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The Cost Equation for CSTDs
Can a hospital make a sound economic evaluation when it comes to purchasing a closed system drugtransfer device (CSTD)?
A group of Canadian researchers say no. They claim the literature addressing the economic impact of CSTDs is sparse, and the evidence in the handful of studies that do tackle the issue lacks robustness (Eur J Hosp Pharm 2020;27[6]:361-366).
But is there a potential for a comprehensive cost-effectiveness analysis of a disposable device that’s essential for preparing and administering hazardous drugs? Such data could be a major benefit to hospitals making the case to their C-suites for investing in the devices, which can cost hundreds of thousands of dollars per year for a high-volume cancer treatment center.
Patricia C. Kienle, RPh, MPA, BCSCP, the director of accreditation and medication safety at Cardinal Health, told Pharmacy Practice News that the answer is yes. Furthermore, it is imperative to do so, she said, because “cost is the biggest barrier to adopting CSTDs.” But cost, Kienle said, should only be one piece of an equation that she termed the “big triad” of decision-making factors, which also include safety and efficacy. It’s the same trio that pharmacists use to assess formulary drugs, she noted.
Safety may be the easiest aspect to evaluate. Despite what the Canadian researchers found in their review, Kienle said, “there are plenty of studies in the literature that say these devices absolutely work to protect personnel against contamination of chemotherapy when used correctly” (J Oncol Pharm Pract 2019;25[5]:1160-1166).
Setting standards for assessing efficacy may be more challenging. After nearly four years of waiting, the National Institute for Occupational Safety and Health (NIOSH) still has not published the final unified testing protocol that could help hospitals decide which of the CSTDs they have under consideration—either the mechanical barrier types or the air-cleaning models—are most effective in preventing hazardous drug escape and personnel exposure.
Then there’s the economics portion of decision making. Kienle ticked off three key determinants in weighing whether a purchase makes sense financially: the price of the device itself; the available reimbursement; and the cost of antineoplastic drugs—a big-budget item that some health systems have tried to moderate by using CSTDs to optimize the value of single-dose drug vials through beyond-use dating (BUD).
Unlike Europe and Canada, she said, in the United States device cost “is largely driven by which group purchasing organization the hospital uses. And sadly,” she added, “the decision is often made solely by materials management looking at which one is cheapest, without involving pharmacy and nursing to see which one works best in their organization. That’s a problem from a cost perspective.”
As for reimbursement, Kienle noted that the CSTD economic study mentioned above was done by Canadian researchers and published in a European journal, but the way health systems get paid in this country is far different from Europe or Canada. Moreover, most health systems do rate safety and efficacy above cost when assessing CSTDs.
At Cone Health, in Winston-Salem, N.C., for example, Andre Harvin, PharmD, the director of Pharmacy, Oncology Services, told Pharmacy Practice News that although cost was a consideration in deciding on a CSTD upgrade, “it was never from a ‘hey, this is going to save us money’ perspective.”
“It’s a big pill to swallow,” Harvin conceded, referring to the cost of CSTDs, “but what we look at is the potential for preventing exposure to our technicians and nursing staff and reducing spills around the hood.”
Last year in the midst of the COVID-19 pandemic, Harvin said, “we did look at the relative cost per component to find ways we could save money.” But the savings, he added, were “nothing earthshattering.”
He drew a parallel between the benefits of CSTDs and Cone Health’s automated robotic compounding technology. The latter, he said, “is a multimilliondollar system that is not only a robot, but also provides gravimetrics for anything drawn up by hand.” He added: “That’s a hard return on investment to talk about. We justify it by safety and reducing low-level exposure for technicians.
—Andre Harvin, PharmD
It’s safety, it’s quality, it’s accuracy that we’re really looking for.” The same standard applies to CSTDs, he said.
“I never get the argument of why you have to bring an ROI to the table for some of these [technologies],” Harvin added. “Either you invest in quality and safety, or you don’t.”
Drug Vial Optimization
The use of CSTDs for drug vial optimization (DVO) could help to offset part of the devices’ acquisition costs. But the practice remains controversial. It requires elaborate safety testing to prove the drugs remain stable and uncontaminated as a result of CSTD use. The tests are complex and remain beyond the reach of most hospitals. Kienle said accrediting organizations have been citing hospitals throughout the country for using the devices to extend vial BUD unless they have performed the required tests.
