Pharmacy Practice News (August 2020) by McMahon Group

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Corporate Profiles Section begins on page 17.

CLINICAL

Building a just culture of safety ............................... ID pharmacist: fast isn’t always foolproof in COVID-19 .....................

POLICY

Doing the ‘Gemba Walk’ toward cleanroom compliance ..................... 33 SPECIALTY PHARMACY

Pandemic offers lessons for payors, health plans ....................

COVID-19 Spurs Renewed Crisis in OUD Patients

he controversy over the use of hydroxychloroquine (HCQ) and chloroquine (CQ) for COVID-19 has left pharmacists in the middle of the debate, struggling to offer advice. Early anecdotal reports appeared promising, but more recent, betterdesigned studies have shown little or no benefit, and some have demonstrated a risk for cardiovascular and other adverse events. The National Institutes of Health stopped its ORCHID study of HCQ in hospitalized adults with COVID-19 early because the data and safety monitoring board determined that while there was no harm, HCQ provided no additional benefit compared with placebo. An interim analysis of the HCQ arm of RECOVERY (Randomized Trial of COVID-19 Therapy), sponsored by

pioid use disorder (OUD) has become an epidemic within the COVID-19 pandemic, a panel of public health experts said during a webinar organized by the Association of Schools and Programs of Public Health. Without adequate access to treatment, relapse rates among patients with OUD are surging. And when these patients do get access to opioids, their lowered tolerance places them at risk for overdoses, the he experts noted during the webinar. “This is a perilous time for peo-ple with [OUD],” said Brandon n Marshall, PhD, an associate proo-fessor of epidemiology at Brown wn n University School of Public Health, h h, in Providence, R.I. “Counterintuiu uitively, disruptions in the drug supply pply and lack of income to purchase il illicit llicit opioids might have led to a drop in n drug use during the COVID pandemic. However, this could lead to Continued on page 14

Feed the Patient, Fuel the Savings 46

REVIEW ARTICLE

Role of Specialty Pharmacists in Treating Patients With HIV See page 40.

HCQ for COVID-19: Yes? No? I Don’t Know!

Continued on page 10

TECHNOLOGY

Can patients help solve ongoing drug shortages? ......................

Volume 47 • Number 8 • August 2020

new analysis conducted by the American Society for Parenteral and Enteral Nutrition (ASPEN) shows that appropriate nutrition support can save an estimated $580 million in annual Medicare spending. “With evidence from this study, [providers], payors and policymakers must recognize that nutrition support is a linchpin to [providing] high-quality, cost-effective care,” said critical care and nutrition support pharmacist Angela Bingham, PharmD, an associate professor of clinical pharmacy at the University of the Sciences, Philadelphia College of Pharmacy, who was not involved in the research. Continued on page 3

Generics ‘Wall’ Costs Nearly $1B in Lost Savings

recent study in Health Affairs found that when the market entry of generic drugs is delayed due to patent fights and other factors, the price tag for lost savings opportunities approaches $1 billion (2020;39[6]:1011-1017). Among 69 brand-name drugs studied that were expected to lose patent exclusivity in 2010 to 2016, generic entry occurred before or within three months of the expected date for just 38 products (55%), the investigators found. Market entry for generics was delayed by more than three months for 20 products (29%) and did not occur for 11 products (16%). For the 31 products that had delayed or no generic entry, Medicaid spent an estimated

Special Focus:

COVID-19 Pandemic More on pages 4, 12, 16 and 44

$761 million more over seven years, or $109 million annually. Patent litigation was cited as the most common reason for the delays. “Delaying generic entry is one of the key strategies that pharmaceutical manufacturers use to maintain their high revenue streams,” said Aaron S. Kesselheim, MD, JD, MPH, a professor of medicine at Harvard Medical School, in Boston. “That’s a big problem because it raises costs for patients, which reduces patient adherence to important medications. For Medicaid, which provides drug coverage with limited out-ofpocket spending for patients, it raises costs for the health care system.” Continued on page 45

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Clinical

Pharmacy Practice News • August 2020

Nutrition

Good Nutrition Pays Off continued from page 1

As co-author Peggi Guenter, PhD, RN, a senior director of clinical practice, quality and advocacy for ASPEN, and her colleagues noted, disease-related malnutrition (DRM) is common in hospitalized, nursing home and rehabilitation center patients. It can increase inpatient costs by up to twofold, they wrote, citing a study by the U.S. Agency for Healthcare Research and Quality (bit.ly/2J0XJkY). To gain further insight into the economic benefits of addressing malnutrition through nutrition support, Dr. Guenter

and her colleagues created a cost-savings model based on inpatient and outpatient Medicare claims data. Their analysis also included findings from eight studies that focused on the clinical and economic impact of nutrition interventions (J Parenter Enteral Nutr 2020;44[3]:395406). They looked at five therapeutic areas that are among the most affected by nutrition support and had the highest-quality supporting data: sepsis, gastrointestinal cancer, hospital-acquired infections, surgical complications and pancreatitis.

The $580 million in Medicare savings annually was spread across the five key areas. For example, when sepsis patients with acute respiratory distress syndrome (ARDS) receive an enriched enteral nutrition diet, ICU length of stay is 38% shorter, resulting in an estimated $23,000 in savings per person, or $52 million if all sepsis patients with ARDS nationwide were to receive adequate nutrition support, the authors reported. Annual projected savings for other therapeutic areas ranged from $1.82 million for acutely ill adults, due to fewer infections when they receive glutamine supplementation, to $224 million for colorectal surgery patients, who have shorter hospital stays with oral liquid protein supplementation. Explaining a $2 million shortfall associated with early nutrition in patients with severe pancreatitis, Dr. Guenter said early nutrition was so effective in patients with pancreatitis that it saved lives and was associated with more inpatient treatment.

Approaching Payors

“Pharmacists can use these data to approach payors and administrators within their hospital to articulate that nutrition support makes a difference in cost,” Dr. Guenter said. “Pharmacists working with parenteral nutrition, which is considered a relatively high-cost and highalert therapy, can also justify appropriate use of this therapy using our data.”

Dr. Bingham said she was confident these results “only scratch the surface, and if research was expanded to the entire Medicare population beyond the few therapeutic areas included in this study, the savings would be much higher.” Other tools to help pharmacists and providers articulate the value proposition of nutritional support can be found at the ASPEN Value Project (bit.ly/2WrSTFi). —David Wild The sources reported no relevant financial relationships.

More Online Delivering adequate protein to patients in the ICU is critical to optimize outcomes. But how much protein, to which patients, and when, is unclear, according to a presentation at the ASPEN20 Virtual Conference. For more details, view “The Power—and Peril—of Protein in the ICU,” at bit.ly/3ebKhbe.

Early nutrition was so effective in patients with pancreatitis that it saved lives and was associated with more inpatient treatment.

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4 Clinical

Pharmacy Practice News • August 2020

Nutrition

Feeding COVID-19 patients, other practical tips

Improving Outcomes With Early Intervention E

merging evidence shows that nutrition therapy can significantly improve outcomes for many hospitalized patients. But it’s rarely one-sizefits-all, according to presentations at the ASPEN20 Virtual Conference. “We’re moving toward personalized nutrition,” said Philipp Schuetz, MD, MPH, an internal medicine professor at the University of Basel, in Switzerland, who presented during a session supported by Abbott Nutrition Health Institute. “Recent data suggest that it may be possible to better select patients that benefit the most from nutritional interventions.” Malnutrition has long been recognized as an important risk factor for mortality and complications (Nutrition 2010;26[9]:896-901). However, until the last two or three years, research simply demonstrated that malnutrition was implicated in poor outcomes; “it wasn’t clear whether we could change that,” Dr. Schuetz said. In fact, some studies even suggested that nutritional treatment for an acutely ill patient could have a detrimental effect on outcomes (N Engl J Med 2011;365[6]:506-517). Now, larger trials are clearing up some of the confusion. EFFORT (Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial) investigated whether a protocol-guided individualized nutritional support to reach protein and caloric goals reduced the

risk for adverse clinical outcomes in patients at nutritional risk. In that study, Dr. Schuetz and his team found that, compared with standard nutrition provided by a hospital kitchen based on the patient’s appetite, early individualized nutrition managed by dietitians and other clinical experts was associated with decreases in complications (22.9% vs. 26.9%; P<0.05) and mortality (7.2% vs. 9.9%; P<0.05) (Lancet 2019;393[10188]:2312-2321).

Heed Variations Nevertheless, the advantages of nutrition may vary according to patient characteristics and the timing of illness, Dr. Schuetz added. For the polymorbid inpatient, who may present with loss of appetite and muscle mass, nutritional therapy seems to be effective. Patients with high markers of chronic kidney disease also appear to derive significant benefit from nutrition. But it’s important to look at individual factors. One factor that appears to play a significant role is a patient’s level of inflammation. Dr. Schuetz recently co-authored a paper that found patients with high levels of inflammation benefited less from nutrition than those with low or moderate levels of inflammation (JAMA Netw Open 2020;3[3]:e200663). During severe inflammation, the body wants to protect itself from too much external nutrition as it attempts to detoxify and focus on its explained. own protein restructuring, he explained

The T he P Pharmacist’s harmacist’s Role Role

harmacists can play an important role in proactively screening patients to identify those who might benefit from prompt nutrition interventions, according to Angela Bingham, PharmD, an associate professor of clinical pharmacy at the University of the Sciences, Philadelphia College of Pharmacy. “Pharmacists should feel empowered to speak up about the nutrition support needs of their patients,” Dr. Bingham said. “Pharmacists should help the interprofessional team assess feeding tolerance and overcome barriers to nutrition delivery. For example, if a patient is experiencing significant diarrhea, the pharmacist may identify and address a medication-related cause.” Pharmacists also can play a key role in reviewing and then sharing the latest nutrition research with colleagues. “It is essential for interprofessional health care professionals to recognize the value of nutrition support and the significance of emerging research,” said Dr. Bingham, who was not involved in the ASPEN20 Virtual Conference session. “By incorporating nutrition support in interprofessional curricula, we can ensure a pipeline of practitioners with interest and expertise to continue to advance the science and practice of nutrition support.”

—L.P.

Dr. Bingham reported no relevant financial relationships.

“If you [introduce] too many externall proteins to the cells [via nutrition], there is some sort of competition,” Dr. Schuetz said. “With the sickest patients, we need to be careful not to interfere with those detoxification mechanisms.” As a result, “you probably need to be slower with food for the highly inflamed patient,” he added, suggesting the potential relevance to COVID-19, which is a highly inflammatory condition. “Once [COVID-19 patients] are in a stable place, then nutritional treatment is very important, so they don’t lose functional abilities.”

Enteral Nutrition Dr. Schuetz also underscored the importance of using enteral nutrition whenever possible to optimize outcomes in critically ill patients. Co-presenter Kelly Tappenden, PhD, RD, a professor of kinesiology and nutrition at the University of Illinois at Chicago, underscored the point. Although use of the enteral route may appear difficult for some patients due to intestinal intolerances, Dr. Tappenden suggested that apparent intolerances often can be overcome. Many ICU patients have diarrhea, for example, which may appear to result from enteral feeding when it actually is induced by other factors, such as medications that stimulate gastric emptying. “Typically, enteral nutrition is not the cause and does not need to be held,” she said. Dr. Tappenden highlighted several reasons why enteral is the much preferred route of feeding, including its tendency to help stimulate the gut, the microbes within the gut, and the immune system. Indeed, 70% of immune system function occurs in the gut, Dr. Tappenden explained. “When you bypass that, you are bypassing an important part of the immune system and other physiological processes, such as liver metabolism.” Studies have linked early enteral nutrition with improved outcomes, including a 74% reduction in infectious morbidity, a 31% reduction in pneumonia, a 70% reduction in mortality, and a 2.2-day decrease in hospital length of stay (Crit Care Med 2001;29[12]:2264-2270; Intensive Care Med 2009;35[12]:20182027; JPEN J Parenter Enteral Nutr 2016;40[2]:159-211). But there are exceptions, she added. “When enteral nutrition is not feasible or sufficient, then start parenteral nutrition early in high-risk or poorly nourished patients.” The other key, according to Dr. Tappenden, is providing adequate protein. “In recent years, it’s become quite

Studies have linked early enteral nutrition with a:

74% reduction in infectious morbidity

31% reduction in pneumonia

70% reduction in mortality

2.2-day decrease in hospital length of stay. Source: Crit Care Med 2001;29(12):22642270; Intensive Care Med 2009;35(12):20182027; JPEN J Parenter Enteral Nutr 2016;40(2):159-211. Photo credit: ICU Medical

clear that we really need to work hard to provide protein to patients,” she said. Aiming for 70% of daily kilocalorie requirements is probably fine, she suggested, as long as protein requirements are met or exceeded (JPEN J Parenter Enteral Nutr 2016;40[2]:159-211). Again, she said, this is critical for COVID-19 patients. Her basic advice: Feed them early, feed them the right amount, and feed them enterally. She recommended that when a patient is admitted to the ICU, providers should assess the patient for nutrition risk, calculate energy and protein requirements to determine goals of nutritional therapy, initiate enteral nutrition within 24 to 48 hours, and increase to goals over the first week. She also noted a few strategies to reduce aspiration risk and improve tolerance to enteral nutrition, such as use of a prokinetic agent, continuous infusion, chlorhexidine mouthwash, and elevating the head of the bed. Dr. Schuetz underscored the importance of further research. “Maybe in the future,” she said, “we will learn that we should use different kinds of foods, calories or protein goals for different populations based on inflammation and other biomarkers.” —Lynne Peeples Dr. Schuetz reported financial relationships with Abbott, Nestlé and the Swiss National Foundation. Dr. Tappenden reported financial relationships with Abbott Nutrition Health Institute, Alcresta, Dannon Institute International, Oley Foundation, Takeda, VectivBio and Zealand Pharma.

