Enteral Nutr. 40(2): 159-211.

the manufacturer,â&#x20AC;? he said. â&#x20AC;&#x153;The requirement that everything needs to come through one dispensing pharmacy inhouse at one hospital, where that entity may cover five or six hospitals with literally thousands of prescribing physicians, seems untenable.â&#x20AC;?

Duplicate Discounts an Issue The manufacturers do have some solid arguments, according to Mark Ogunsusi, JD, PharmD, an associate with the Powers law firm. â&#x20AC;&#x153;The reason they are requesting the 340B claims data centers around the duplicate discount provision of the 340B statute, that prevents manufacturers from having to both pay rebates and also sell drugs at or below the 340B ceiling price. Manufacturers also do have audit authority under the 340B statute, and are permitted to audit covered entities for matters directly related to the 340B statuteâ&#x20AC;&#x2122;s prohibitions on duplicate discounts and diversion.â&#x20AC;?

Covered entities are particularly troubled by manufacturers working on their own to regulate 340B participation without HRSA guidance. â&#x20AC;&#x153;They believe the manufacturers shouldnâ&#x20AC;&#x2122;t be doing this outside of standard notice and comment rulemaking,â&#x20AC;? Ms. Tighe said.

Dr. Minkoff suggested that any loss of health-system revenue due to 340B constraints will not occur in a vacuum. â&#x20AC;&#x153;There will be pushback on commercial plans to increase their hospital pricing to raise revenue, and pushback on Medicaid,â&#x20AC;? he said. â&#x20AC;&#x153;Health plans and payors may start to see downstream consequences.â&#x20AC;?

There also could be HIPAA implications if covered entities transfer their data to the manufacturersâ&#x20AC;&#x2122; online platforms, such as 340B ESP. â&#x20AC;&#x153;Iâ&#x20AC;&#x2122;ve heard covered entities say they donâ&#x20AC;&#x2122;t feel comfortable giving that to the manufacturer or their audit entity without some kind of clear line that theyâ&#x20AC;&#x2122;re absolutely protected should that information be hacked,â&#x20AC;? Ms. Tighe said, noting that several supply chain partners, including Optum Specialty & Diplomat and CVS Healthâ&#x20AC;&#x2122;s Wellpartner have sent letters about this issue. â&#x20AC;&#x153;As it is not a required element for 340B compliance, at this time CVS does not authorize a covered entityâ&#x20AC;&#x2122;s disclosure of any other data to 340B ESP, including, but not limited to, Medicare Part D claims and commercial claims,â&#x20AC;? the Wellpartner letter stated.

The purpose of 340B is to extend scarce resources to reach populations in need, and contract pharmacies aid that mission, Mr. Ogunsusi noted. â&#x20AC;&#x153;Hopefully, a more collaborative approach of resolving these issues will be reached such that the health care safety net is not threatened.â&#x20AC;? â&#x20AC;&#x201D;Gina Shaw

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

The sources reported financial relationships with 340B entities and/or service providers. Š2020, Fresenius Kabi USA, LLC. | All rights reserved. | 0845-SMF-05-07/20

Technology

Pharmacy Practice News • October 2020

19

Infectious Disease

Technology Can Help With Vancomycin Dosing H

ouston Methodist Hospital (HMH) is leading a shift this September toward AUC (area under the curve) vancomycin dosing in all eight facilities of the Houston Methodist health system, said William L. Musick, PharmD, BCIDP, a clinical specialist in infectious diseases at HMH’s 1,200-bed flagship location.

“We knew for almost two years this would be the direction of the new vancomycin guidelines, and the direction we had to move,” Dr. Musick said.

Still, to validate this dosing strategy, HMH analyzed target blood attainment levels and patient safety data of approximately 3,500 courses of vancomycin administered in 2018 and 2019, roughly one-third via the newer AUC approach and two-thirds by the traditional trough level–guided method.

“We [achieved] a 30% relative reduction in AKI [acute kidney injury] events and a 20% relative reduction in the likelihood of abnormally high or low vancomycin trough levels when guided

by AUC,” said Dr. Musick, citing the yearlong research and quality project largely done by Joshua Knight, PharmD, a pharmacy infectious diseases resident at HMH. HMH’s AUC study predated the new vancomycin guidelines issued in March 2020 by ASHP, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists (Am J Health Syst Pharm 2020;77[11]:835864; bit.ly/3hIFl0c).