Kienle said: “I really want this extended BUD to work, and I’ve been saying this for years. I want to save drug and I want to save money. But I wouldn’t do it at the expense of not knowing the safety to the patient.”
Dmitry Walker, PharmD, the assistant director of Oncology, Infusion and Investigational Drug Services at West Virginia University (WVU) Medicine, in Morgantown, said the use of CSTDs for DVO would “give hospitals the potential to extend dating and realize cost savings by reducing the amount of wasted drug that is left over in each vial after compounding patient-specific doses.” But the challenge, he said, is performing the BUD stability studies required for every drug and concentration. “I would like to be able to do that here at WVU Medicine for a lot of our monoclonal antibodies because of their high cost,” he said.
He cited four examples of “drugs we were interested in pursuing”: polatuzumab vedotin-piiq (Polivy, Genentech), nivolumab (Opdivo, Bristol Myers Squibb), trastuzumab (Herceptin, Genentech) paclitaxel protein-bound (Abraxane, Bristol Myers Squibb), and applicable biosimilars.
“The issue we’re running into is that they are large-molecule drugs; [it’s] not as easy as doing stability studies for regular molecule drugs like chemo,” Walker said. “The molecules are so large they require more sophisticated technology, and that is very expensive and very difficult to do for a health system. So, that’s the main barrier of being able to show the financial value of using CSTDs for the new agents that make up the large percentage of the drug spend at oncology centers nationwide.” —Bruce Buckley
Kienle is a member of the USP Compounding Expert Committee, but her comments in this article are her own and not those of USP or Cardinal Health, her employer. Harvin and Walker reported no relevant fi nancial disclosures.
A pharmacist uses a proposed NIOSH vapor containment testing protocol to evaluate the facility’s CSTD equipment.
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More on Web Buprenorphine In Chronic Pain Management: A New Look at a Familiar Agent
RELEASE DATE: AUGUST 5, 2020 EXPIRATION DATE: SEPTEMBER 30, 2021
This activity is jointly provided by Global Education Group and Applied Clinical Education.
This activity is supported by an educational grant from BioDelivery Sciences International, Inc.
Distributed by Anesthesiology News, Pain Medicine News, and CMEZone.com
Faculty
Joseph V. Pergolizzi Jr, MD
Senior Partner Naples Anesthesia and Pain Associates, Inc. Naples, Florida
Yvonne D’Arcy, MS, APRN, CNS, FAANP
Pain Management & Palliative Care Nurse Practitioner Point Verde Beach, Florida
Lean Thinking For CSTDs
FRED MASSOOMI, PHARMD, RPH, BCSCP, FASHP SETH EISENBERG, RN, OCN, BMTCN JIM JORGENSON, RPH, MS, FASHP
St. Paul, Minnesota Visante Inc.
Lean management principles have been used effectively in manufacturing scenarios for decades, particularly in Japan. More recently, the use of Lean concepts in health care1 has caught the interest of regulators, who suggest that the discipline be a guide for training pharmacists who are involved in pharmacy compounding procedures. One of those procedures—the use of closed system drug transfer devices (CSTDs)—may well be an under-recognized area for Lean applications.
The first step is to understand the basics of Lean management principles. Lean thinking begins by driving out waste so that all work adds value and serves customers’ needs. Identifying value-added and non–value-added steps in every process is the beginning of the Lean initiative. More specifically, Lean thinking comprises five principles: 1) defining value, 2) mapping the value stream, 3) creating flow, 4) using a pull system and 5) pursuing perfection.2
Too often in our everyday work in health care, we don’t really think about these principles as we make decisions about technology or design work processes. Often, consideration for things such as value stream mapping only happens once something has broken and needs repair. But the application of Lean principles should be a consideration on the “front end” of technology selection and process design and should periodically be reevaluated for all key processes.