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6 Clinical

Pharmacy Practice News • August 2020

Medication Safety

Using Chemo Safely for Patients Without Cancer I

t’s Wednesday morning, and your coffee is still warm. You’re reviewing your patient list before interdisciplinary rounds, when a new medication order alert pops up: A physician has prescribed the chemotherapy drug cyclophosphamide for a nononcology patient. You think, “Wait ... what?” Pulling up the patient’s chart, you see she is a 55-year-old woman who was admitted to the hospital for lupus nephritis. Your first call is to the medical resident, who says she wants to start the patient on an infusion of highdose cyclophosphamide because, as an immunosuppressant, it can be helpful for rheumatic and autoimmune diseases such as lupus. Cyclophosphamide is metabolized by the liver, and the patient’s bilirubin is within the normal range. Still, the drug can cause serious side effects, so the resident asks for your help in designing a supportive care plan. For decades, rheumatologists and other specialists have used cancer therapy to treat immune disorders and other conditions. But many doctors who don’t prescribe oncology drugs regularly may not know how to develop a supportive care plan and the required monitoring. This is where pharmacists can help. Patients need pharmacists’ expertise, particularly for off-label orders of chemotherapy drugs, said Cassia Griswold, PharmD, a clinical oncology pharmacist at Mayo Clinic in Phoenix. At the 2019 ASHP Midyear Clinical Meeting, Dr. Griswold and Emily Hennes, PharmD, a clinical pharmacist at UW Health’s Pharmaceutical Research Center, in Madison, Wis., shared tips about how pharmacists can implement appropriate monitoring and supportive care to mitigate the toxicity of these drugs. For pharmacists who don’t practice at a large institution or an academic center, it’s likely rare to see chemotherapy drugs being used for noncancer conditions, said Carolyn Oxencis, PharmD, a clinical assistant professor in the Department of Clinical Sciences at the Medical College of Wisconsin, in Milwaukee, who moderated the session. “But when it does happen, the pharmacist bears a significant responsibility for ensuring the patient’s safety and optimal outcomes.” The goal of the presentation, she told Pharmacy Practice News, was to help pharmacists fill that role. “The intent was hopefully to make pharmacists who don’t work in oncology … comfortable seeing these medications being used in noncancer patient populations.”

Follow USP <800> Since cyclophosphamide downregulates the immune system, it’s commonly used off-label for conditions such as

rheumatoid arthritis (RA), multiple sclerosis, and other rheumatic and autoimmune diseases. Because many oncology drugs are classified as hazardous, Dr. Hennes cautioned that pharmacists should use the utmost caution and follow USP Chapter ‹800› standards, which include using engineering controls during compounding and closed system drug-transfer devices during administration. Pharmacists should provide patients with instructions about safe handling of oral chemotherapy, such as washing hands with soap and water before and after administration to prevent transmission of drug residue, and storing the drug in a separate medication box from other long-term medications to prevent contamination (bit.ly/2EiqLgU). Although the dosing schedule might differ from that given to cancer patients (the patient with lupus mentioned above was prescribed 1,500 mg of IV cyclophosphamide given over one hour), the side effects are often the same. Cyclophosphamide can induce a host of toxicities, especially if supportive care plans are not implemented. Pharmacists can help monitor patients for urinary toxicity, cardiotoxicity, pulmonary toxicity and hyponatremia and can recommend supportive medications to prevent other side effects, such as opportunistic infections, nausea and diarrhea. For instance, the patient with lupus received ondansetron and dexamethasone 30 minutes before the infusion and additional ondansetron as needed to prevent nausea. For other potential antiemetic regimens, they recommended consulting the National Comprehensive Cancer Network antiemesis guidelines as a place to start and modifying the regimen to fit the patient (bit.ly/2WPx3vX). Another common side effect of cyclophosphamide that pharmacists can help thwart is hemorrhagic cystitis, which results from prolonged exposure to acrolein, one of the drug’s metabolites, and can lead to severe bleeding. To help prevent this toxicity, many pharmacists recommend treating the patient with mesna, which supplies a molecule that binds to acrolein, preventing further damage. In addition to optimizing the patient’s IV fluids, it is important to educate the patient to stay hydrated throughout the day to help the body flush out the toxic metabolite (Adv Biosci Biotechnol 2013;4[88]:10.4236/abb.2013.48A2002). For the 55-year-old patient with lupus, Dr. Hennes recommended that pharmacists include antiemetics and

Table. T Ta abl ble e.. R Recommended ecomm eco ec ommen om mend me nded dL Lab ab M ab Monitoring onit on ito orrin ing For P Fo Pa ati tien entts sR ec ec cei eiivin e ving vi ng C yclo yclo yc loph phos hos o ph ham amide iid de For Patients Receiving Cyclophosphamide B Basel Ba Baseline asel seline seline in n ne

Eve Every very ry 2-4 2 We 2W Weeks eeks k

Ev Eve E Every very Mon Month Mo Month t

• CBC wi with th dif differ differential fer erent ent ntial tial i • Serum creatinine • Urinalysis • Hepatitis B and C serologies • Liver function tests

• CBC with with differential • Serum creatinine • Electrolytes

• Liver function tests • Urinalysis

CBC, complete blood count McCune WJ, Clowse MB. General principles of the use of cyclophosphamide in rheumatic diseases. In: Furst DE, ed. UpToDate; 2020. Cyclophosphamide injection and tablets [prescribing information]. Baxter; October 2018.

mesna, add hydration before the infusion, obtain extra baseline labs (Table), and review the patient’s current medication list to identify any drug interactions that could worsen the side effects of cyclophosphamide. Even when doctors have already ordered this additional support and monitoring, “a lot of our role as pharmacists is being that double-check,” Dr. Griswold told Pharmacy Practice News. Pharmacists ensure that other providers are doing what they are supposed to be doing and that all orders, medicationspecific monitoring and adjustments for patients’ comorbidities are taking place, she said. “Pharmacy’s job is essentially making sure the boxes are all checked.”

Rituximab: Also Use With Caution Another chemotherapy that is often used off-label or in noncancer conditions is rituximab, a monoclonal antibody that has been approved for use in some autoimmune conditions, such as RA. Because the medication is not a hazardous drug, pharmacists can use standard precautions. According to the rituximab package insert, RA patients should receive two 1,000-mg infusions two weeks apart every six months; the manufacturer recommends 100 mg of methylprednisolone or another glucocorticoid 30 minutes before each infusion (bit.ly/2UB2JSL). Even though rituximab is less hazardous than other types of chemotherapy, pharmacists have an important

monitoring role, Dr. Griswold said. Since rituximab targets B cells, it can reactivate hepatitis B infections, she noted. So every pharmacist should ask doctors to screen patients for the virus before administering the drug. Rituximab also puts patients at risk for opportunistic infections, and they should avoid any live vaccines during treatment. Some patients also have infusion reactions, so pharmacists should brush up on management of both mild and severe related symptoms, Dr. Griswold said. Physicians who prescribe chemotherapy for patients who do not have cancer may not be oncologists, so they may not understand the intricacies, cautions, safe handling and monitoring involved, Dr. Oxencis said. Pharmacists can recognize the safety issues, advocate for patients and act as a drug information resource, particularly if patients read the package labeling and get confused after they don’t see their condition. “We are the safety net,” she said. The ASHP talk was designed “to empower the internal medicine pharmacist, or any pharmacist, to feel comfortable working outside of their specialty,” Dr. Griswold said. “We all have the ability to handle these types of medications. Having someone to point you in the right direction can be so useful.” —Alison McCook The sources reported no relevant financial relationships.

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8 Clinical

Pharmacy Practice News • August 2020

Medication Safety

Strategies that avoid the perils of punishment

Switching From a Blame Culture to a Just Culture A

n organizational culture that blames and punishes workers for medication errors will be ineffective in reducing the risk for additional mistakes. Instead of a punitive approach, hospital and health-system leaders should implement a “just culture,” rewarding staff for informing leaders of errors and close

Mandatory, nonconfidential medication error reporting systems

discourage reporting of patient safety incidents

calls, according to several medication safety experts. “Having a sense of trust in your colleagues and organization is very important if you want to seriously improve patient safety,” said Natasha Nicol, PharmD, the director of accreditation and medication safety, Innovative Solutions, Cardinal Health. Instilling trust is indeed critical, given that fear of punitive repercussions is one of the most common reasons errors are not reported 2005;293[11]: ( (JAMA 1359-1366).

(69%) and

‘Organizations that successfully integrate a just culture include it in every step of the way, from the onboarding process right through to the exit interview.’ —John Hertig, PharmD In contrast to a blame culture, “a learning culture, where leadership examines both underlying behavioral choices and systemic weaknesses that contribute to an error, and try and understand why people drift from safety protocols and processes when they do so,” will be more likely to reduce error risk, Dr. Nicol said. “Once leaders have this information, they can focus

encourage lawsuits

(79%) while having no

effect or a negative effect on patient safety

(73%). Source: Hospital CEO/COO survey; JAMA 2005;293(11):1359-1366.

6 ‘Just’ Approaches To Managing a Medication Error Crisis Avoid the crisis. “Create an organization-wide learning culture where staff are encouraged to report not only errors but [also] risks, good catches and barriers to safe work,” said Matthew Grissinger, RPh, the director of error reporting programs at the Institute for Safe Medication Practices (ISMP), in Horsham, Pa. Mr. Grissinger also said leaders can glean valuable insights into process weaknesses by asking employees directly what they believe could go wrong with the processes they use. “Ask staff what keeps them up at night and what they think the next disaster might be,” he urged. This information can be used to scrutinize medication-use systems and identify at-risk behaviors, and then refine systems to prevent events, he noted. Review errors reported by other organizations. Part of this process should include reading through literature on medication risks and errors each month, turning to sources such as the ISMP’s Medication Safety Alert! (www.ismp.org/newsletters). “Using this information, identify any weaknesses that could lead to similar errors at your organization, and take action to reduce this risk,” Mr. Grissinger said.

Prepare for a crisis. Put a crisis management team in place that represents departments ranging from legal affairs to pastoral care. “When a crisis happens, it should be clear who gets together and what needs to happen,” Mr. Grissinger said, emphasizing the need for “transparency and institutional accountability” as

important components of a crisis response in a just culture. “Plan to be open with patients, families and staff.”

Respond to and contain the crisis. Organizations should make patients and their families a priority, addressing their concerns “and telling them how you’ll prevent a similar event from happening in the future,” Mr. Grissinger said. “Never let them encounter a dead end, inappropriate body language, emotional distancing or excuses. And always think about how you’d want to be treated if you were in their shoes.” Don’t forget front-line staff. Particular attention needs to be paid to “second victims” (see sidebar on page 38) and then to the wider organization. “Again, be open and honest with staff, apologize and explain that your top priority is the patient and family, but that you’re conducting an investigation into why the system failed and that the organization will be using the event to implement more reliable, safer systems.”

on strengthening systemic and process weaknesses that could lead to errors.”

Implementation Hinges On Leadership Several Joint Commission (TJC) Sentinel Event Alerts have highlighted the value of cultivating a culture of openness, Dr. Nicol noted. In 2018’s Sentinel Event Alert 60, TJC encouraged reporting of actual errors as well as close calls, which Dr. Nicol said is a hallmark of a just culture (bit.ly/3cM6ahe). “Close calls are so important to know about because they reveal weak points in the system that leadership can look at and also understand what stopped the event from actually happening,” she said. In Sentinel Event Alert 57, TJC emphasized the importance of leadership taking the reins in developing and implementing a patient safety culture (bit.ly/2WA7Zbv). “Competent and thoughtful leaders … understand that systemic flaws exist and each step in a care process has the potential for failure simply because humans make mistakes,” TJC wrote. According to John Hertig, PharmD, an associate professor at Butler University College of Pharmacy and Health Sciences, in Indianapolis, a lack of strong leadership commitment often is the primary obstacle to implementation of a just safety culture. Institutions that task an individual or small group of workers with championing a just safety culture, he noted, can see these efforts fall flat if those champions retire or leave their position or organization. “Unless everyone’s on board to truly integrate a just culture, it’s really hard to implement it successfully,” Dr. Hertig said. “Organizations that see JUST CULTURE, page 38

Resolve and learn from the crisis. Conduct a root cause analysis, and understand the sequence of events that led to the error. Doing so could uncover process gaps that might have contributed to human error or unsafe behavioral choices, Mr. Grissinger said. “Finetune your crisis management plan based on lessons learned,” he advised, also urging attendees to share information on their errors and risk reduction strategies with outside organizations and to stay abreast of reports from other organizations.