Software Help To help make the AUC shift more effective, the health system has become an early adopter of integrated software—VigiLanz precision dosing powered by Tabula Rasa Healthcare’s DoseMeRx—to handle the complex calculations of the AUC approach. This integrated software became available in April 2020, after the HMH analysis.

“Knowing that AUC leads to more favorable outcomes, it has to be our

‘Knowing that AUC leads to more favorable outcomes, it has to be our primary method for making dosing decisions. This integrated software eliminates hurdles of complicated math I can’t ask my pharmacists to do.’

—William L. Musick, PharmD

primary method for making dosing decisions. This integrated software eliminates hurdles of complicated math I can’t ask my pharmacists to do,” said Dr. Musick, who heads a team of five infectious disease pharmacists.

HMH has used VigiLanz to aggregate data on antimicrobial usage, dosing and microbiology, and to alert pharmacists about potential antibiotic stewardship issues requiring intervention for the past decade; it has used DoseMeRx to optimize patient-specific dosing for the past five years. Both ran as stand-alone software products, but DoseMeRx will now operate within the VigiLanz platform, which sits atop HMH’s Epic pharmacy management system and Epic electronic health and medication administration records systems, Dr. Musick noted.

This means that patient-specific demographics, laboratory results, medication orders and antibiotic doses administered populate DoseMeRx fields so the software can quickly calculate optimal dosing for adult and pediatric patients. “This expedites dose changes as needed, eliminates the possibility

of data entry errors by end users, and saves a lot of labor time. I think we’ll see better patient outcomes,” he added.

The software is cloud-based, accessible to pharmacists via browser, and issues patient-specific alerts by emails and pagers.

COVID-19 Drives Need For Efficiency The COVID-19 pandemic increased the need for streamlining vancomycin dosing, Dr. Musick noted. The infectious diseases pharmacy team at HMH “easily faced a 25% increase in patients monitored daily on antibiotics, plus the additional workload on investigational agents for COVID-19 because we’re involved in the day-to-day maintenance and screening of all patients in clinical trials for potentially new COVID medications,” he explained in mid-August, when Houston was a hot spot and HMH was caring for between 160 and 170 COVID-19 inpatients.

The added COVID-19 workload made it “quite timely for us getting to speed on this technology, though combining see VANCOMYCIN, page 20

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20 Technology

Infectious Disease

VANCOMYCIN continued from page 19

two former stand-alone systems also required more IT [information technology] support and infrastructure, new trials, and a huge push by us for metrics,” Dr. Musick said. The HMH beta testing of the technology over the past six months hasn’t yielded data that could be disclosed, because “we’re still validating implementation.”

VigiLanz and Tabula Rasa do not have access to HMH’s outcomes data.

But Dr. Musick is seeking a possible collaborative project with both companies to share such data. The goal, he noted, would be to customize use of the programs based on HMH’s patient population rather than generalized patterns of infection and treatment.

Asked to comment, Ronak Gandhi, PharmD, a senior clinical pharmacist in infectious diseases at Massachusetts General Hospital (MGH), in Boston, said, “What Houston Methodist Hospital is doing is a novel, innovative approach. It may provide alternative options to other hospitals that may use both of these software products.

Quickly assessing dosing is absolutely of the essence if a patient has sub- or

supratherapeutic levels of vancomycin.”

Still, Dr. Gandhi noted that buying third-party software for such initiatives is not the only option, as evidenced by his own experience at MGH. He is part of an antimicrobial stewardship team at MGH that augmented its electronic health record system to monitor patients with positive blood cultures in real time last year, without incurring the expense of third-party surveillance software. “Many hospitals of all sizes could emulate our DIY approach if their stewardship team is large enough and the number of positive blood cultures per day isn’t too great,” Dr. Gandhi said.

If, however, a hospital chooses to partner with a vancomycin dosing software vendor, he suggested a few key factors to consider (box).

—Al Heller The sources reported no relevant financial relationships.