By dismissing Lean principles, health systems lose the opportunity to benefit from its tool kit of efficiencies, consistency, safety and waste reduction. Also lost is the opportunity to improve complex processes while delivering substantial gains to the bottom line.3
Given those benefits, it’s not surprising that the use of Lean concepts in health care has caught the interest of the Massachusetts Board of Registration in Pharmacy, which has published “An Introduction and Guide to the Practices and Implementation of Lean Concepts in a Pharmacy Setting.” The document notes that “sterile compounding, complex non-sterile compounding, and institutional sterile compounding pharmacies shall ensure their employees are trained in lean concepts before renewing their pharmacy license.”4
Making the Initial Assessment
Since the introduction of the first CSTD to the U.S. market in 1998, many new CSTDs have emerged, providing organizations with a variety of options that best fit their compounding and drug administration processes (Table). Preferred features of a CSTD, based on general Lean principles, would include intuitive connections, pre-bonded components to limit the number of attachment/ disconnection steps, pre-purging displacement air into the system, wetting potential of filters, and locking mechanisms that clearly indicate complete connection. In addition, systems also should limit the pressure required to engage and disengage the components, thus reducing the risk for repetitive stress injuries. The risk for repetitive motion injuries is a concerning yet underappreciated issue with drug compounding.5
Each device is very unique in the number of components, component options, mechanism of protection, integration with existing systems and costs, and, thus, should be assessed individually as a system versus generically categorizing the devices as a “CSTD.” The overall effect of integrating any device into medication safety systems must consider each end user’s use of the device(s), standard operating procedures, primary engineering controls, infusion pumps, disposal, staff perception of safety, number of components and overall costs.
Another factor to consider is the FDA’s clearance code for CSTDs, “ONB.” The code is applied to devices that have indications for use with antineoplastic and other hazardous drugs. Regardless of their technology, all devices cleared by the FDA under the ONB code are considered CSTDs.
Lean Attributes of CSTDs
Within updated USP Chapter <800> standards6 and nursing and pharmacy guidelines, the
Table. Closed System Drug Transfer Devices
Device Manufacturer FDA Cleared
BD PhaSeal Becton Dickinson and Company 1998
Spiros ICU Medical Inc 2005
ChemFort or OnGuard with Tevadaptor Simolivia Healthcare Ltd. B. Braun (U.S. Distributor) TEVA Medical Ltd (manufacturer) 2006
ChemoClave ICU Medical Inc 2006
Equashield Equashield LLC 2008
ChemoLock ICU Medical Inc 2013
EquaShield II Equashield LLC 2014
Halo Corvida Medical Inc 2015
Arisure Baxter International Inc 2017
BD PhaSeal Optima Becton Dickinson and Company 2018
NeoShield JMS North America 2018
introduction of CSTDs was mandated for antineoplastic drug administration and recommended for compounding of hazardous drugs. In deciding which CSTD to deploy and how to effectively integrate a CSTD into compounding and administration processes, it is useful to think about these processes in the context of the five Lean principles.
1. Defining Value
Value at the simplest level is the quality delivered plus the customer satisfaction at a defined cost. It is imperative for a new technology such as a CSTD to meet the actual needs of the users. To select the optimal product and integrate that most effectively and efficiently into pharmacy and nursing practices, end-users have to clearly understand what they want and the price they can afford. For a CSTD, this can be challenging because the technology has two main user groups in nursing and pharmacy, both of which come with different needs and elements driving satisfaction. The primary value proposition for both health care professionals in regard to choosing a CSTD is protection—for their patients and for themselves. Compounding and administering medications require diligence in balancing timeliness and expected attributes while ensuring safety from needlesticks and exposure to hazardous drugs.
2. Mapping the Value Stream
In value stream or process mapping, the goal is to use the customer’s defined value as the desired end point and then to identify and map all the activities in the processes that contribute to these values. Activities that do not add value to the end user would be identified as waste. The waste can be further delineated into two categories: non-value added but necessary and nonvalue added and unnecessary. The first category should be reduced as much as possible, and the second category is just pure waste and should be eliminated to the maximum extent possible.
By reducing and eliminating unnecessary processes or steps in compounding and administration, including the steps for CSTD application, users can improve the likelihood that they are getting exactly what they want while reducing their costs. In compounding, eliminating the concern for possible needlesticks, overpressurized drug vials resulting in spills/sprays, and lapses in aseptic technique due to individual variations with the use of traditional compounding tools (ie, syringe in combination with a needle) are non-valued waste that may be eliminated by a CSTD.
3. Creating Flow
After reducing wastes from the value stream, the next consideration is to ensure that the flow of the remaining implementation steps runs smoothly, without interruptions or delays. From the moment a CSTD is integrated from the vial, it is in a system of “flow” from compounding, to delivery, to administration and, finally, to disposal. Health systems that employ CSTDs minimize angst by not having to worry about needlesticks, drug vaporous sprays, lapses in aseptic technique and Luer line disconnections and spills, which can lead to delays in therapy and loss of revenue.