—David Wild

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10 Clinical

Pharmacy Practice News • August 2020

COVID-19 Pandemic

Hydroxychloroquine? continued from page 1

Oxford University in England, showed mortality trends favoring usual care (25.7% with HCQ vs. 23.5% with usual care; hazard ratio, 1.11; 95% CI, 0.98-1.26). Based on these results, the World Health Organization also stopped the HCQ arm of the Solidarity trial. Although these trial results led to the termination of several HCQ/CQ trials and the withdrawal of the FDA’s

emergency use authorization, other trials continue. Such trials are looking at different doses, combining them with zinc, giving the drugs earlier, and even giving them as pre- or post-exposure prophylaxis, explained Shmuel Shoham, MD, an infectious disease specialist who is on data and safety monitoring boards for several HCQ studies. So, the door might be closing on HCQ,

but it hasn’t shut. However, right before efore press time, another randomized trial found that early administration of HCQ CQ did not substantially reduce symptom om severity in outpatients with early, mild COVID-19 (Ann Intern Med 2020 Jul 16 [Epub ahead of print]), and the door closed a little more. The most important advice experts can give health care professionals is to understand that, as of today, the evidence shows there is “no benefit or very low benefit, but mostly unknown benefit,” admitted Dr. Shoham, an associate professor of

Read Specialty Pharmacy Continuum Anywhere, Anytime!

medicine at Johns Hopkins Medicine, in Baltimore. This is why the management guidelines from the Infectious Diseases Society of America recommend only using HCQ/CQ in the context of a clinical trial, so that clinicians can get the definitive answers they need, stressed Dr. Shoham, who is on the guidelines panel. “It’s OK to say that we don’t know,” agreed C. Michael White, PharmD, the department head and a professor of pharmacy in the Department of Pharmacy at the University of Connecticut School of Pharmacy, in Storrs. “Right now, we can say that if you are in the hospital and you are taking hydroxychloroquine, it’s unlikely that it is going to provide you with a lot of benefits.”

Science Versus Politics

www.specialtypharmacycontinuum.com

Unfortunately, the science behind HCQ/CQ is taking a back seat to politics, and being in the middle of a political debate today is difficult. This is exactly where Dr. White found himself when he tried to weigh the evidence for clinicians in a review in the Annals of Internal Medicine (2020 May 27. [Epub ahead of print]). The Annals review, a living document—which will be updated periodically as more data become available—assessed published studies about the use of the two antimalarial drugs for COVID-19, looking at the overall strength of the evidence by determining their risk for bias and comparing different end points. The reviewers found that evidence in support of their use for COVID-19 was weak, and there was insufficient evidence to recommend for or against these medications. That’s when things really became interesting. When Dr. White published an article for The Conversation, sharing his findings with the general public, he received more than 100 comments, when he would usually only receive 10 to 20, and got many more comments on Twitter. People were citing general news and social media reports supporting the efficacy of the drugs. As the principal investigator at UConn Health Outcomes, Policy, and Evidence Synthesis, Dr. White wanted to know where they got their data. He found that most of the outlets were reciting information from the Association of American Physicians and Surgeons (AAPS) website, which provided a table of studies to bolster claims that HCQ has “90% success” against COVID-19, defined “as the percent of no mortality or probability of preventing death.” In a commentary, Dr. White contrasted how his research group evaluated the studies using recommendations of the

Clinical

Pharmacy Practice News • August 2020

COVID-19 Pandemic Agency for Healthcare Research and Quality and the Cochrane Collaborative versus Coc how ho ow the o t AAPS evaluated the studiess (J ( Clin Pharmacol 2020 Jun 12. [Epub [E Epu ahead of print]). The AAPS cited cite cit t mostly anecdotal experiences, considering only people who took HCQ. Rather than perform a statistical analysis, the AAPS did a straight math problem to determine the medication’s success, dividing the number of people who were alive by the number who were treated. In one instance, a physician treated 399 patients with HCQ and two died; therefore, the medication was said to be 99.5% successful. However, Dr. White pointed out that without a control group, there is no way to know how many would have survived without taking HCQ or whether the two who died would have survived if they just received usual care. In another example, HCQ was given to 600 people without COVID-19, and they did not contract the disease; therefore, it was deemed successful at preventing infection. However, there was no discussion of the risk that these people had of contracting SARS-CoV-2. “Controlled studies have never been the only approach to scientific inquiry, and in treating disease, particularly a new one, physicians have always been encouraged to use off-label medication,” the AAPS told Pharmacy Practice News. Agreeing that controlled studies are not the only approach, Dr. White explained that anecdotal evidence, however, is among the weakest forms of evidence because it is “inherently biased” and “extremely weak in terms of proving any kind of association.” He gave this example: Most heart attacks occur in the morning between 5 and 11 a.m., and coffee is a popular morning beverage. “You might believe that coffee is causing everyone to have heart attacks, but the truth is that is not what’s causing the heart attack. It’s just a cofounder that got thrown into the mix,” he explained. “The reality is that, in addition to the anecdotal experiences that they put together, we do have data from published studies that tell a very different story about hydroxychloroquine.”

Seek First to Understand Because HCQ/CQ is such a hot button, clinicians are just as likely to see a patient who demands one of the antimalarials as they will someone who refuses to enter a clinical trial of the drugs because they “know” the treatment doesn’t work. It is incumbent upon clinicians to understand the data to help explain that information, Drs. White and Shoham said. In addition to comparing the analysis methods, Dr. White discussed the importance of that communication. He

suggested that if patients are requesting HCQ/CQ, clinicians should ask what they have heard about the treatment; and if “they quote the 99% success that hydroxychloroquine allegedly has,” then ask what that means. The AAPS said Dr. White’s commentary “oversteps the ethical role of pharmacists in suggesting the questioning of patients and second-guessing medical decisions to prescribe a safe, non-addictive medication.” However, Dr. Shoham said that conversation is important, not only with patients

but also physicians who may feel compelled to use HCQ so they can offer something to their patients. He urged clinicians to share the data and the strength of that data, as well as information about potential adverse events (see story, page 16). “The best approach is to ‘seek first to understand, and then to be understood’ when talking to a patient or a colleague. Try to understand where the person is coming from,” Dr. Shoham said. “Then make a decision together as to how to move forward. Overwhelmingly, I think that decision should be to not take HCQ

unless it’s part of a clinical trial.” “The reality is that you should be enrolling patients in these clinical trials,” Dr. White agreed, “so that three months or six months from now, we are not all still guessing and groping around in the dark.” —Marie Rosenthal Drs. Shoham and White reported no relevant financial relationships. Before COVID-19, Dr. White appeared regularly on a local Fox News affiliate. to help viewers understand medications.

Approved for use in interscalene brachial plexus nerve block

CHANGE THE FACE OF POSTSURGICAL RECOVERY Choose long-lasting pain control that can reduce or eliminate the need for opioids1* In an inﬁltration study, EXPAREL signiﬁcantly reduced pain and opioid use vs bupivacaine HCl1†‡ 78% FEWER OPIOIDS

13.6% LESS PAIN

overall opioid consumption (P<0.005)

cumulative pain scores (P<0.04)

10% OF PATIENTS WERE OPIOID FREE WITH EXPAREL VS 0% WITH BUPIVACAINE HCI (P=0.01)

*The clinical benefit of the decrease in opioid consumption was not demonstrated in the pivotal trials. † Results from a phase 4, double-blind, randomized, active-controlled, parallel-group study that compared the efficacy and safety of EXPAREL 266 mg (20 mL) (n=70) and bupivacaine HCl (n=69) in a total knee arthroplasty (TKA). Primary end points: area under the curve of visual analog scale pain intensity scores 12 to 48 hours postsurgery; total opioid consumption 0 to 48 hours postsurgery. Rescue opioids for pain were available upon patient request. Rates and types of adverse events were similar between treatment groups. The most common adverse events in the EXPAREL group were nausea, muscle spasms, and vomiting.1 ‡ In patients undergoing a TKA; reductions were measured through 48 hours.1

Indication EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Safety and efficacy have not been established in other nerve blocks. Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia. Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via inﬁltration were nausea, constipation, and vomiting; adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation. 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 population: patients <18 years old 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 Speciﬁc 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.

11/19

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. Warnings and Precautions for Bupivacaine-Containing Products 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-RX-EXPAREL (793-9727). Reference: 1. Mont MA, Beaver WB, Dysart SH, Barrington JW, Del Gaizo DJ. Local infiltration analgesia with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: results of a randomized controlled trial. J Arthroplasty. 2018;33(1):90-96.

Find out more by visiting www.EXPAREL.com and request to meet with one of our representatives.

12 Clinical

Pharmacy Practice News • August 2020

COVID-19 Pandemic

Cancer and COVID-19 Are a Deadly Mix

wo studies of registry data presented at the 2020 virtual annual meeting of the American Society of Clinical Oncology (ASCO) and followup results from one of the studies published in late July shed some light on how patients with cancer are faring amid the COVID-19 pandemic. Data from a COVID-19 and Cancer Consortium (CCC19) cohort study presented at ASCO showed that active

Brief Summary (For full prescribing information refer to package insert) INDICATIONS AND USAGE EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and 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 amide-containing 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 18 years old • 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 Nerve Block Clinical Studies The safety of EXPAREL was evaluated in four randomized, double-blind, placebocontrolled 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 co-administration 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.

cancer progression, older age, a smoking history, and a diminished ability to perform activities of daily living were among the factors associated with deaths from COVID-19 in cancer patients. An expanded data set confirmed these findings, showing that increased age, increased baseline COVID-19 severity, active cancer and ECOG performance status (PS) of 2 or greater are associated with increased mortality. In addition, the new data show

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 embryo-fetal 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 Safety and effectiveness in pediatric patients have not been established. 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

that remdesivir possibly is associated with decreased mortality among cancer patients, whereas hydroxychloroquine (HCQ) and high-dose corticosteroids are associated with increased mortality in this population, the latter of which contrasts with results in COVID-19 patients as a whole (see bit.ly/394TOjv). Another study, of 400 patients with thoracic cancers, found that patients treated with chemotherapy within three

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 for injection 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 in Adults Local Analgesia via Infiltration 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. Regional Analgesia via Interscalene Brachial Plexus Nerve Block 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 November 2018

months of a COVID-19 -19 diagnosis had a signifiificantly increased morortality risk (64%). The effects of COVID-19 on patients ients with cancer remain poorly l underd stood, said Jeremy Warner, MD, the lead author of the CCC19 study and an associate professor of medicine and biomedical informatics at Vanderbilt University Medical Center, in Nashville, Tenn. Published reports have been small or focused on specific geographic regions, Dr. Warner noted. He and others created a larger cohort, anticipating that patients with cancer could be at greater risk for death from COVID-19 because of their age, comorbidities, increased contact with the health care system, and decreased immunity and PS. They began to collect data for the CCC19 registry on March 17. More than 100 cancer centers from Canada and the United States are participating; the registry also is accepting data on patients in Argentina and Europe. Dr. Warner and his colleagues presented their findings on 928 patients at the ASCO meeting (abstract LBA110) and in the Lancet (2020 May 28. [Epub ahead of print]) and the follow-up on 2,186 patients in Cancer Discovery (2020 July 22. [Epub ahead of print]). The median age of the larger cohort was 67 years. In all, 1,115 patients (51%) were in remission, 607 (28%) had cancer that was stable or responding to treatment, and 239 (11%) had actively progressing cancer. Most of the patients had solid tumors (81%); the most common types were breast, prostate, gastrointestinal and thoracic cancers, and lymphoma. The investigators found that 357 patients (16%) from the larger cohort died within 30 days of a COVID-19 diagnosis— more than twice the typical death rate of all patients contracting SARS-CoV-2. The investigators found that patients with an ECOG PS score of 2 or greater had a death rate of 35%. Death rates were higher among patients aged 75 years or older and those with ECOG scores of 2 or greater who either were admitted to the ICU or intubated (54%-85%). In the follow-up study, the investigators evaluated the use of several treatments for COVID-19 and their effects on outcomes. Patients received HCQ, azithromycin, remdesivir, high-dose corticosteroids, tocilizumab, and other therapy alone or in combination, or no treatment was reported. “We did not find evidence of benefit, with the possible exception of remdesivir as compared to positive controls,” the authors noted. In contrast, they added, HCQ “with other medications

Clinical

Pharmacy Practice News • August 2020 0

COVID-19 Pandemic

( (most commonly, azithromycin) remained associated with increased 30-day all-cause mortality, after extensive adjustment.” In addition, they wrote, “the encouraging findings for corticosteroids in the prospective UK RECOVERY trial were not replicated in this cohort of patients with cancer.” The investigators acknowledged that “in observational studies such as this, isolation of the treatment effect is complicated due to non-randomized, nonstrictly controlled conditions for treatment.” Still, they maintained that the data provide “a useful indicator of what occurs in real-world clinical settings.”

were at significantly higher risk for death from COVID-19. Therapy administered to treat COVID-19 was not significantly associated with outcomes, and treatment with immunotherapy and tyrosine kinase inhibitors did not appear to affect the risk for death. Data collection is ongoing, with additional analyses planned to look at patient and provider perceptions of COVID-19’s effects on cancer care, Dr. Horn said. “There are a lot of data we need around managing COVID in patients with malignancy,” commented Bhavesh

Shah, RPh, the senior director of hematology/oncology and specialty pharmacy for Boston Medical Center Health System. “It’s great that registries are being created to capture these data,” said Dr. Shah, a co-investigator on an American Society of Hematology registry of patients with hematologic malignancies and COVID-19. “Currently, what we can say is we don’t know the impact of cancer patients with COVID, but what we can do is monitor them closely and continue to utilize registries to identify other risk factors that

—Karen Blum and Sarah Tilyou Dr. Warner reported financial relationships with IBM and Westat. Dr. Horn reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Genentech, Incyte, Merck, Pfizer, Tesaro and Xcovery. Dr. Shah reported no relevant financial relationships.