WATCH: Guideline author Michael J. Rybak, PharmD, discusses vancomycin monitoring (bit.ly/33PxPL7-PPN).

4 Tips for a Good Vendor Match

H

ospitals need to consider many factors before using third-party software to manage vancomycin dosing. Here’s a good place to start:

1. Size matters. How great is the need for third-party software, judging by how many patients are in the hospital, how many get vancomycin, and which ones get area under the curve-based dosing? There are no definitive benchmark numbers to determine this; rather, base the decision on a hospital’s usage patterns.

That said, hospital and antimicrobial stewardship leadership teams ought to address how to optimize the monitoring of patients on vancomycin. If, for example, there is a good pharmacist-to-patient ratio with a pharmacist on every floor, then the need for third-party software is lower. If there is just one pharmacist for multiple floors, then the need for third-party software to boost efficiency is higher. If a hospital uses a lot of vancomycin, even with a good pharmacist-topatient ratio, it could still require third-party software.

2. Ensure programs are validated. There are several validation steps, but the overall goal is to determine whether a vancomycin software program pulls in the correct data, uses the right pharmacokinetic profiles, can be individualized as needed, and integrates optimally into electronic medical records.

Serving managed care health-system and specialty pharmacy decision makers

3. Optimize maintenance costs. If your hospital is part of a health system, you may be able to negotiate better contract prices for ongoing maintenance of vancomycin dosing software, although it may require payment of multiple contracts. If your health system has both large and small institutions, is it worth the contract price for smaller institutions that have lower patient volumes that are less acute, compared with focusing efforts on larger institutions with larger volumes of more acute patients?

4. Don’t skimp on education. Expect to educate staff to properly use the software, and count on vendors to be available to help with this.

Source: Ronak Gandhi, PharmD.

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Technology

Pharmacy Practice News • October 2020

21

IV Workflow Management

The ROI on IV-WMS continued from page 1

respectively (P<0.001), for a cost savings of $144,019 over three months, and a projected annual savings of $576,076 (Int J Med Inform 2018;115:73-79).

There were 1,160 errors detected during the post-implementation period, with the IV-WMS intercepting 983 errors (84.74%) and pharmacists detecting 177 errors (15.26%).

The hospital’s total number of doses dispensed declined from 110,963 in the pre-implementation study period to 101,765 in the post-implementation study period, and that decline has remained consistent, said co-author John Hingl, BSPharm, the pharmacy manager at Cincinnati Children’s.

“We have not done further calculations of cost savings since we completed the study, but numbers of doses dispensed, if we use that as a metric, have remained proportionally lower. So the cost savings should be continuing,” Mr. Hingl told Pharmacy Practice News.

Some of the savings generated by the new system stem from the ability to efficiently implement changes to the batch schedule. “Although this could be achieved in a manual system, this would be labor intensive as personnel would need to manually sort and print labels required for each batch while real time orders were being created and cancelled,” Mr. Hingl and his co-investigators wrote.

“In a large hospital, this can result in wasted doses being compounded and new doses being missed unless personnel are continuously dedicated to monitoring which orders are being cancelled and created.

“The IV-WMS assists this process by automatically queuing the medications to be compounded, discontinues cancelled orders in real time, and prints each label immediately prior to preparation.”

Mr. Hingl cautioned, however, that implementing batch schedule changes can reach a point of diminishing returns. “We started with batches every two hours, and that just overwhelmed our delivery capacity,” he said. “At our institution, we’ve found that between two and three IV batches per day is the ‘sweet spot,’ but that will be institutionspecific. But regardless of the interval, by using IV-WMS to cut errors and streamline your batching, you can still reduce 90% of IV drug waste.”

General hospitals and health systems may not find quite the same level of savings from IV-WMS as did Cincinnati Children’s, Mr. Hingl noted.

“In a pediatric institution, we do all of our doses in a patient-specific way

that is highly customized,” he said.

“When you are dealing primarily with adults, there is much more standard dosing, often in premade bags that are frozen and can be reused, so your dollar losses from wasted or missing

study showing that 23% of the errors detected by a new IV-WMS implemented at Boston Children’s Hospital were undetectable by the pharmacy’s previous verification practices (Am J Health Syst Pharm 2014;71[15]:13111317). Of those errors, 167 were judged to pose the potential for adverse drug events resulting in moderate (n=146) or severe (n=21) harm.