Further aiding flow, almost all CSTD manufacturers make options that allow connecting integrated CSTD tubing with the IV bag. When these direct spikes are used in compounding, they eliminate the need to prime tubing in the biological safety cabinet. This not only frees up pharmacy or technician time but also removes large, bulky items from the sterile compounding area. Examples of direct spikes can be seen in the Figure.
4. Establishing Pull
Inventory is considered one of the biggest wastes in any production system. The goal of a pull-based system is to limit inventory and workin-process items while ensuring that the requisite materials and information are available for a smooth workflow. The uniqueness of each CSTD brings a significant variation in the number of components required for use. It is important to understand each component of CSTD systems to determine which components are required for a site’s medication management processes. Value stream mapping is a valuable tool to visualize the number of steps requiring CSTD components and which components are required. If you do not have all required components, this will result in delays, frustrations and safety issues. The importance of nursing and pharmacy defining the specific CSTD components and putting them together helps to understand what works for a particular site.
5. Pursuing Perfection
Waste is prevented or minimized through the achievement of the first four Lean steps. The fifth step of pursuing perfection makes Lean thinking a continuous process improvement endeavor. Pharmacy and nursing should actively promote and encourage continuous learning. As such, they always should look to find ways to use CSTDs to make the process of hazardous drug compounding and administration safer, more efficient and more cost-effective.
Future application of CSTDs includes use outside of hazardous drugs handling, where the noted Lean advantages can be applied to all sterile compounding, and the application of the devices to minimize potential medication waste through drug vial optimization programs.7 As the individual devices continue to evolve and the demand for sterile compounding continues to increase, CSTDs can serve as tools for growth.
Figure. Almost all CSTD manufacturers make options that allow connecting integrated CSTD tubing with the IV bag. When these direct spikes (shown above) are used in compounding, they eliminate the need to prime tubing in the biological safety cabinet. Standard Work
Another hallmark of Lean management is eliminating variations in practice that can lead to increased waste and decreased quality and safety. CSTD components are designed to be modular and integrated in such a way as to standardize a specified method of drug compounding and drug administration. In addition, a well-designed CSTD provides a safe method for flushing tubing after the drug has been administered.8 Since nurses do not have the benefit of working in the same type of contained, controlled environment associated with compounding, the proper use of CSTDs helps to prevent widespread environmental contamination in the patient care areas. In addition, the more intuitive a system is to use, the easier it is to lessen variances in compounding and to facilitate effective training.
The device that integrates into pharmacy and nursing practices with perceived protection from both disciplines is the ideal CSTD. Other Lean attributes to consider are devices with the least number of components, packaging, steps for user-to-device interfacing, steps for device-todevice interfacing and drug transfer. These attributes should be fully vetted and validated at each site to ensure the advertised benefits of a specific CSTD meet the expectations of the staff using the devices. Ultimately, a CSTD should meet the efficiency needs of pharmacy and nursing with the benefits of saving time, controlling costs, minimizing line items and training.
References
1. Going Lean in Health Care. IHI Innovation Series white paper. Institute for Healthcare Improvement; 2005. 2. Womack JP, Jones DT, Roos D. The Machine That Changed the World. Free Press; 2007. 3. Shaw G. The ‘Gemba walk’ and its role in compounding quality assurance. Pharmacy Practice News. June 25, 2020.
Accessed March 16, 2021. bit.ly/3tsYxV0 4. The Commonwealth of Massachusetts; Executive Offi ce of
Health and Human Services; Department of Public Health;
Bureau of Health Professional Licensure; Massachusetts
Board of Registration in Pharmacy; Policy No. 2016013: An Introduction and Guide to the Practices and
Implementation of Lean Concepts in a Pharmacy Setting.
August 2016. Accessed March 13, 2021. bit.ly/3luAl1F 5. Abbot L, Johnson T. Minimizing pain resulting from the repetitive nature of aseptic dispensing. Hospital
Pharmacist. March 2002.
6. USP General Chapter <800> Hazardous Drugs—Handling in
Healthcare Settings. Accessed April 6, 2021. www.usp.org/ compounding/general-chapter-hazardous-drugs-handlinghealthcare
7. Buckley B, Buckley J. Is drug vial optimization set to expire? Pharmacy Practice News. June 8, 2018. Accessed
March 17, 2021. bit.ly/3qUg9aI 8. Polovich M, Olsen M. ONS Safe Handling of Hazardous
Drugs. 3rd ed. Oncology Nursing Society; 2018.