DRIVEN TO FULFILL THE PROMISE OF BIOSIMILARS— THE PFIZER WAY

Thoracic Cancer Registry Another study presented at ASCO provided data on the first 400 patients in a global registry to track the impact of COVID-19 on patients with thoracic malignancies (abstract LBA111). Called TERAVOLT (Thoracic cancERs international coVid 19 cOLlaboraTion), the registry includes data from 26 countries. Patients with thoracic malignancies were thought to be at particularly high risk from COVID-19, given their older age, smoking habits and preexisting cardiopulmonary comorbidities, noted lead investigator Leora Horn, MD, MSc, the director of the thoracic oncology program at Vanderbilt. TERAVOLT aims to determine the demographic factors, comorbidities, cancer characteristics and therapies that place patients with thoracic malignancies who develop COVID-19 at highest risk for hospitalization and death. Among the first 400 patients, the median age was 68 years; 31% were women and 79% were current or former smokers. Hypertension and chronic obstructive pulmonary disease were the most common comorbidities. Of this group, 169 recovered, 141 died, and 118 were still battling SARS-CoV-2 as of May 8, the cutoff for the ASCO presentation, Dr. Horn said. The investigators found that 79% of the deaths (112 cases) were due to COVID-19, with only 10% of deaths attributed to cancer. Seventy-eight percent of patients required hospital admission, lasting a median of 10 days. Risk factors associated with mortality included age of 65 years or older, comorbidities, and a lower PS. Patients taking steroids or anticoagulants before contracting SARS-CoV-2 were at increased risk for mortality. Patients on chemotherapy, either alone or in combination with immunotherapy, also

would be negative overall.” For more information on the registries, see ccc19.org, teravolt-consortium. org and www.ashresearchcollaborative. org/s/covid-19-registry.

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To learn more about Pfizer’s oncology biosimilars, visit us online at PfizerBiosimilars.com References: 1. IMS Institute for Healthcare Informatics. Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets. Parsippany, NJ: IMS; March 2016. 2. Drugs.com. How many biosimilars have been approved in the United States? https://www.drugs.com/medical-answers/many-biosimilars-approved-united-states-3463281/. Updated December 8, 2019. Accessed April 6, 2020. 3. McGowan S, Jesse M. Biosimilars Pipeline Report. AmerisourceBergen. https:/www.amerisourcebergen.com/-/ media/assets/amerisourcebergen/biosimilars-pipeline-report_0420_v3.pdf?la=en&hash=1071304C7B66ED62628201B8268C0B633 627CB6B. Updated May 1, 2020. Accessed June 4, 2020. 4. Data on file. Pfizer Inc., New York, NY.

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14 Clinical

Pharmacy Practice News • August 2020

COVID-19 Pandemic

A Tale of 2 Crises

‘We … need to view treatment facilities as health care facilities with providers on the front line, and states need to do their own part ensuring access to [OUD] treatment.’

continued from page 1

a surge in overdoses in the next few months,” Dr. Marshall said. “People in recovery, even long-term recovery for several years, are relapsing,” added Anne Hazlett, JD, the special advisor for rural affairs in the White House Office of National Drug Control Policy. “We’re also hearing anecdotally of increases of alcohol consumption.” Additionally, some people with OUD have turned to benzodiazepines as a temporary substitute for lack of access to opioids, and suicides due to depression and/or unemployment are occurring, the panel noted. Adding to the crisis, they said, are increased calls to law enforcement about bout domestic violence. Because schools ols are closed, however, calls from nurses ses and other authorities warning about out potential child abuse and neglect are down, Ms. Hazlett said.

to maintain separation from family or previous associates.

Reaching Patients The pandemic provides a natural experiment through which treatment facilities can determine how best to reach people interested in receiving treatment for their addictions, noted Regina LaBelle, JD, the director of the Addiction and Public Policy Initiative at Georgetown University Law Center, in Washington, D.C. Telehealth has been important in both rural and urban locations during this time, she said, and looking at the patient experience and outcomes could help inform changes in policy. “We also need to view treatment

—Regina LaBelle, JD facilities as health care facilities with providers on the front line,” she said, “and states need to do their own part ensuring access to treatment.” It is challenging to track precise causes of death in this crisis, Brown University’s Dr. Marshall said. Because COVID-19 is a respiratory illness, if someone is using opioids—which could cause fatal respiratory depression— and has the virus, it may be difficult to

Policy Changes Could d Help On a positive note, agencies encies such as the Drug Enforcement Administration and the Substance Abuse se and Mental Health Services Administration ministration have made numerous policy licy changes recently to increase access cess to care, Ms. Hazlett said (box). “Much of the focus of the administration tration has been to ensure, from the he start of this public health emergency, gency, that there is flexibilityy in policy as well as resources— ces— whether information orr dollars—to make sure accesss to treatment and recovery support pport are available.” Another positive trend: end: Some treatment and recovcovery centers are reportingg that phone calls and admissions ions for those able to accept new w patients are up, and providers are seeing a surge of appointments being kept because telemedicine has taken away the barriers of travel el time and transportation, Ms. Hazlett ett said. However, the pandemic emic created some challenges for patients with OUD trying to access care, she noted. Many people in recovery lost their jobs and, therefore, e, cannot pay rent for transitional housing ousing offered through some programs. s. Those who have social enterprise work programs may have been suspended ed due to the pandemic. Additionally, some recovery facilities closed because ause of a positive COVID-19 test result from staff members or residents, leaving some patients with no place to go—a dangerous scenario for people who need

determine the cause of death. In addition, surveillance systems that track opioid overdoses may be hindered by the pandemic, because coroners may not have the resources to follow up on opioid-related deaths, and those in hospitals may be too busy to report overdoses to the same extent. There also is some evidence that people who have overdosed overdose are staying away from hospitals, due to fear of contracting the coronavirus. Ms. Hazlett remained undaunted. will need to be innovative “We simply w and build new partnerships to do our jobs and save llives,” she said.

A Pa Pain Pharmacist’s Perspective Pers

Policy Efforts to Fight OUD During COVID-19 The DEA is allowing registered providers to prescribe medication-assisted treatment to patients across state lines through telemedicine. The DEA and SAMHSA are permitting practitioners to prescribe buprenorphine to new and existing patients with OUD through telehealth or telephone. CMS has allowed opioid treatment programs to provide therapy and counseling using telephone calls in addition to two-way interactive audiovisual technology. SAMHSA is allowing programs to provide stable patients with 28 days of take-home methadone doses to reduce in-person interactions. CMS, Centers for Medicare & Medicaid Services; DEA, Drug Enforcement Administration; SAMHSA, Substance Abuse and Mental Health Services Administration

Addiction is a disease of isolaAddic tion, and alt although recovery programs temporarily h have turned to online or to continue serphone appointments appo vices, it’s easier for participants to disengage through these methdiseng ods than through live, in-pert son so sessions, commented Ernest Dole, PharmD, a clinical pharmacist at the Pain Consultation and Treatment Center of the University of Ne New Mexico Hospitals, in Albuquerque. Albuqu People who are committed Peo to getting help still should do ge well in this scenario, he noted, but for fo those less interested, it could be easier to slide. co For such individuals, smaller in-person meets ings that adhere to social i distancing are more helpful, Dr. Dole noted, adding, “This whole new reality is stressful, stressful even under the best of circumstances.” circumstances —Karen Blum The sources s reported no relevant financial relationships.

More Online With tec technology transforming so many aspects of health care, addiction specialists sa say it’s time to apply hightech solutio solutions to opioid use disorder management. For more details, see “Novel Technologies to Improve Management of Opioid Use Disorders” at bit.ly/2ZZ2DqO.

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16 Clinical

Pharmacy Practice News • August 2020

Opinion

COVID-19 pandemic:

With a Quarter Left to Play, Still Plenty to Learn Steven Smoke, PharmD, BCPS, BCIDP Saint Barnabas Medical Center Livingston, N.J.

s a clinical pharmacist who specializes in infectious diseases, I work closely with doctors, pharmacists and nurses to ensure safe and effective antibiotic use within my hospital. With COVID-19, the role is essentially the same, except with more questions and few answers. Trying to keep up with emerging data on COVID-19 involves rapid sharing of information, which is both a blessing and curse. For years, I’ve used Twitter to share influential research and gather insights from the smartest people in infectious disease, all around the world. But fast is not always foolproof. When discussing clinical studies, training and experience are needed to pick up on the nuances that separate landmark conclusions from preliminary findings. Let's look at an example: a highly publicized trial comparing remdesivir with placebo in patients hospitalized with severe COVID-19, published in the Lancet (doi.org/10.1016/ S0140-6736[20]31022-9). The investigators found that remdesivir did not meet its primary end point—a significant difference in time to clinical improvement (hazard ratio, 1.23; 95% CI, 0·87-1.75). Put simply, the antiviral didn’t work. But importantly, the researchers also fell short of their projected patient enrollment; as a result, the study was underpowered. This fault is similar to calling a football game at the end of the third quarter—in which case, congratulations to the San Francisco 49ers, Super Bowl LIV champions! They were up 10; it was over, right? Wrong. So does this mean the trial was useless? Well, were the first three quarters of the Super Bowl useless? No, there’s plenty to learn from preliminary results. But any conclusions must be tempered; there is still a quarter left to play. When the rest of the world joins these conversations, desperate for answers, the nuances can be missed. And words carry tremendous weight. A single premature shout of warning—“taking ibuprofen can aggravate COVID-19”—can be shared, echoed and bounced around the world in hours. Level-headed questions such as “what's the source for this claim?” (a letter in the Lancet; bit.ly/ 3e8wceC) get lost in the noise. In the thick of the debate, proving the absence of evidence is impossible, while the provocative rumor spreads faster than,

well, a virus. In the aftermath, words of caution or repeal, such as those issued by the FDA warning clinicians not to base treatment decisions on the Lancet letter (bit.ly/2Z1o2QV), never spread with the intensity of the original report. When this cycle repeats over and over, the result is a flood of misinformation.

Preprint Confusion In the medical community, the increasingly popular preprint also has contributed to the confusion. Preprints, such as those appearing on bioRxiv.org, are scientific studies shared online before formal peer review (bit.ly/3e26PeA). There’s no double check for quality, just “look what I found.” These preprints come from good intentions: rapid sharing of study results. But there is a price to skipping the steps that ensure the slow but essentially forward march of scientific progress. That price is confusion, when the important studies get mixed with those that are much more suspect. That confusion is magnified when preprints of questionable merit are shuffled across the world in a flurry and widely shared by media outlets. With so many COVID-19-related questions, people look in all directions for answers. Sometimes they look to me. Sharing speculation based on flimsy evidence does not bring clarity to the situation. Rather, during this COVID-19 pandemic, my most common answer is the most difficult one: “I don’t know.” Equally as important is recognizing when a question is not yours to answer, but instead is better suited for someone else. For me, “Are medications returned from COVID-19 units safe?” is not a pharmacy question, but rather one more appropriately posed to my infection preventionist colleagues. “Will there be a second wave?” Again, not for a pharmacist, but for an epidemiologist. The list goes on. As tempting as it is to share your thoughts, it is important to consider the power of your words. Do not become a part of the misinformation. Fight it by not being afraid to say, “I don’t know,” and by directing people to those who might. The COVID-19 pandemic has brought some unique challenges to my job. My role does not have me on the front lines, at the bedside. I work more like a football team’s offensive coordinator, except less controlling and more advisory—maybe like Tom Brady’s offensive coordinator. One of my tasks is to work with a diverse group of experts to provide formal recommendations to our physicians on the treatment of COVID-19. We are faced with two opposing pressures. On the one

hand, we must respect the importance of evidence-based medicine. No practice should be recommended without adequate evidence of safety and efficacy. This is essential to protect patients. On the other ther hand, these are extraordinary times. The pandemic will not wait for high-quality clinical trials to reveal which therapies are safe and effective. The surge of patients is here, now. By any nonpandemic standard, there is not adequate evidence to recommend for or against many COVID-19 therapies. But this nonanswer provides no help to the clinicians on the front lines, swamped with patients, looking for some kind of direction. So, how do we provide help in a way that doesn’t contribute to misinformation? Do we provide nuanced recommendations full of conditional statements and warnings like “based on preliminary evidence”? Such statements can feel safe for those writing them but can come across as confusing and unclear to the physicians reading them, particularly when a physician may be reviewing the recommendations late at night after an exhausting day of endless patients and the constant search for personal protective equipment. Much like this article, I can belabor each word and phrase to deliver a very specific, particular message. But those efforts will never eliminate the fact that readers, with their unique experiences, beliefs and circumstances, will always have an influence on exactly how the message is received.

Finding Answers So, how can we find treatments that work? The answer is through randomized controlled trials (RCTs). Other study designs can point us in the right direction, but RCTs actually will move us forward. Outside of an RCT, simply observing patients who try an experimental therapy cannot prove that it works because it is impossible to know if those patients would have had similar or different results had they not received the drug. In an RCT, participants are randomly assigned to receive an unproven therapy or placebo. If patients who receive the therapy have better outcomes than those receiving placebo, efficacy is proven. Enrolling in a trial is a decision that, rightfully so, ultimately lies with the patient. When it comes to COVID-19, that will not be a simple choice. A

number of potential COVID-19 therapies are repurposed drugs, meaning they are already proven safe and effective for another use. Take, for example, hydroxychloroquine, itself the subject of sometimes conflicting reports on its safety and efficacy (see page 1). Unlike new investigational medications, these agents can be prescribed by a physician outside of a clinical trial. This means patients and physicians are faced with an important choice when considering unproven drug X for COVID-19: Option A: Enroll in a randomized clinical trial, where the patient will be randomly assigned to drug X or a placebo. Option B: Decline trial enrollment. Simply choose to try drug X. The implications of this decision for the patient are clear. Implications for society are also critically important. Option A moves us closer to an answer. Option B does not. No patient deserves judgment for decisions made under the stress of severe illness. But right now we have several treatment options, largely unproven. If COVID-19 persists for six months, one year or further out, we will or will not know if they work. If we do have that knowledge, it will be because of patients who chose option A, and chose to drive medicine forward for the greater good.