‘[With IV-WMS], everybody does everything the same way, step-by-step, so you get the same output. That consistency of process results in a very consistent product.’

—John Hingl, BSPharm

Pyxis Cubie [System; BD] usually don’t exist within the pharmacy.”

Beyond merely detecting IV preparation errors, IV-WMS adoption, with its detailed, barcode-based reports, also aids hospitals and health systems in identifying underlying factors contributing to those errors, said Dr. Lin, an assistant professor of pharmacy at the James L. Winkle College of Pharmacy.

In another study, Dr. Lin and Mr. Hingl and their colleagues found that analysis of the hospital’s IV-WMS error reports identified four significant predictors of error risk (Am J Health Syst Pharm 2016;73[12]:887893). One was site of care: According to the investigators, critical care areas

IV-WMS Successes ss se es Reduced wasted and missing IV d doses ses b by 14,176 14 176 and 2,268 doses, respectively.

Saved $144,019 over three months; $576,076 annually (projected).

Flagged 1,160 errors post-implementation; 983 intercepted (84.74%). Pharmacists detected 177 errors (15.26%).

Source: Int J Med Inform 2018;115:73-79.

doses will likely be less. Nevertheless, you could adopt the methodology from our study to assess savings from IVWMS at any institution.”

Barcoding Function a Major Plus The primary value of IV-WMS lies in its barcoding function, said Thomas Moniz, PharmD, the director of pharmacy operations at Northern Light Eastern Maine Medical Center, in Bangor, and a co-author of a seminal 2014

“Barcode medication administration and dispensing have already been proven to decrease medication errors, and this is now a standard from which nursing shall not deviate,” Dr. Moniz said.

“Pharmacy compounding and manipulation of drugs is often more complex than administration with fewer safeguards. For me to grab a wrong vial that is a look-alike or sound-alike is so much easier in the pharmacy IV room, since controls such as profiled

had more errors, which they attributed to the urgency of dosing. Other predictors included staff shift, with the night shift actually having fewer errors than day/evening shifts; day of week, with Sundays and Mondays having higher error rates; and compounding staff type, with technicians having a higher risk than pharmacists, perhaps because of their higher compounding workload. “Risk-factor analysis offers another potential benefit to institutions adopting these systems,” Dr. Lin said.

“But the greatest benefit by far is safety,” Mr. Hingl stressed. With IV-WMS, he explained, “everybody does everything the same way, step-bystep, so you get the same output. That consistency of process results in a very consistent product.”

—Gina Shaw Dr. Lin reported research funding from Baxter. Mr. Hingl and Dr. Moniz reported no relevant financial relationships.

22 Clinical

Pharmacy Practice News • October 2020

Review Article

Practical Considerations for Implementation of Biosimilars in Oncology

Biosimilar Information Technology Integration: Part 2 of 3

DOUGLAS HACKENYOS, PHARMD, BCOP

A

s of August 2020, the FDA has approved 9 antineoplastic biosimilars—biologics that are highly similar to and have no clinically meaningful differences from an approved reference product with respect to safety, purity, and potency.1

As additional biosimilars hit the market, health care institutions face growing challenges in appropriately managing their use. This article is the second in a 3-part series focusing on management and uptake of biosimilars in oncology practice. Biosimilar product selection was reviewed in the first installment, and this article focuses on biosimilar information technology integration. The third article will highlight the role of the pharmacist in provider and patient education about biosimilars. (Part 1 is available at bit.ly/3iVAkSi-PPN.)

Electronic Health Record Build Successful incorporation of biosimilars into the electronic health record (EHR) begins with well-constructed building blocks: electronic prescriptions or medication records. It is important to recognize that biosimilar products have distinct National Drug Codes (NDCs), billing codes, and names that will not allow them to be interchanged as are conventional brand-name and generic medications. Biosimilar electronic medication records (eMARs) should include the unique NDC, HCPCS J code, generic name (with 4-letter suffix), and brand name associated with each unique product. Comprehensive biosimilar builds minimize look-alike/sound-alike (LASA) errors

that may arise with order entry, verification, preparation, and administration (Table). LASA warnings also may be added to each build so they appear on the eMAR and drug labels.