White Bagging Slammed
continued from page 1
the medical benefit to the pharmacy benefit, barring the hospital from purchasing the drug itself and requiring that a prescription be sent to a payor-designated specialty pharmacy for fulfillment and shipment to the hospital.
“A primary motivator for payors to adopt white bagging is that they can dictate who the purchaser of the drug is, mandating that the drugs come from a specific source—often a plan-affiliated specialty pharmacy that is not associated with the health system,” explained Kyle Robb, PharmD, a state policy and advocacy associate with ASHP, during a webinar on the topic. “They believe white bagging gives them more control in negotiating the pricing, reimbursement and distribution channels for these drugs.”
White bagging has been around for years, but hospital and health-system pharmacies have reported an increase in the practice recently, with many of the white-bagging restrictions now being a mandatory component of the drug’s dispensing. The practice “is growing at astronomical rates of double digits per year,” Robb said. “More than 10% of the annual spend year-over-year is being shifted from the medical benefit to the pharmacy benefit for many of these drugs.”
“White bagging takes formulary development and health system-specific policies and procedures around safety and completely disrupts this,” said David Chen, BSPharm, the assistant vice president for pharmacy leadership and planning at ASHP. “This process adds at least 10 extra steps for each patient unique for that payor, and this is happening with multiple payors. It runs counter to all Lean and patient safety models to reduce risk and ensure the best outcomes.”
In addition to potential treatment delays and other difficulties for patients in accessing their medications, Chen noted that white bagging disrupts the ordering process and potentially introduces errors. “With the complexity of these treatments, a complete drug therapy plan is often built into our electronic health records, and this disrupts that. It also can require duplicate ordering and management [processes] because this is technically a patient’s own medication.”
A representative of the FDA told Pharmacy Practice News that the agency “is aware of payor-mandated white bagging activities and is looking further into these and other models that may impact patient safety and supply chain security.”
Chen said ASHP and its members are concerned that payor-mandated white bagging models are being described as cost-saving measures, but in reality are increasing the total cost of care and risks to patients due to significant added cost to coordinate care, a negative impact on managing transitions of care, and medication waste resulting from misdirected and inappropriately dispensed white-bagged medications from payor-designated pharmacies. He added that cases of the detrimental effects of payor-mandated white bagging policies are mounting nationwide.
“ASHP is receiving case studies daily, ranging from a premature baby requiring palivizumab [Synagis, Sobi] for prevention of RSV [respiratory syncytial virus] that took over 13 days to resolve, patients who had their MS [multiple sclerosis] and RA [rheumatoid arthritis] treatment delayed by more than two months due to complications with the payor-designated specialty pharmacy, and medications being sent to the provider multiple days after the treatment dose was due.”
Cost Savings Questioned
At Citizens Memorial Hospital and Health Care Foundation (CMH), in Bolivar, Mo., a rural health care network that provides care to the residents of eight counties in southwestern Missouri, 17 patients are currently affected by white bagging requirements. “They have a lot of frustration with the process,” said Mariah Hollabaugh, PharmD, the system pharmacy director. “At least five of those patients have had to be rescheduled and had delays in care because the specialty pharmacy didn’t have their drugs here on time. We do not have those delays when we order the drugs in advance through our wholesaler.”
Hollabaugh estimated that the patients, three of whom are taking omalizumab (Xolair, Genentech/ Novartis) for asthma, one who is taking belimumab (Benlysta, GlaxoSmithKline) for lupus, and one who is taking rituximab (Rituxan, Genentech/Biogen) for
RA, have experienced average treatment delays of one to two weeks due to white bagging. “When you are talking about conditions that flare up if there is a delay in a monthly medication, and you have the window for treatment delayed by up to 50%, that definitely affects their health,” she said.
One patient, who receives IV iron for chronic anemia, hasn’t just had her treatment delayed—she hasn’t been able to get it at all since January. “We have the drug, but we aren’t allowed to supply it,” Hollabaugh said. “Their specialty pharmacy hasn’t been able to ship it to us for some reason, while we can get it from our wholesaler and could give it to her tomorrow. At some point, if we continue to be unable to get this drug through their specialty pharmacy, she will probably have to travel somewhere else to get her infusion. But that will mean more inconvenience for her; if we aren’t able to offer someone an infusion here, most of our patients have to travel between 40 and 90 minutes one way to Springfield.”