A Once-in-a-Generation Opportunity Finally, for people in pharmacy, as well as many, many others, this is the event. This is the one that will change the world. It will be the teaching example for our generation, to be referenced time and time again for the rest of our career. Make no mistake, this is a devastating tragedy. But buried in the devastation are a million stories of heroism. My coworkers, in dozens of different roles, face extraordinary challenges with strength, resilience, selflessness and bravery. The list of heroes is long. The list of those with fascinating stories is even longer. I urge everyone to ask for those stories. Tell those stories. And listen to them. ■

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American Health Packaging Safety, efficiency and compliance are each critical to pharmacy staff and caregivers in facilitating positive patient outcomes. In striving to meet relevant objectives, hospital, institutional and long-term care pharmacies seek quality barcoded medications to dispense to their patients. American Health Packaging supports customer barcode medication administration (BCMA) initiatives through a robust line of barcoded unit-dose products. Our portfolio supports critical needs for pharmacies and provides key benefits for customers and patients as facilities prioritize superior quality care.

Liability Management Pharmacy repackaging operations can be subject to distractions from a variety of sources. An active pharmacy environment can cause lapses in concentration and present opportunities for staff errors. Since these errors may vary in severity and impose liability on the facility and caregivers, mitigation of risk is key. Unit doses from American Health Packaging can help shift liability burden away from staff.

Ensuring the right medication is given to the right patient at the right time, and in the right strength, is imperative. As facilities compete to demonstrate that they provide the highest quality care, pharmacies can assist by providing caregivers with as many products in unit-dose format as possible. American Health Packaging products enable hospital pharmacies to obtain a broad range of unit-dose products easily, and help ensure safe medication delivery

for patients through accurate packaging and barcoding that scans correctly as intended.

Pharmacy Efficiency Pharmacies also strive to process orders efficiently and supply medications for patients as quickly as possible. Managing a complex in-house repackaging chain slows down this process. It also distances clinicians from their core patient care competencies. American Health Packaging is committed to providing a portfolio containing both high-demand and difficult-to-find unit-dose products meeting various needs. These items arrive at your pharmacy ready to dispense. Our broad offering closes the gap between what caregivers need to dispense at the patient bedside and what is available on the market in prepackaged unit doses.

Special Advertising Section Pharmacy Practice News

2550-A John Glenn Ave. Columbus, OH 43217 (800) 707-4621 customersupport@americanhealthpackaging.com www.americanhealthpackaging.com

President and CEO Bruce Bennett

Cost Savings Patient Safety

AT A GLANCE

Facilities that repackage on-site are subject to direct costs associated with hosting operations. These expenses are related to repackaging supplies, capital equipment, and paying highly trained professionals to perform, manage and support non-core work. American Health Packaging unit doses allow facilities to minimize these direct costs while controlling potential expenses associated with in-house repackaging errors.

About American Health Packaging In business for more than 30 years, American Health Packaging is the market leader in providing barcoded unit-dose oral solids to the health care marketplace. We provide a specialized portfolio of nearly 500 oral solid, liquid and inhalational products to support bedside point-of-care initiatives. Our manufacturing facility is registered with the FDA, adheres to current Good Manufacturing Practices (cGMP), and is licensed by the Drug Enforcement Administration (DEA) to package Schedule II to IV controlled substances.

Corporate Profiles 2020

AuroMedics Pharma LLC Providing Transparency and Flexibility for Better Patient Care

AT A GLANCE 279 Princeton Hightstown Road East Windsor, NJ 08520 www.auromedics.com

Affordable Medicines for Greater Patient Access

Transparency and flexibility is a tenet we strive to accomplish for our customers and their patients AuroMedics Customer Service each day. As a manufacturer of critical sterile (888) 238-7880 | Option 1 for injectables, it means we share our inventory levels General Information and product shipment dates with our customers to communicate our pending supply of our Drug Safety/Medical Information FDA-approved medicines to the U.S. market. This (888) 238-7880 | Option 2 transparency is vital to us as it strengthens the continued trust our customers have in us and our President products. Achieving flexibility for our customers Mark Fedele is always a welcome challenge, including shipping direct where we can, employing the efficiencies and logistics of our empowered wholesalers, and adjusting our forecasts to best serve our institutional and clinical customers when drug shortages hit hard.

Sustainable Supply of Medicines For Uninterrupted Care Year after year, AuroMedics has been a reliable supplier of drug shortage products, such as piperacillin and tazobactam, lidocaine, pantoprazole and bupivacaine. Our ability to pivot quickly and increase capacity to meet the demands of the expanding and contracting sterile injectables market is directly related to our relationship with our parent company, Aurobindo Pharma. We develop our own forecasts, and collaborate with our manufacturing sites in production scheduling and with our logistics staff in scheduling our air and sea shipments. With this capacity, weâ&#x20AC;&#x2122;ve developed a deep understanding of our health care practitionersâ&#x20AC;&#x2122; need to provide uninterrupted care to patients. To this end, we work diligently with the FDA, ASHP, group purchasing organizations, integrated delivery

Corporate Profiles 2020

networks, distributors and wholesalers to ensure our medicines are supplied to the necessary forecasted demands.

About AuroMedics Pharma LLC Headquartered in East Windsor, N.J., AuroMedics Pharma, LLC is the sterile generic injectable U.S. commercial division of Aurobindo Pharma Limited, a world-leading marketer and manufacturer of generic pharmaceuticals and active pharmaceutical ingredients with revenues exceeding $2.5 billion. AuroMedics markets and distributes high-quality, safe alternatives to more costly branded molecules, improving patient access to affordable medicines. Therapies provided within the growing AuroMedics portfolio include anti-infectives, antiemetics, oncology supportive care, anesthesia, cardiac, neurological treatments and more. AuroMedics has a robust pipeline of more than 100 molecules, focusing on formulations that bring administration closer to the patient bedside for safety and efficiency. The recent launch of our 565,000-square-foot, state-of-the-art distribution center in central New Jersey, dedicated to warehousing, manufacturing, packaging, and research and development, reinforces our commitment to future growth and continued supply to our U.S. customers. Learn more at www.auromedics.com.

Special Advertising Section Pharmacy Practice News

Central Admixture Pharmacy Services, Inc. (CAPS®)

AT A GLANCE

Who we are. What we believe. We are the nation’s largest network of outsourcing admixture pharmacies. With 22 regional 503A pharmacies and three 503B-registered outsourcing facilities, CAPS offers the convenience of both batch compounding and customized compounding for customers nationwide.

We Are Growing To Support Our Customers • While others have exited the drug compounding business, CAPS is expanding its product portfolio to help meet our customers’ needs for high-quality, safe and readily available compounded medicines. • Our ability to supply new products is supported by CAPS’ recently completed 250,000-square-foot 503B outsourcing facility in Phoenix, AZ, as well as continuing investments at our 503B facilities in the Lehigh Valley, PA, and San Diego, CA.

When It Comes To 503A And 503B Services, Our Customers Speak Volumes

‘Being a CAPS customer enables my hospital to provide quality parenteral nutrition to our patients and allows our pharmacists to devote more of their time, skills and resources to providing other patient-specific intravenous medications. It eases the burden of continued drug shortages related to parenteral nutrition solutions.’ —M. Petrea Cober, PharmD, BCNSP Clinical Coordinator–NICU Akron Children’s Hospital

Our Commitment To Quality And Safety Has Never Been More Important • CAPS has established a legacy of safety by providing hospitals and their patients with the highest quality compounded therapies. • Our Test, Hold and Release (THR®) quality assurance program put us at the forefront of addressing patient safety. • We perform 100% batch level testing on every batch that comes from our 503B outsourcing facilities, and each distributed batch is accompanied by a Certificate of Release.

16800 Aston Street, Suite 150 Irvine, CA 92606 (800) 853-6498 www.CAPSpharmacy.com

Join Us • Learn more about our services, the expansion of our product portfolio and our advocacy for patient safety. • Call us or visit our website for additional information: (800) 853-6498; www.CAPSpharmacy.com

We Advocate For Strong Regulations To Protect Patients • We believe the FDA’s policy for 503B outsourcing facilities to only compound from FDA-approved, commercially available products is essential to ensuring the safe supply of compounded drugs.

‘Patient safety and well-being have always been our highest priority— one that is shared by the hospitals we partner with. We will continue supporting policies and practices to ensure that compounded therapies are prepared to the highest standards of patient safety.’ —Tom Wilverding President, CAPS We’re Here to Help • Our experts at CAPS Consulting help hospitals, home infusion pharmacies and surgery centers navigate through the complex and changing compounding regulatory environment. • As the market leader in customized parenteral nutrition (PN) delivery, we offer PN Clinical Training Services to help you deliver patient-specific solutions. • We are committed to providing customers with programs and services that help them focus on standardization and improving patient care. • Pharmacists perform a PN double check and identify interventions to catch and correct medication errors.

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Corporate Profiles 2020

Fagron Sterile Services US A 503B Outsourcing Solution You Can Rely On.

AT A GLANCE

Experience Spanning 3 Decades Trusted by more than 7,300 U.S. health care facilities, Fagron Sterile Services US (FSS) delivers high-quality 503B outsourcing— supporting millions of lives each year. FSS offers specialized pharmaceutical solutions to hospitals, ambulatory surgery centers, clinics and physician offices. FSS holds integrated delivery network agreements within all major group purchasing organizations.

8710 E. 34th St. N Wichita, KS 67226 (877) 405-8066 (toll-free) info@fagronsterile.com www.fagronsterile.com Social: @fagronsterile

• Significant expertise in pharmaceutical manufacturing, repackaging, patient safety, regulatory guidance and pharmacy • Heavy investment in state-of-the-art facilities with independent cleanrooms and industry-leading automation • Shared belief in the need to improve safety and efficiency for 503B outsourcing facilities compounding sterile preparations (CSPs)

Centered Around Quality FSS complies with all DEA and FDA regulations, cGMP, GDP and cGLP while advocating for the advancement of patient-focused quality standards. Cleanrooms are equipped with independent HVAC systems and fitted with automation and depyrogenation technology. DEA- and FDAinspected in-house quality testing labs feature multiple vapor-phase hydrogen peroxide isolators for sterility testing. • 16 independent ISO 5–classified aseptic fill rooms • State-of-the-art environmental monitoring • 100% of batches tested for sterility, particulate matter and potency • In-house lab testing capabilities for both stability and sterility • Industry-leading automation

Product Overview • • • • •

Operating room (OR) and topical anesthesia Ophthalmics Pain management Urology (mitoMYcin Bladder) Dialysis

Ready-to-Administer OR Anesthesia Time and accuracy matter in the OR, which is why every OR syringe from FSS is tested for sterility, particulate matter and potency. No syringe is released from quarantine until all testing is complete and approved by our Quality team. All OR syringes are clearly labeled while adhering to ASTM, DQSA, and ISMP medication and anesthesia color-labeling standards. This includes TALLman lettering, presentation specifications, barcodes, expiration dating and room temperature storage requirements. FSS offers multiple presentations of the most commonly used anesthesia syringes.

OR Anesthesia Solutions: • • • • • • • • •

atropine bupivacaine ePHEDrine fentaNYL ketamine glycopyrrolate HYDROmorphone lidocaine methadone

• • • • • • •

midazolam morphine neostigmine PHENYLephrine rocuronium ropivacaine succinylcholine

Ophthalmics

Ophthalmic compounding is one of the cornerstones of DQSA because of the need for high-concentration, small-volume sterile preparations.

Ophthalmic Solutions • bevacizumab (Avastin®) • moxifloxacin HCl (generic for Avelox®) • moxifloxacin HCl (Vigamox®) • vancomycin • combination eye drops • EPINEPHrine • mitoMYcin • PHENYLephrine • lidocaine 1%/ PHENYLephrine 1.5% in balanced salt solution

Committed Supply Philosophy No excuses. No compromise. Committed supply— period. FSS is committed to delivering a reliable supply of high-quality sterile medication. Enjoy the benefits of inventory segregation (committed vs. transactional clients), continuous monitoring of product ordering patterns, enhanced pricing, and greater than 97% same-day fill rate on orders placed before cutoff times. Learn more; email CSPprogram@fagronsterile.com.

Customer Service You can talk directly to a member of our attentive and knowledgeable staff who will handle your requests quickly and accurately. Access to FSS’ pharmacists allow for quick answers to some of your most important questions. Request a free consultation at fagronsterile.com, and set up an account to access a mobile-friendly web shop for convenient 24/7 ordering and quick access to full order history, COAs and invoices, batch details, shipment tracking, environmental monitoring reports, centralized purchasing and more.

Visit Our State-of-the-Art 503B Facilities FSS is dedicated to the safety of the customers and patients we serve at each of our 503B outsourcing facilities, located in Wichita, Kan. With over 15,000 square feet of space dedicated to cleanroom suites, our facilities are designed to ensure unilateral movement of products and people. Doses are produced with industry-leading automation and quality control systems, so you and your patients can count on FSS—one of the most advanced DEA- and FDA-registered 503B outsourcing providers in the United States. Schedule your virtual or in-person site visit today!

