Affordable alternatives to pricey ethanol locks

Affordable Alternatives to Ethanol Lock Therapy

Ethanol lock therapy—the use of dehydrated alcohol in central line catheters to prevent catheter-related bloodstream infections (CRBSIs)—has been used widely for pediatric patients on home parenteral nutrition (PN). But with ethanol locks becoming exponentially more expensive, clinicians are employing creative alternatives, a speaker said at the ASPEN 2021 Nutrition Science and Practice Conference.

Problems started as a result of the FDA’s Unapproved Drugs Initiative (UDI), implemented in December 2020, through which drugs marketed prior to current safety and efficacy requirements needed to be reviewed again, said Ruba Abdelhadi, MD, CNSC, the director of nutrition support at the University of Missouri-Kansas City School of Medicine. Products such as ethanol locks (dehydrated alcohol), neostigmine methylsulfate, vasopressin and selenium had been grandfathered into use but are no longer approved, Abdelhadi said. Then, through the UDI, Belcher Pharmaceuticals in 2018 received orphan drug designation for an injection of dehydrated alcohol, with exclusivity through 2025. The company has been charging $1,000 per milliliter, according to published data from Vizient, increasing the wholesale acquisition cost by 668%. (Belcher did not respond to repeated requests for comment.)

‘Disastrous Impact’

“The impact of the ethanol shortage has been disastrous for our patients on home PN,” Abdelhadi said. The UDI “really backfired. It was supposed to be a safety initiative, but now it’s putting our patients in danger of developing CRBSIs.”

There are other options that clinicians can consider depending on patient profiles, Abdelhadi said:

Using ethanol locks with less fre-

quency. Some studies demonstrated a significant reduction in CRBSIs using ethanol locks three days per week (J Pediatr Surg 2010;45[6]:1287-1293) or once weekly (Nutr Clin Pract 2013; 28[2]:226-231) instead of daily.

Using different concentra-

tions. Many centers use 70% ethanol, but in a recent survey by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Intestinal Rehab Special Interest Group, two centers reported using either 50% or 20% ethanol. Using antimicrobial locks. This could be done as a preventive strategy for patients with long-term hemodialysis catheters, limited venous access and a history of recurrent central line–associated bloodstream infections (CLABSIs), or those at increased risk for severe sequelae from a CLABSI. Check with your antimicrobial stewardship program at your institution first, Abdelhadi advised.

Using other agents shown to reduce CRBSIs that reduce bacterial bur-

den. These agents include tetrasodium EDTA or taurolidine-citrate solution.

Abdelhadi also encouraged clinicians to advocate for their patients by informing legislators about this issue, urging the FDA to regulate pharmaceutical products to avoid shortages, asking the FDA to expedite the approval of competing drugs looking to reenter the market, and asking professional society advocacy groups for support. The NASPGHAN Intestinal Rehab Special Interest Group, for example, partnered with the American Academy of Pediatrics to send a letter to the editor of the Journal of Pediatric Gastroenterology and Nutrition, stating the need to “rapidly regain access” to ethanol or other agents used internationally, Abdelhadi said (J Pediatr Gastroenterol Nutr 2020;70[6]:e140-e141).

“There’s not necessarily a shortage of these products, but they’re so expensive that we’re having to pull out our drug shortage management toolkit to try to figure out how to use less,” said Erin R. Fox, PharmD, the senior director of drug information and support services at the University of Utah, in Salt Lake City. “It’s really unfortunate.” Abdelhadi’s suggestions to preserve costs are reasonable, commented Steven Lucio, PharmD, BCPS, the senior principal of pharmacy solutions at Vizient. “These products were pretty narrowly defined in terms of their use,” he said. “You might have some ways to manage it, but by and large you don’t have great ways to completely avoid the increased costs.”

Additional product categories also were affected by the UDI, Lucio said. For example, in 2014, Par Pharmaceuticals received FDA approval for its vasopressin injection Vasostrict, with patent protection through 2035; the company raised the price by as much as 1,644% for a 25-count package (Table).

In most cases, manufacturers going through the UDI process did not conduct new clinical studies but did test purity of the products and reviewed studies already published in the medical literature, summarizing what the drug has done, Lucio said. This makes the price spikes “appear even more egregious,” he stressed. “The increases, as well as the duration of time that competition is removed, seems disproportionate to the work being done.”

Given the potential for regulators to revisit the decision on the UDI, Vizient has shared recommendations to support findings of safety and efficacy for unapproved drugs while avoiding the unintended consequences of this initiative, Lucio said: “We’re very much waiting to see what transpires.”

Table. UDI-Related Price Spikes for Five Drugs

Drug Regulatory History Price Increase

Dehydrated Alcohol 98% to Dehydrated Alcohol 99%

Neostigmine Methylsulfate

Selenium 40 mcg/mL to Selenious Acid 60 mcg/mL

Tralement (trace elements injection)

Vasopressin to Vasostrict • Dehydrated alcohol 98% injection solution was first introduced in 1993 for relief of intractable chronic nerve pain • UDI Status: Received 7-year orphan indication.