Smaller hospitals and health systems, such as CMH, are particularly affected by white bagging requirements because of their limited negotiating power. Truman Medical Centers/University Health in Kansas City, two hours northwest of Bolivar, also has faced pressure to accede to these arrangements. “It’s become more frequent over the last few months,” said Joel Hennenfent, PharmD, the chief pharmacy officer. “But our pharmacy team has successfully worked with finance to let the payors know that our policies do not allow that practice and our medical staff does not support it from a safety perspective. We then have to work at negotiating the contract to change the terminology to stipulate that we do not accept medications from outside our inhouse pharmacy for safety reasons.”
But CMH is an 86-bed rural health care system and Truman is a 298-bed medical center with twice the patient revenue. “When you’re talking about a handful of patients per payor at our institution, they aren’t going to listen to us when we say no,” Hollabaugh said. “Their stance is that you have to use their pharmacy and there’s no wiggle room. Then, once the delayed product finally gets here, sometimes we get three months of doses because they overshipped to ‘rectify’ the situation from earlier. So, now we have storage issues as well as workflow problems. Our system is designed to charge for medications that we supply, so interrupting that and changing the coding adds to our process. We always have to maintain a list of patients for whom we have to undo our documentation, coding and billing. That doesn’t even touch on the thousands in lost revenue for not being able to bill on those medications, when we barely break even every year.”
The Payors’ Defense
Payors argue that white bagging is saving money for patients. “In 2020, we delivered $10.2 million in savings to Tennessee employers through our Advanced Specialty Benefit Management program,” said Natalie Tate, PharmD, the vice president of pharmacy management for Blue Cross Blue Shield of Tennessee. “Using our specialty pharmacy network, our members can save money right away. Someone whose employer participates in this program and has a high-deductible health plan would see their share of the cost for a specialty drug drop for each visit. If a member is taking [infliximab], for example, they could see their cost drop by around $400 per treatment.”
Tate also said that, for her organization at least, white bagging is not a requirement but a choice. “We’ve offered multiple options for our in-network providers
—David Chen, BSPharm
—Natalie Tate, PharmD
based on their feedback, including one that allows them to continue a ‘buy and bill’ approach. We started by offering a six-month continuity of care program— essentially a transition period during the first half of 2020. During that time, we expanded our specialty pharmacy network and gave providers the option to join it. We had at least one large hospital system and six infusion centers join the network. We’re also offering ‘dispensing provider agreements’ to in-network providers. That’s like a middle ground. Providers can continue to buy and bill for specialty drugs, but at the same rates as our in-network specialty pharmacies. But they don’t have to actually become or set up a true specialty pharmacy.”
Delays in treatment should not be a problem, Tate said. “The specialty pharmacies in our network can deliver drugs in under 24 hours and make sure they’re handled appropriately based on the drug’s requirements. Because they are delivering individual doses just in time for treatment, these specialty pharmacies should also be prepared to handle any type of recall situation as they fulfill orders for our members.”
There is no simple answer or solution to white bagging; “it’s completely site-ofcare dependent,” said pharmacy consultant Bonnie Kirschenbaum, BSc, MS, a member of the Pharmacy Practice News editorial advisory board. “Some hospitals will be radically opposed to it and want to keep their buy-and-bill model, because the loss of revenue looms very large. But there are other facilities that want to retain patients and avoid a devastating cost of product themselves, and stave off financial toxicity for their patients. They will take a completely different attitude toward white bagging.”
Ms. Kirschenbaum pointed to a recent AIS Health Daily industry poll, which asked readers’ views on white-bagging policies: 50% of respondents supported the practice, 43% opposed it, and 7% were neutral.
—Gina Shaw
The sources reported no relevant fi nancial disclosures.
Brief Summary (For full prescribing information refer to package insert) INDICATIONS AND USAGE
EXPAREL is indicated for single-dose infiltration in patients aged 6 years and older to produce postsurgical local analgesia and in adults as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Limitation of Use: Safety and efficacy has not been established in other nerve blocks.
CONTRAINDICATIONS
EXPAREL is contraindicated in obstetrical paracervical block anesthesia. While EXPAREL has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death.