Biosimilar Order Sets In addition to their many other benefits, electronic order sets and oncology treatment pathways can aid biosimilar uptake substantially. A preferred formulary biosimilar may be set as the default agent in a plan to bolster use and prevent provider confusion at order entry. Statements added to treatment plans and electronic consent forms can be used to further highlight formulary preferences and promote patient education related to biosimilars. Defaulted treatment plans also may assist in streamlining the prior authorization referral process and make the preferred biosimilar selection clear to authorization staff.

Default selection of a preferred formulary product within a treatment plan also must be balanced with a need for flexibility. Ideally, plans should be designed to accommodate third-party payor preferences and nonpreferred products supplied by specialty pharmacies or manufacturer assistance programs. Sophisticated EHRs may allow for “toggling” between biosimilars and reference products within a treatment plan to allow pharmacist substitution of the required product. Efforts to minimize or avoid use of brand names in oncology treatment pathway titles, plan parameters, and other order set fields outside of the specific medication order may make future substitutions or product conversions more efficient.

Dispensing Technology Technology within the pharmacy can drastically improve an institution’s ability to incorporate biosimilars into practice. Inventory management systems with electronic barcode scanning can help pharmacy staff differentiate between biosimilars

Table. Tips for Minimizing Look-Alike/Sound-Alike Medication Errors With Biosimilars Order Entry

• Discrete medication records for each biosimilar with full generic name, 4-letter suffix, and brand name • Default order sets/treatment pathways to formulary product preference

Verification

• Discrete medication records for each biosimilar with full generic name, 4-letter suffix, and brand name • Minimize need for substitution upon verification

Preparation

• Barcode scanning • Segregated inventory locations for reference, biosimilar, and subcutaneous product formulations

Administration

• Barcode scanning • Discrete medication records for each biosimilar with full generic name, 4-letter suffix, and brand name • Segregated inventory locations in automated dispensing cabinets

Oncology Pharmacy Clinical Coordinator Department of Pharmacy UConn Health Farmington, Connecticut

and reference products as soon as medications enter the pharmacy. Biosimilar products may be assigned segregated locations using inventory management technology to avoid confusion during stocking and picking of physical inventory. Barcode scanning, image capturing, and dose compounding verification technology also can minimize preparation errors that may result from LASA biosimilar products. Dose preparation and verification technology also may help prevent preparation errors that may result from differences in the preparation of specific products.

For example, vial sizes, reconstitution instructions, and the need for sterile water for injection (SWFI) versus bacteriostatic SWFI vary between singleand multidose trastuzumab products.2,3 Inventory management and dose preparation may be further complicated by the need to stock multiple biosimilars as well as subcutaneous formulations for any given reference product; barcoding technology is essential to avoid errors in such scenarios.

Medication Administration Technology Technology greatly facilitates safe administration of all medications including biosimilars.

The use of barcode scanning and smart infusion pumps can reduce errors that may come with multiple product options. Many institutions are opting to minimize build and maintenance work for their smart pump libraries by using a single entry under a generic name to address both reference and biosimilar products with identical administration instructions. Some eMARs also may allow the addition of intranet links to drug information and patient education resources for biosimilar products for easy access at the point of care.

Conclusion Implementation of a preferred oncology biosimilar product is a complex process that benefits greatly from the use of information technology systems. Comprehensive eMAR builds and technology involved in dispensing and administration will support uptake and minimize errors related to biosimilar use. With third-party payor preference being a major factor in determining biosimilar product selection, it is essential to maintain flexibility in eMAR and oncology treatment pathway design.

References 1.

FDA. Biosimilar product information: FDA-approved biosimilar products. bit.ly/2G3Pnes-PPN. Accessed September 17, 2020.

2. Kanjinti (trastuzumab-anns) [prescribing information].

Amgen, Inc; 2019.

3. Herceptin (trastuzumab) [prescribing information].

Genentech, Inc; 2018.

Dr. Hackenyos reported no relevant financial relationships.

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