Stay Informed Learn more, sign up for email notifications and download a complete list of products and services at fagronsterile.com

Ophthalmic preparations support patient health, safety and effective treatment outcomes, but can present unique production challenges for health care facilities. FSS is an industry leader in sterile ophthalmic medication outsourcing.

Corporate Profiles 2020

Special Advertising Section Pharmacy Practice News

Grifols Caring for People Grifols is a global health care company founded in Barcelona that since 1909, has enhanced the health and well-being of people around the world. Its four divisions—Bioscience, Diagnostic, Hospital and Bio Supplies—develop, produce and market innovative solutions and services in more than 100 countries. Grifols, with more than 24,000 employees in 30 countries, is committed to a sustainable business model that sets the standard for continuous innovation, quality, safety and ethical leadership in the industry.

AT A GLANCE

Diagnostic As a recognized leader in transfusion medicine, the Diagnostic Division offers a comprehensive portfolio of solutions designed to enhance safety from donation through transfusion. The division advances patient care with diagnostic solutions to improve disease detection and management, as well as simplify laboratory operations.

2410 Lillyvale Ave. Los Angeles, CA 90032 (888) 474-3657 www.grifols.com

Hospital INCLUSIV from Grifols is a comprehensive, integrated portfolio of proven technology, software and services designed to meet the safety and compliance challenges of sterile compounding preparation, while optimizing operational efficiencies. INCLUSIV encompasses cleanroom systems, IV robotics, pharmacy operations software, and three-year KLAS Category Leader for IV Workflow Management: PharmacyKeeper Verification. (See 2020 Best in KLAS report.)

Bio Supplies The Bio Supplies Division provides high-quality biological materials for biotechnology research, clinical trials, and for manufacturing pharmaceutical and diagnostic products.

Grifols, Socially Responsible As fundamental corporate values, quality and safety are fostered by Grifols’ corporate culture and integrated into every stage of the value chain. The company’s vertically integrated business model further enhances its control over production processes.

Bioscience As pioneers in the field of plasma science, the Bioscience Division is one of the largest plasma companies, with a growing network of donor centers worldwide. We develop this plasma into essential medicines used to treat chronic, rare and, at times, life-threatening conditions. To ensure a safe and consistent source of plasma-derived medicines worldwide, we have a vertically integrated production process from plasma collection through fractionation and purification at our facilities in the United States and Spain. Key essential plasma-derived products include immunoglobulins, alpha-1 antitrypsin, albumin, clotting factors and specialty plasma products.

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Grifols aspires to make a positive impact on society, actively collaborating with local communities, research organizations and academic institutions. In addition, we are convinced that our operations must be efficient and respectful of the environment. Long-term growth is impossible without sustainability.

Normal Saline Grifols now provides 0.9% Sodium Chloride for injection 500 mL in the United States. The commercialization of Grifols Normal Saline represents an important step forward to mitigate the current shortage that hospitals have been facing since 2014. Grifols Sodium Chloride is provided in the Fleboflex® container that is made with polypropylene and is free of PVC, DEHP and latex.

Corporate Profiles 2020

ICU Medical AT A GLANCE 951 Calle Amanecer San Clemente, CA 92673 (800) 824-7890 www.icumed.com

At ICU Medical, our focus is on bringing you intuitive, patient-centric infusion therapy products and services that provide meaningful clinical differentiation, consistent innovation and superior value. We design our products to work within your existing workflows to minimize disruption and maximize the time clinicians spend with patients. The unsafe handling of hazardous drugs used to treat many forms of cancer poses a significant health hazard to health care workers and patients. In response to these risks, ICU Medical has developed oncology systems—closed system drug-transfer devices (CSTDs), automated compounding systems, smart infusion pumps and safety software—that work together to cost-effectively help you safely and more efficiently prepare and deliver medications to patients.

Streamline the Preparation Process With Automated Compounding The Diana™ compounding workflow system is the first and only system to combine both automated compounding and IV workflow technologies with wireless pharmacist notification to let you remotely verify each preparation on a handheld tablet display without having to gown up and enter the cleanroom. With its integrated high-definition cameras, you can visualize the workflow for faster, more accurate high-volume compounding, while our closed system components help you comply with U.S. Pharmacopeial Convention (USP) General Chapter <800>. Unlike automated technologies that require huge investments and do not fit within existing workflows, Diana’s compounding module fits in as small as a three-foot hood, so you can cost-effectively incorporate automation without reconfiguring your cleanroom.

Maintain a Closed System From Pharmacy Through Administration With ICU Medical’s ChemoLock™ or ChemoClave™ CSTD components at every connection point, we help minimize drug exposure and comply with USP <800> CSTD safe handling guidelines during reconstitution and compounding. The ChemoLock CSTD helps speed up preparation times by eliminating the need to assemble multiple components, and it snaps together with an audible click, ensuring a safe and secure connection. Both CSTDs are designed to prevent the escape of hazardous drug or vapor concentrations, block the transfer of environmental contaminants into the system, and eliminate the risk for needlestick injuries. During administration, the Plum 360™ infusion pump’s closed system air management allows automated back priming to remove air from

With the Diana compounding workflow system’s integrated high-definition cameras, you can visualize the workflow for faster, more accurate high-volume compounding, while closed system components help you comply with USP <800> guidelines and keep your pharmacists and technicians safe from exposure.

the line without disconnection, helping you maintain a closed system throughout drug delivery.

Track Preparation Data and Streamline the Flow Of Information With Diana, you can automatically record each order preparation for easy reporting and archiving for traceability. Our Plum 360 and LifeCare PCA™ infusion systems help you accurately document infusion administration through our IV-EHR Interoperability solution, and our LifeCare PCA is the only patient-controlled analgesia pump with IV-EHR capabilities.

Improve Efficiencies and Maximize Profitability With the ICU Medical MedNet™ complete IV-EHR interoperability solution, you can automatically program your Plum 360 infusion system with medication orders—direct from the pharmacy—helping to reduce medication errors and setup time. The system also sends all infusion information back to the patient’s electronic health record, improving accurate documentation of start and stop times and creating additional revenue capture opportunities, even on secondary administrations. The unique delivery system of the 2018, 2019 and 2020 Best in KLAS Plum 360 allows for concurrent delivery of compatible medications at independent rates from a single pump, which can help reduce chair time. In addition, the cassette technology for Plum 360 can trap up to 1 mL of air before alarming, reducing air-in-line alarms for more efficient delivery. Our ChemoClave luer-based CSTDs connect directly to the Plum 360 dedicated administration sets, eliminating the need to assemble multiple components and increasing drug delivery efficiencies. You can even offset implementation costs and reduce packaging waste with the option to order commonly used CSTD components in multipacks.

Focused and Committed to Helping You Deliver Excellence in Infusion Therapy From Preparation To Administration Bringing new and innovative technologies to oncology pharmacists, technicians and nurses is at the core of who we are. We are committed to providing safe, cost-effective and easy-to-use solutions that maximize workflow efficiency, helping to keep clinicians and patients safe from exposure to hazardous drugs. Contact us today to learn how we can help you improve your IV medication safe handling practices by calling (800) 824-7890 or visiting www.icumed.com.

The 2018-2020 Best in KLAS Plum 360 features smart pump programming capabilities, helping you reduce infusion setup time while improving safety.

Corporate Profiles 2020

Special Advertising Section Pharmacy Practice News

International Medical Industries, Inc. Increase pharmacy productivity and safety with innovative and economical devices designed to protect your compounded sterile preparations.

AT A GLANCE 2981 Gateway Drive Pompano Beach, FL 33069 (800) 344-2884 sales@imiweb.com www.imiweb.com

Company Background For over 50 years, International Medical Industries has worked closely with pharmacists and compounding professionals to create innovative sterile products that meet very specialized needs. A prime example is the Prep-Lock™ Tamper Evident Syringe Cap technology. The Prep-Lock product family has become the tamper evidence standard among hospital pharmacies and outsource compounders everywhere. IMI remains at the forefront of developing new products specifically designed for the compounding industry. In addition, IMI has established long-standing partnerships with some of the biggest names in health care. Through these partnerships and directly, IMI is delivering the kind of high quality and high-value products that pharmacy operations demand. All IMI products are manufactured in the United States under the strictest quality standards at our FDA-registered, ISO 13485–certified facility.

Prep-Lock Tamper Evident Caps—For Oral Syringes (Non-Sterile) Drug diversion concerns continue to be a catalyst for enhanced drug security programs. Securing oral syringes with Tamper Evident Caps provides benefits that extend beyond diversion mitigation. When Oral Syringe Medication is required, dosing accuracy is often a particular concern. Unlike standard oral tip caps that can easily dislodge and fall off, the Prep-Lock™ Tamper Evident Cap provides a secure, tamperevident, leak-free closure, to oral syringes. Once applied to the syringe, removal or reinstallation is not possible without clear evidence of access. Administration of oral medications presents unique challenges; that’s why IMI’s Oral Tamper Evident Caps now feature a retained indicator ring to improved control over disposable components. Tamper Evident Caps help ensure that medications arrive to patients uncompromised, increase pharmacist and practitioner confidence, and advance patient safety.

Prep-Lock Tamper Evident Caps—Now Available For CADD Medication Cassettes (Sterile)

Product Overview Prep-Lock Tamper Evident Caps— For Luer Lock IV Syringes (Sterile) Compounded sterile preparations (CSPs) are at their greatest risk when they leave the custody of your pharmacy. The Prep-Lock Tamper Evident Cap greatly reduces the risk of your CSP being compromised either accidentally or intentionally. It ensures that product integrity is maintained from the time the CSP leaves the sterile hood until it is administered by an authorized clinician. If you partner with a compounding outsourcer, chances are you are already familiar with the Prep-Lock Tamper Evident Cap that is widely used by all the top 503B compounders. You can easily incorporate the use of this cap into your in-house preparations, which will provide standardization of all syringes throughout your hospital. As a result, your clinicians will not need training for administering syringes with multiple tamper evident methods. Installation of the Prep-Lock Tamper Evident IV Syringe Cap in your compounding operation is highly efficient. Each sterile tray of 10 caps offers a unique “keyed” feature allowing the pharmacist the ability to quickly install the cap with a simple twist of the syringe. This helps to reduce the risk of touch contamination and enhances aseptic technique. Best of all, you save time when compounding several syringes at once. Administering a syringe is very easy for the clinician. Simply pull off the outer sleeve of the tamper evident cap, unscrew the remaining luer lock cap and discard. Clinicians appreciate not having to deal with sticky tamper evident tape or frustrating shrink wrap. A choice of three different colored caps and two outer sleeve styles allows the pharmacy the ability to color-code either specific drug classes or processes. When you consider the cost of ordinary syringe caps combined with the cost of other tamper-evident methods, the Prep-Lock Tamper Evident Syringe Cap offers extraordinary value. More importantly, it makes a clear statement about how seriously your facility takes drug safety.

Special Advertising Section Pharmacy Practice News

The newest member of the Prep-Lock Tamper Evident Cap family provides protection for CADD Medication Cassettes. The male luer lock connector allows for quick installation on the cassette’s female tubing connector. The Prep-Lock Tamper Evident Cap for CADD Medication Cassettes offers the same proven features that have made the IV syringe version the number one choice for securing CSPs.

Additional Product Lines IMI offers a variety of sterile devices designed for the compounding pharmacist: • Prep-Seal™ Sterile Luer Lock Caps and Plugs • Prep-Fill™ Sterile Luer Lock Connectors • Rx-Vent™ Sterile Venting Needles • Rx-Tract™ Sterile Aspirating Needles

Product Distribution Contact IMI today and request FREE product samples for evaluation. IMI products are available direct or through one of our valued distribution partners. Visit us at www.imiweb.com or call (800) 344-2884.

Corporate Profiles 2020

Leiters. Compounding Health™ This is the place where quality means everything

AT A GLANCE 13796 Compark Boulevard Englewood, CO 80112 Phone: (800) 292-6772 Fax: (408) 288-8252 info@leiters.com www.leiters.com

Hospital and Surgery Center Products and Services • Prefilled syringes, vials and bags • Avanos ON-Q® Pain Relief System Fill Service • Opioid-free surgical pain services • Compatible with the Kit Check automated medication tray management system • Cardioplegic solutions • Partnered with Prodigy Health to provide access to their innovative pharmacy supply chain services

Ophthalmology Products and Services • Prefilled syringes, vials and dropper bottles • Comprehensive portfolio including: – Injections, antibiotics, dilating agents and topical anesthetics • FDA-Compliant Repackaged Avastin® Service – Multiple presentations available based on physician preference • Compatible with Besse Medical’s inventory management systems

Leiters, founded in 1926, is an FDA-registered 503B outsourcing provider of high-quality compounded sterile preparations and pharmacy services. Our team of industry experts provide a sophisticated understanding of what it takes to elevate quality and consistency of supply in outsourcing. We combine our team, our robust processes and our state-of-the-art outsourcing facility to ensure the highest quality outsourced medications for you and your patients. Through three key pillars, People, Place and Product, Leiters is elevating the standards in pharmaceutical outsourcing.

People • Our highly trained multifunctional teams of pharmaceutical experts ensure quality and regulatory compliance for all released products. • Our team has relevant industry experience with sterile injectable pharmaceutical companies, hospital pharmacies and academia. • Our customer experience team of regionally based account representatives, account managers and customer service specialists work together to provide you with consistent and reliable service.

Place

• We are licensed to ship to all 50 states and the District of Columbia. • Continuous facility environmental monitoring to maintain product quality standards.