WARNINGS AND PRECAUTIONS Warnings and Precautions Specific for EXPAREL
As there is a potential risk of severe life-threatening adverse effects associated with the administration of bupivacaine, EXPAREL should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity. Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amidecontaining products. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration. • epidural • intrathecal • regional nerve blocks other than interscalene brachial plexus nerve block • intravascular or intra-articular use EXPAREL has not been evaluated for use in the following patient population and, therefore, it is not recommended for administration to these groups. • patients younger than 6 years old for infiltration • patients younger than 18 years old for interscalene brachial plexus nerve block • pregnant patients The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days as seen in clinical trials.
ADVERSE REACTIONS Clinical Trial Experience
Adverse Reactions Reported in Local Infiltration Clinical Studies The safety of EXPAREL was evaluated in 10 randomized, double-blind, local administration into the surgical site clinical studies involving 823 patients undergoing various surgical procedures. Patients were administered a dose ranging from 66 to 532 mg of EXPAREL. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, constipation, and vomiting. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration were pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus, tachycardia, headache, insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain. Adverse Reactions Reported in All Local Infiltration Clinical Studies in Pediatric Patients Aged 6 to Less Than 17 Years The safety of EXPAREL in 110 pediatric patients between the age of 6 and 17 years old undergoing various surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site. Patients were administered a weight-based dose of EXPAREL at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg). In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritus, and tachycardia. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration were bradycardia, muscle spasms, tachypnea, hypoesthesia oral, anemia postoperative, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment. Adverse Reactions Reported in Nerve Block Clinical Studies The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies involving 469 patients undergoing various surgical procedures. Patients were administered a dose of either 133 or 266 mg of EXPAREL. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, pyrexia, and constipation. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration as a nerve block were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, hypoesthesia oral, pruritus generalized, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, body temperature increased, edema peripheral, sensory loss, hepatic enzyme increased, hiccups, hypoxia, post-procedural hematoma. Postmarketing Experience These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes (SOCs): Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin and Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).
DRUG INTERACTIONS
The toxic effects of local anesthetics are additive and their coadministration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:
Examples of Drugs Associated with Methemoglobinemia:
Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic cyclophosphamide, flutamide, hydroxyurea, ifosfamide, agents rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Bupivacaine Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. Non-bupivacaine Local Anesthetics EXPAREL should not be admixed with local anesthetics other than bupivacaine. Nonbupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. There are no data to support administration of other local anesthetics prior to administration of EXPAREL. Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior to administration. Water and Hypotonic Agents Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles
USE IN SPECIFIC POPULATIONS Pregnancy
Risk Summary There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Clinical Considerations Labor or Delivery Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has not been studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death. Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Data Animal Data Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/ kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryofetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity. Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day buprenorphine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation).
Lactation
Risk Summary Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EXPAREL and any potential adverse effects on the breastfed infant from EXPAREL or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of EXPAREL for single-dose infiltration to produce postsurgical local anesthesia have been established in pediatric patients aged 6 years and older. Use of EXPAREL for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 6 years and older. Safety and effectiveness have not been established in pediatric patients aged less than 6 years old for local infiltration or less than 18 years old for interscalene brachial plexus nerve block.
Geriatric Use
Of the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. Of the total number of patients in the EXPAREL nerve block clinical studies (N=531), 241 patients were greater than or equal to 65 years of age and 60 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical experience with EXPAREL has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease.
Renal Impairment
Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. This should be considered when performing dose selection of EXPAREL.
OVERDOSAGE
Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution. Signs and symptoms of overdose include CNS symptoms (perioral paresthesia, dizziness, dysarthria, confusion, mental obtundation, sensory and visual disturbances and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia and asystole). Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,500 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL. Management of Local Anesthetic Overdose At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, maybe indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.
DOSAGE AND ADMINISTRATION Important Dosage and Administration Information
• EXPAREL is intended for single-dose administration only. • Different formulations of bupivacaine are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL. • DO NOT dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles. • Use suspensions of EXPAREL diluted with preservative-free normal (0.9%) saline for injection or lactated Ringer’s solution within 4 hours of preparation in a syringe. • Do not administer EXPAREL if it is suspected that the vial has been frozen or exposed to high temperature (greater than 40°C or 104°F) for an extended period.
• Inspect EXPAREL visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer EXPAREL if the product is discolored.