• Developed in 1931; gained formal FDA approval in 2013 • UDI Status: de facto exclusivity

• Parenteral selenium first introduced in the 1980s; received formal FDA approval as injection on April 30, 2019 • UDI Status: five-year NCE exclusivity through April 2024

• Parenteral trace elements were introduced in the 1970s; Multitrace-5 was first marketed in 1993. • Tralement received formal FDA approval on July 2, 2020. • UDI Status: five-year NCE exclusivity through April 2024 • Developed in 1928; granted formal FDA approval in 2014 • UDI Status: Patent approved as innovation through 2035 • $1,295 ➞ $9,950 • WAC increase of 668% on package of 10

• $157.90 (prior to UDI) ➞ $987.50 (peak during exclusivity) ➞ $173.40 (current) • WAC increase of 525% on package of 10, then gradually decreased to 9.8% above prior WAC price

• $443.25 ➞ $8,575 • WAC increase of 1,190%c on package of 25

• $312.50 ➞ $537.50 • WAC increase of 72% on package of 25

• $283.25 ➞ $4,939 • WAC increase of 1,644% on package of 25

Effect on U.S. Drug Spending (annualized, millions)

Before UDI After UDI

28 215a

60.6 205.8b

8.52 84.9d

34.1 58.7e

30.8 791c

—Karen Blum

Pediatric PN Algorithm

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appropriate initiation, weaning and discontinuation of PN at the hospital, the number of PN orders written per day declined from an average of 45 to 32, said Amber Pulido, PharmD, BCPS, BCNSP, a parenteral nutrition program pharmacist at the medical center. In addition, PN, which had been the most prevalent risk factor for CLABSIs, present in 49% of cases at the medical center, dropped to the fifth most prevalent risk factor, present in 29% of cases, Pulido reported at the virtual ASPEN 2021 Nutrition Science and Practice Conference (abstract 947414).

In 2018, Pulido and her colleagues noted that growth in PN use was challenging the limits of their ordering system. They hypothesized that overprescribing of PN due to inappropriate initiation and/or duration was causing the high utilization. “Overprescribing of PN increases costs, compromises PN component supplies in an era of frequent shortages, and increases the risk of errors and complications including CLABSIs,” she said.

One issue they observed was a hesitancy to prescribe enteral nutrition for children who didn’t want to eat but had a working GI tract, Pulido said. “It was perceived as more gentle to the patient to receive PN, when in actuality there’s a lot of risks associated with that.”

Intervention efforts began in February 2019, with an educational campaign. During monthly meetings of dietitians and pharmacists who wrote PN orders, the team first reviewed ASPEN consensus guidelines on when PN is appropriate (JPENJ Parenter Enteral Nutr 2017;41[3]:324-377) and discussed with them how the recommendations applied to their hospital patient population. One tip they gleaned: PN is indicated if an infant is going to be NPO for three days. They also provided education on the hospital’s goal to reduce CLABSIs and how PN is a risk factor for these infections, and conducted focused case reviews of recent PN patients who had contracted CLABSIs.

Next, to ensure appropriate initiation, Pulido’s team asked dietitians to report all new start PN orders so they could audit them according to recommended clinical practice guidelines (JPENJ Parenter Enteral Nutr 2002;26 [6]:377-381). They also conducted random sample audits of active PN orders, looking for ongoing appropriateness, and celebrated prevented inappropriate PN starts through monthly team meetings and weekly huddles among the dietitians.

The investigators recruited two internal multidisciplinary teams to help establish an algorithm for appropriate weaning and discontinuation of PN. One team drafted guidelines, and the other affirmed and validated those standards in relation to the hospital’s recent cases. The algorithm divided patients into those who were more nutritionally at risk and those who were more nutritionally stable, with a separate work flowchart for each group.

The team implemented their new standards and audited all PN discontinuations, looking for alignment with the new algorithm. Over a five-month period from April to

September 2020, more than 90% of PN discontinuations aligned with the algorithm. “Education and engagement were critical to our success with this [quality improvement] project,” Pulido said. “We were able to create a cultural shift where, instead of emphasizing only our patients’ unique needs for our most intense nutrition intervention, we brought into focus patients’ risks from overintervention. Whereas previously we might have talked about costs, workload or the virtues of the gut to try to discourage overprescribing of PN, we found that avoidance of patient harm was a powerful motivator for change.”

A Similar Plan

The approach that Pulido and colleagues took is reasonable, commented M. Petrea Cober, PharmD, BCNSP, BCPPS, a clinical pharmacy coordinator in the neonatal ICU (NICU) of Akron Children’s Hospital, in Ohio.

Cober and colleagues worked on a similar plan regarding the use of starter PN solution for newborns in their NICUs. With multiple NICUs and three neonatology groups, some people’s interpretation of who needed the solution right away was broader than others, Cober said. Pharmacists developed a protocol for which patients most required it (lowbirthweight infants under 1,800 grams) and worked to educate the NICU and neonatology staffs. As a result, orders dropped significantly during the last three months of 2020. The protocol not only avoids potential errors but also helps the pharmacy stock less product, Cober said. Details were scheduled to be presented at the Pediatric Pharmacy Association’s virtual annual meeting in late April.

“It’s good to be able to see pharmacists justify protocols at their own institutions,” Cober said. “With drug shortages, if you can judiciously use the products, then you know that the people who truly need it are going to get it.”

YES NO

YES NO NO

YES

YES NO

Do NOT order a PN providing <20% PN goal kcalc

a If oral intake is unable to advance to goal within 2-3 days of demonstrating adequate GI function, a feeding tube should be placed to facilitate weaning off PN. b For well-nourished otherwise well infants, consider discontinuation when EN expected to reach ≥ 60% goal kcal in the next 24 hours. c Unless severe malnutrition/malabsorption/very low birth weight. —Karen Blum

The sources reported no relevant fi nancial disclosures.