Product • All sterile preparations are produced under 503B of the Food, Drug, & Cosmetic Act (503B Guidance), cGMP and USP Chapter <797>. • Release, stability, potency and sterility testing is performed on every batch made. • We provide a Certificate of Analysis (CoA) with every shipment.

Your Journey to Better Medicine Begins Here Leiters provides medicines and pharmacy services across the continuum of care, including hospitals, surgery centers, clinics and physicians’ offices. We are also strategically partnered with many market–leading, innovative health care companies that complement what we do here at Leiters. The products and services offered by these partners—and available through Leiters—may provide additional value to your organization.

We Don’t Want to Simply Tell You About What We Do, We Want to Show You We invite you to visit our facilities to better understand the cGMP regulations, sterile manufacturing processes and automation we use to elevate the quality of our products and services. Come join the growing list of organizations that have visited our facilities. To schedule a site visit or learn more about how Leiters is Compounding Health™, please visit www.leiters.com.

• We serve our customers from our Current Good Manufacturing Practices (cGMP) compliant facility, using state-of-the-art technology. • Our facility has been inspected by the FDA, State of California Board of Pharmacy, multiple health systems, group purchasing organizations and other independent accreditation organizations.

Corporate Profiles 2020

Special Advertising Section Pharmacy Practice News

Medi-Dose/EPS For more than 40 years, the Medi-Dose System has been used by facilities of all sizes to package solid oral, unit-dose medications. With input from pharmacists and technicians, Medi-Dose has been designed to be the easiest, fastest and most costeffective way to unit-dose and barcode your inventory.

for USP <800> medications. Ultraviolet-inhibitant blisters provide additional protection from light. Plus, a combination of special blister plastics with aggressive tamper-evident label adhesives pro70 Industrial Drive vides either six-month or one-year beyond-use Ivyland, PA 18974 dating for all your unit-dose packaging needs. Phone: (800) 523-8966 The Medi-Dose System offers these additional Medi-Dose began in 1971, when Milton Braverman, a former pharmaFax: (800) 323-8966 benefits: ceutical company territory manager, formed his own company. Robert info@medidose.com • Sealed units can be left in sheets or easily Braverman, president, remembers, “My dad was acutely aware of the www.medidose.com torn down to individual doses. requirements of hospital pharmacy. He saw the need for inexpensive, Products • Lid-Label Covers are available in 8 1/2˝ x 11˝ manual unit-dose packaging allowing hospitals to convert from tralaser sheets of 25 doses or 4˝ x 6 1/4˝ direct ditional dispensing. He developed systems to package, handle and • Medi-Dose® (Solid) and TampAlerT® (Liquid) Oral thermal sheets of five doses. dispense predetermined amounts of medication so they would be Unit-Dose Packaging • Laser Lid-Label Cover Sheets are available accessible for one regular dose.” • Medi-Cup® PLUS packaging in a wide variety of colors to for extended beyond-use dating facilitate color coding of medi• MILT® by Medi-Dose unit-dose cations. and barcoding software • Circular and Oval Blisters have • LiquiDose® labeling, IV additive been designed to fit your disand filtration products pensing machines and storage • Nultraviolet® ultraviolet light cabinets. inhibitant bags • New MPB® - Multi-Purpose • Steri-Dropper sterile ophthalmic Blisters allow you to easily dropper bottles package, label and secure • High Alert and IV Line Tracing even more sizes and types of Labels medications, including large • Resealable bags, bottles, and other medications, compounded pharmacy supplies and disposables drugs, double and triple “0” capsules, unit-of-use packaging, repackaged medications and suppositories. • All Medi-Cup Blisters and Lid-Label Covers work with our MILT 4 Software, which can be used for all your barcoding and labeling needs. Adapts to Your Needs: With our MILT 4 Software, you can design your labels any way you want (for solids, liquids, syringes, ampules, IVs—even equipment and supplies). In addition to the ability to use graphics, special fonts and shapes—even logos and symbols—to better identify your medications, MILT 4 has been designed to easily create barcodes with the information your barcode-enabled point-of-care and barcode medication administraBrightly colored Lid-Label Covers call attention to medication requiring special handling. tion systems require. Popular 1D and 2D barcode formats can be created with National Drug Code numbers, beyond-use dates, lot numbers and special codes. Although familiar today, launching the idea of unit dose was a huge Plus, MILT 4 suggests tall man lettering options (e.g., DOPamine problem the new company faced. “We were one of the pioneers, instead of DOPAMINE) for medications as recommended by the the innovators promoting unit dose in hospitals,” Robert Braverman FDA and the Institute for Safe Medication Practices. In addition, recalled. “Due in part to Medi-Dose’s educational efforts, pharmacists newly entered and previously saved medication names are comand nurses accepted the validity of unit dose.” pared with the CDC’s “NIOSH List of Antineoplastic and Other Inexpensive, Easy and Flexible: Because of its unique Cold-Seal Hazardous Drugs in Healthcare Settings.” If a match is found, the technology, the Medi-Dose System is simple to use and requires no user is notified that this medication may potentially be hazardous special in-service training or additional space. Medi-Cup blisters are to handle. available in 15 styles and eight sizes to accommodate the largest medications or the smallest storage spaces, and are particularly ideal

AT A GLANCE

To get started, all you will need is: 1. 2. 3. 4.

Medi-Cup Blisters: 15 styles to suit your packaging needs. Lid-Label Covers: Laser or Direct Thermal labels to seal the blisters. MILT 4 Software: Design and manage Lid-Label Cover printing. Fil-Form and Roll-E-ZY: Aligns Lid-Label Covers to Medi-Cup Blisters, ensuring a positive seal between labels and blisters. Inexpensive. Flexible. Tamper-Evident. If you are looking for a system to handle any or all of your unit-dose or barcoding needs, then the Medi-Dose System is the perfect fit for you!

Using our MILT 4 Software, you can label and identify all your medication, complete with graphics and a barcode.

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Corporate Profiles 2020

Pacira BioSciences, Inc. AT A GLANCE 5 Sylvan Way, Suite 300 Parsippany, NJ 07054 973-254-3560 pacira.com EXPAREL.com iovera.com

Medical Inquiries 855-793-9727

Pacira BioSciences, Inc. is a leading provider of nonopioid pain management and regenerative health solutions dedicated to advancing and improving outcomes for health care practitioners and their patients. Pacira is driven by a dynamic workforce committed to optimizing patient care and driving improved patient outcomes with opioid-reducing strategies.

A First-of-Its-Kind, Single-Dose Local And Regional Analgesic In 2012, Pacira successfully launched EXPAREL® (bupivacaine liposome injectable suspension), the first and only single-dose, long-acting analgesic approved for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Safety and efficacy have not been established in other nerve blocks. EXPAREL provides prolonged pain control that reduces or eliminates the need for opioids without requiring cumbersome catheters or pumps.

A Proprietary Drug Delivery Platform Utilized by EXPAREL, DepoFoam® is a proprietary drug delivery platform designed to extend a medication’s duration of action without altering its molecular structure. The DepoFoam carrier matrix is made up of multivesicular liposomes that encapsulate a drug. Each chamber is separated by lipid membranes that naturally erode to release the drug over a desired period of time.

A Revolutionary Cryotherapy Platform In 2019, Pacira added the FDA-approved iovera° system to the company’s commercial offering. The iovera° system is a novel treatment that alleviates pain through a mechanism known as cryoneurolysis, which applies intensely focused cold therapy to a specific nerve to interrupt its ability to transmit a pain signal. Results can be

Important Safety Information for EXPAREL EXPAREL is contraindicated in obstetrical paracervical block anesthesia. Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via infiltration were nausea, constipation, and vomiting; adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation. 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 population: patients <18 years old 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 Specific 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 intraarticular 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.

Warnings and Precautions for Bupivacaine-Containing Products Central Nervous System (CNS) Reactions: There have been reports of adverse neurologic reactions with the use of local anesthetics. These include

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felt immediately after iovera° treatment with nonopioid pain relief that can last three months, and in some cases longer, as the nerve regenerates over time.

Shifting the Pain Management Paradigm The era of opioids as the gold standard of pain management is over. Pacira is setting new expectations for clinicians and patients alike: low- and no-opioid pain management through innovative alternatives that offer better outcomes. Overreliance on opioids—particularly in the postsurgical setting—can have unintended downstream consequences for patients, communities and our nation’s overall societal well-being. Pacira is committed to working to address this growing societal burden by providing clinicians with innovative alternatives that reduce or eliminate the need for opioids. The company’s efforts are buoyed by a groundswell movement led by government and independent health care organizations that are recommending a shift toward nonopioid-based multimodal pain management regimens in order to mitigate patient exposure to unwanted and potentially severe opioid-related side effects.

The Pacira Advantage Discovery, innovation and proprietary expertise are the hallmarks of the Pacira competitive advantage. The company not only holds the exclusive rights and expertise to DepoFoam, but owns the unique distinction of being the only company in the world with the ability to manufacture DepoFoam-based products on a large commercial scale. With steadily increasing demand and a growing list of potential clinical applications, Pacira, EXPAREL and iovera° are poised to become vital fixtures in the nonopioid pain management arena. For more information about Pacira BioSciences, Inc., visit www.pacira.com.

B I O S C I E N C E S ,

I N C .

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. Full Prescribing Information is available at www.EXPAREL.com.

Important Safety Information for iovera° Contraindications The iovera° system is contraindicated for use in patients with the following: cryoglobulinemia, paroxysmal cold hemoglobinuria, cold urticaria, Raynaud’s disease, and open and/or infected wounds at or near the treatment site.

Potential Complications As with any surgical treatment that uses needle-based therapy and local anesthesia, there is a potential for site-specific reactions, including, but not limited to ecchymosis, edema, erythema, local pain and/or tenderness, and localized dysesthesia. Proper use of the device as described in the User Guide can help reduce or prevent the following complications: At the treatment site(s): injury to the skin related to application of cold or heat, hyper- or hypopigmentation, and skin dimpling; and Outside the treatment site(s): loss of motor function. For more information, please visit www.iovera.com.

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QuVa Pharma®

AT A GLANCE

503B Accountability and Leadership QuVa Pharma was purpose-built to change 503B outsourcing for the better—making it more safe, efficient and reliable—and with deep expertise in cGMPs and sterile injectable pharmaceutical manufacturing, they are leading the way. QuVa Pharma is licensed in all 50 states to deliver ready-to-administer, compounded sterile products of industry-leading quality. QuVa Pharma is proud to be the 503B partner of choice for many of the nation’s leading hospitals and health systems. Our cGMP processes and proven FDA compliance record are second-tonone; we hold each and every product batch until the results of a rigorous testing schedule are confirmed to be within specifications. While our industry leading cGMP processes, sterile-to-sterile product range and approximately 240,000 sq. ft. state-of-the-art production facilities are hallmarks of QuVa’s success, they are underpinned by our commitment to transparent and customer-focused service. As a solutions-focused ally, we collaborate to meet customers’ specific needs, anticipate market challenges and communicate regulatory updates to ensure that safe and effective medications are always available. Also, through our Product Development team, we provide you expertise in formulating and delivering new products to help meet important clinical needs. QuVa Pharma is accountable to be a valuable and reliable resource as an extension of your pharmacy operation.

was founded by leaders with expertise in sterile pharmaceutical manufacturing, our comprehensive understanding of regulatory requirements governed the development, from the ground up, of an integrated quality management system, which guides all QuVa production processes. We promptly address all agency comments with appropriate corrective actions to further strengthen our already robust quality management system and remain in a strong state of control.

3 Sugar Creek Center Blvd., Suite 250 Sugar Land, TX 77478 (888) 339-0874 www.quvapharma.com Customer.Service@QuVaPharma.com

QuVa Pharma’s Industry-leading Quality Management System is Based on 7 Pillars 1. Facility Systems: Room certification, maintenance and calibration of equipment 2. Regulatory and Pharmacy: Compliance with all relevant agencies, especially FDA, DEA and state boards of pharmacy 3. Validation: Qualification of equipment and process for proof that our operation is in a state of control 4. Materials: Supplier qualification and testing before bringing any materials into the system 5 Production: Sterility assurance, including cleanroom design, aseptic technique, operations under the hood, all the way to core building airflows 6. Quality Assurance: Independent quality unit that oversees the production system, continuous improvement, and corrective and preventative action programs 7. Quality Management System: Integrated processes that ensure adherence to regulations and provide the requirements to ensure we operate in a compliant manner

Going Above and Beyond Industry Standards Pictured above is QuVa Pharma headquarters in Sugar Land, Texas; 3 additional manufacturing locations include Sugar Land, TX; Temple, TX; Bloomsbury, NJ

Expansive Capacity and Scale to Meet Nationwide Demand QuVa Pharma has a full sterile-to-sterile product portfolio spanning: Anesthesiology and OR, Anti-Infectives, General Medicine, Labor and Delivery, Pain Management, and Cardioplegia. Our three state-of-the-art, FDA-registered facilities of approximately 240,000 square feet, give us the expansive production capacity, redundancy and flexibility to meet customers’ dynamic needs. This scale and our strategic supplier relationships allow us to compete as one of the largest sterile-to-sterile 503B suppliers in the industry. QuVa can also manufacture sterile products to ensure continuous supply during critical drug shortages and to meet clinical needs. This enables QuVa Pharma to provide full service, resiliency and peace of mind so you can focus on patient care.