Recommended Dosing
Local Analgesia via Infiltration Dosing in Adults The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266mg (20 mL), and is based on the following factors: • Size of the surgical site • Volume required to cover the area • Individual patient factors that may impact the safety of an amide local anesthetic As general guidance in selecting the proper dosing, two examples of infiltration dosing are provided: • In patients undergoing bunionectomy, a total of 106 mg (8 mL) of
EXPAREL was administered with 7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue. • In patients undergoing hemorrhoidectomy, a total of 266 mg (20 mL ) of
EXPAREL was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block. Local Analgesia via Infiltration Dosing in Pediatric Patients The recommended dose of EXPAREL for single-dose infiltration in pediatric patients, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), and is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery. Regional Analgesia via Interscalene Brachial Plexus Nerve Block Dosing in Adults The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg (10 mL), and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair.
Compatibility Considerations
Admixing EXPAREL with drugs other than bupivacaine HCl prior to administration is not recommended. • Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. • Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and
EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. The toxic effects of these drugs are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. • When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, the site should be allowed to dry before EXPAREL is administered into the surgical site. EXPAREL should not be allowed to come into contact with antiseptics such as povidone iodine in solution. Studies conducted with EXPAREL demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of EXPAREL any more than they are by saline. None of the materials studied had an adverse effect on EXPAREL.
Non-Interchangeability with Other Formulations of Bupivacaine
Different formulations of bupivacaine are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL and vice versa. Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute.
CLINICAL PHARMACOLOGY Pharmacokinetics
Administration of EXPAREL results in significant systemic plasma levels of bupivacaine which can persist for 96 hours after local infiltration and 120 hours after interscalene brachial plexus nerve block. In general, peripheral nerve blocks have shown systemic plasma levels of bupivacaine for extended duration when compared to local infiltration. Systemic plasma levels of bupivacaine following administration of EXPAREL are not correlated with local efficacy.
PATIENT COUNSELING
Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.
Pacira Pharmaceuticals, Inc. San Diego, CA 92121 USA Patent Numbers: 6,132,766 5,891,467 5,766,627 8,182,835 Trademark of Pacira Pharmaceuticals, Inc.
For additional information call 1-855-RX-EXPAREL (1-855-793-9727) Rx only March 2021
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Indication
EXPAREL® (bupivacaine liposome injectable suspension) is indicated for single-dose infi ltration in patients aged 6 years and older to produce postsurgical local analgesia and in adults as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Safety and effi cacy have not been established in other nerve blocks.
Important Safety Information
EXPAREL is contraindicated in obstetrical paracervical block anesthesia. Adverse reactions reported in adults with an incidence greater than or equal to 10% following EXPAREL administration via infi ltration were nausea, constipation, and vomiting; adverse reactions reported in adults with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation. Adverse reactions with an incidence greater than or equal to 10% following EXPAREL administration via infi ltration in pediatric patients six to less than 17 years of age were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritis, and tachycardia. If EXPAREL and other non-bupivacaine local anesthetics, including lidocaine, are administered at the same site, there may be an immediate release of bupivacaine from EXPAREL. Therefore, EXPAREL may be administered to the same site 20 minutes after injecting lidocaine. EXPAREL is not recommended to be used in the following patient populations: patients <6 years old for infi ltration, patients younger than 18 years old for interscalene brachial plexus nerve block, and/or pregnant patients. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease.
Warnings and Precautions Specifi c to EXPAREL
Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. EXPAREL is not recommended for the following types or routes of administration: epidural, intrathecal, regional nerve blocks other than interscalene brachial plexus nerve block, or intravascular or intra-articular use. The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days, as seen in clinical trials.
Central Nervous System (CNS) Reactions: There have been reports of adverse neurologic reactions with the use of local anesthetics. These include persistent anesthesia and paresthesia. CNS reactions are characterized by excitation and/or depression. Cardiovascular System Reactions: Toxic blood concentrations depress cardiac conductivity and excitability, which may lead to dysrhythmias, sometimes leading to death. Allergic Reactions: Allergic-type reactions (eg, anaphylaxis and angioedema) are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. Chondrolysis: There have been reports of chondrolysis (mostly in the shoulder joint) following intra-articular infusion of local anesthetics, which is an unapproved use. Methemoglobinemia: Cases of methemoglobinemia have been reported with local anesthetic use.
Please refer to brief summary of Prescribing Information on adjacent page. For more information, please visit www.EXPAREL.com or call 1-855-793-9727.
Reference: 1. Data on File. 6450. Parsippany, NJ: Pacira BioSciences, Inc.; January 2021.