Industry-leading FDA Compliance Record As regulatory, compliance and operational requirements become more stringent, having the right partner to support you is more valuable than ever. QuVa Pharma operates according to strict cGMP standards to meet or exceed all current FDA guidelines. In other words, our standards are set above the standard. Since QuVa Pharma

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QuVa Pharma builds in other ways to ensure the integrity of our product: • Stability testing on products to establish Beyond Use Date (BUD) • Potency testing using Ultra Performance Liquid Chromatography (UPLC) vs High Performance Liquid Chromatography (HPLC) • Container-closure integrity testing on our primary product container • UV-blocking overwrap for light-sensitive products • Shipment requirements adjusted for extreme weather conditions • Availability of Kit Check™ for radio frequency identification (RFID) tracking of pre-filled syringes • NEW, intuitive and user-friendly ordering portal that puts you in control of your orders and inventory

Your Partner of Choice QuVa Pharma is your accountable ally and a comprehensive resource with unmatched 503B expertise that will ensure you always have an answer for your 503B Outsourcing needs. We closely monitor industry dynamics and leverage industry trends to your benefit. Our model is one of true partnership—we strive to understand each customer’s perspective, to understand what challenges you face, and what success looks like for you, so we can help deliver the solutions you need.

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Pharmacy Technology Report AT A GLANCE 545 W. 45th Street, 8th Floor New York, NY 10036 Phone: (212) 957-5300 Fax: (212) 957-7230 Website: pharmacytechnologyreport.com

Editorial Director David Bronstein davidb@mcmahonmed.com Ext. 212

This biannual supplement to Pharmacy Practice News and Specialty Pharmacy Continuum covers best practices in automation, informatics and patient safety. Our mission is to give health-system and specialty pharmacists the content they need to provide technology-enhanced, highquality patient care in the most cost-effective manner possible.

Featured Content

Pharmacy Technology Report (PTR) focuses on automated dispensing, robotics, clinical decision support (CDS), telepharmacy, remote temperaPublication Director ture monitoring and other key pharmacy techDave Kaplan nologies. Articles include how to perform vendor dkaplan@mcmahonmed.com evaluations, staff training, return-on-investment Ext. 912 calculations, C-suite negotiations and team Senior Editors building with nursing, physician providers and other stakeholders. Marie Rosenthal PTR also includes profiles of innovative health mrosenthal@mcmahonmed.com Ext. 265 systems that have added pharmacy technology to their operations. In our next issue, in Sarah Tilyou October 2020, look for a feature on how sevsmtilyou@mcmahonmed.com eral leading hospitals are using telepharmacy durExt. 216 ing the ongoing COVID-19 pandemic. Thanks to the remote technology, these hospitals are able to Sales Account Manager provide cutting-edge emergency care and mediSarah Rezvani cation therapy management services to patients in SRezvani@McMahonmed.com medically underserved areas despite the need for Ext. 260 continued social distancing. Other technologies on tap in the next issue include smart infusion pumps, RFID, robotics and automated dispensing cabinet (ADC) optimization.

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Timely Coverage PTR also prides itself on covering “hot” practice issues that continue to challenge health systems. Here are a few examples of technology initiatives that help meet these challenges from the October 2020 issue: • A hospital’s electronic medical record (EMR)-driven antibiotic stewardship effort that achieved a 50% reduction in Clostridioides difficile infections • A strategy for optimizing inventory management in ADCs that cut overstocking of drugs and saved a health system millions of dollars annually • Several state-of-the-art cleanroom renovations that helped hospitals comply with the latest regulations from USP and other regulatory bodies We will continue to keep an eye on the horizon for technology that has the potential to shake up pharmacy practice.

PharmacyTechnologyReport.com This digital home for PTR has archived articles that can be shared via Facebook, Twitter, LinkedIn and other social and business networking sites. Additionally, web-only news stories are posted regularly, and we plan to add more video interviews with the nation’s top pharmacy informatics experts. Twice a month, our opt-in e-newsletter features a mix of print and web-only content. To sign up for the PTR e-newsletter, visit PharmacyTechnologyReport.com and click on the “Sign Up for our FREE e-newsletter” link at the top of the page.

A Proven Formula The practical, peer-driven content of PTR is the same formula that has made Pharmacy Practice News the No. 1-read publication in its field. Because PTR is mailed with Pharmacy Practice News and Specialty Pharmacy Continuum, it benefits from powerful ride-along readership. We plan on continuing to hone the PTR content mix, so please send your ideas and feedback to davidb@mcmahonmed.com.

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Best practices in automation, informatics and patient safety

Policy

Pharmacy Practice News • August 2020

Compounding

The room where it happens:

The ‘Gemba Walk’ Toward Cleanroom Compliance

oes your hospital pharmacy have a designated specialist assigned to walk through your sterile compounding space every single day, looking for what the FDA deems “insanitary conditions,” such as rust or paint chips, signs of water leakage, or visible microbial contamination? That’s what they’re doing at the Moses Cone Memorial Hospital, in Greensboro, N.C. In 2016, the FDA issued “Insanitary Conditions at Compounding Facilities,” a draft guidance document that was revised in 2018, to provide examples of conditions that the agency deems insanitary to assist compounders in identifying similar conditions in their own operations. “That got us thinking differently about how we are addressing these conditions,” said Kevin Hansen, PharmD, the assistant director of pharmacy. “We noticed that when you look at 503B compounding facilities and FDA inspection documentations, their observations and warning letters are almost all focused on insanitary conditions. So, even though we are not a 503B outsourcing facility and [are] operating under Current Good Manufacturing Practices, we wanted to go above and beyond the minimum standards outlined by USP <797>. The environmental monitoring tests identified by USP <797> are lagging indicators, because test results can take multiple days to weeks to finalize. We wanted to identify, correct and prevent problems in a more routine and timely manner.” Dr. Hansen met with certified pharmacy technician specialists Kathleen Forbis, CPhT, CSPT, AAS, and Clinton Meachum, CPhT, CSPT, to develop a strategy. Since Moses Cone had recently gone through Lean management training, they selected the “Gemba Walk,” a key element of the Lean philosophy, as their approach. A Japanese term, ”gemba” means “the place where it happens.” Its purpose is to allow managers and leaders to observe the actual work process and identify opportunities

for continuous improvement. “We can sit at our computers and look at numbers all day, but the real bang for your buck requires you to go to the place where the work occurs and put [your] eyes on what is actually occurring,” Dr. Hansen said. “That can be challenging in the cleanroom setting since you have to fully cleanse and garb, so there needs to be some intentionality of entering the cleanroom suite.”

Practicing at the Top Of Their License Specialist pharmacy technicians such as Ms. Forbis and Mr. Meachum were chosen to conduct the safety walks because of the Moses Cone goal for pharmacy staff to practice at the top of their license. “We’ve done a lot within our profession and our institution to continue to develop and specialize pharmacists, but significant opportunity exists to also develop our pharmacy technicians,” Dr. Hansen said. “We’ve focused our efforts on building new career paths for our pharmacy technicians that give options to step into highly specialized roles. In some cases, our state board of pharmacy even recognizes and allows highly qualified technicians to conduct certain verifications that a pharmacist would normally do, so this presented an opportunity to expand the roles of both our technician and pharmacist workforce simultaneously.” Technicians who wanted to advance their skills and responsibilities in sterile compounding, such as the Gemba Walk, were required to take ASHP’s sterile compounding certification course and complete a Lean project leading to operational efficiencies or

safety within the department. To focus the Gemba safety walk, they used the acronym CLEAN: Checklist: Construct a checklist of items to look for during the safety walk, which was adapted by the FDA insanitary conditions draft. Look: During each shift crossover (three times per day), have staff walk the sterile and nonsterile compounding areas. Evaluate: Staff evaluate what they found and whether there were any concerns that need to be addressed. Address: Staff immediately address any insanitary conditions and communicate with the team. Note: Staff notate any findings from the safety walk and use a web-based application to document remedial actions. “We do this walkthrough every day, constantly visualizing things that might not look right. No visible particles, rust or loose ceiling tiles,” Ms. Forbis said. “If things are not running smoothly, we troubleshoot and take immediate actions.” Cameras are mounted in each of the sterile compounding hoods, and Mr. Meachum and Ms. Forbis review video from those cameras every day to monitor the aseptic technique of each of the compounding technicians. “If we see deviations in technique, we go over that with them,” Ms. Forbis said. “We initially were concerned that the technicians wouldn’t appreciate that, but they’ve all adapted to it very well, and we can really see them making improvements in their aseptic technique practices. When there are safety events, we can go back and see what happened, and focus on how the systems failed,” she said. “If we see an example of poor aseptic technique, we can crop out individuals, focus on the specific anomaly, and share it during our staff meetings. We’ve had some people who have been working in the cleanroom for 15 years say, ‘Nobody ever told me before that doing X is not good practice.’”

When the Gemba walks first began in January 2019, the technicians made frequent reports: dirt in this corner, rust on the bottom of this piece of equipment. “As we got ahead of things and became more consistent in maintaining good practices, reporting and necessary corrective actions began to decline,” Ms. Forbis said.

An Adaptable Strategy Any institution of any size can adapt Moses Cone’s daily Gemba Walk to maintain and improve conditions in its sterile compounding area, said Patricia Kienle, RPh, the director of accreditation and medication safety at Cardinal Health. She noted that the FDA’s insanitary conditions document has been a significant issue whenever the FDA inspects either 503A pharmacies or 503B outsourcing facilities. “A lot of the listed conditions have been in pretty much every hospital IV room, but many people don’t pay attention because, fortunately for them, the FDA hasn’t walked in to look at them yet,” Ms. Kienle said. “But these issues are getting a lot of attention on checklists that the FDA and state inspectors use.” The approach at Moses Cone is innovative, she noted. “While I’m sure there are other institutions doing something like this, I haven’t seen any that are this specific about how they do it, and doing it every day in a standardized way,” she said. “They’ve taken a very well-established quality process and integrated it into the daily life of the cleanroom. I’m very impressed that they have it technician driven. Oversight of IV areas is an outstanding way to develop advanced practice technicians into larger roles.” —Gina Shaw Ms. Kienle reported that she is a member of the USP Compounding Expert Committee. Dr. Hansen and Ms. Forbis reported no relevant financial relationships. The Moses Cone initiative was presented as a poster (4-158) at the ASHP 2019 Midyear Clinical Meeting in Las Vegas.

34 Policy

Pharmacy Practice News • August 2020

Reimbursement Matters

Help With Reimbursement Lingo! O

ne of the most frequent questions surfacing again and again is the request for help in understanding the language and quirks of reimbursement, particularly as applied to the pharmacy revenue cycle in all types of hospitals, ranging from critical access to multicampus systems. That’s quickly followed by overcoming helplessness in staying current with changes. This uptick in interest comes on the heels of pharmacy departments being confronted by their finance teams imploring them to

do their part in bringing in sorely needed revenue. Although cutting-cost drumbeats remain constant, revenue is essential for the facility to operate. In this column we’ll walk through some key steps, and I encourage you to access the Reimbursement Tool Kit (www.pharmacypracticenews.com/ToolKit) to delve more thoroughly into how all the pieces fit together for outpatient areas. The first essential step must be the recognition of knowing who the payor is and their requirements for payment.

As much as you might chafe against this, it’s not your decision, but the payor’s, as to who is eligible for payment and what must accompany a claim to be paid. Is the payor identified as part of the basic information you receive about a patient in your EHR system? If not, fix this now! Next up is the need to submit a clean complete claim that’s not going to be rejected. Denied claims require rework to do what should have been done in the first place and delays payment. Not supplying all of the information such as

codes, HCPCS codes NDC numbers, billing units, ICD-10 codes, PAs (or LCD/NCD documentation), or failure to use modifiers when required equates to reduced or denied payment. Or in plain language, you won’t get paid if you don’t submit the name and dose of the drug, along with the disease state being treated, and follow payor requirements for use. This challenge can be compounded by additional specific requirements imposed by commercial payors, managed care

Table 1. New CY 2020 HCPCS Codes Effective July 1, 2020, for Certain Drugs, Biologicals, and Radiopharmaceuticals Receiving Pass-Through Status CY 2020 HCPCS Code

CY 2020 Long Descriptor

CY CY 2020 2020 SI APC

C9059

Injection, meloxicam, 1 mg

9371

J9358

Injection, fam-trastuzumab deruxtecan-nxki, 1 mg

9353

J7204

Injection, factor viii, antihemophilic factor (recombinant), (esperoct), glycopegylated-exei, per iu

9354

J9177

Injection, enfortumab vedotin-ejfv, 0.25 mg

9364

J0742

Injection, imipenem 4 mg, cilastatin 4 mg and relebactam 2 mg

9362

Q5119

Injection, rituximab-pvvr, biosimilar, (ruxience), 10 mg

9367

C9061

Injection, teprotumumab-trbw, 10 mg

9355

J1429

Injection, golodirsen, 10 mg

9356

C9063

Injection, eptinezumab-jjmr, 1 mg

9357

C9122

Mometasone furoate sinus implant, 10 micrograms (sinuva)

9346

J0896

Injection, luspatercept-aamt, 0.25 mg

9347

or Medicare Part C payors, such as the use of specific distributors, adherence to their formularies, and white bagging.

“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

The Challenges of Limited Staff You might ask how it’s possible to stay abreast of the myriad reimbursement changes coming your way, when so many facilities face significant staffing challenges. The good news is that it actually requires very little time to stay current with changes. More problematic is the lack of basic reimbursement lingo/knowledge and a good working lingo/kno relationship between your revenue cycle, relationsh information technology and pharmacy informatio departments. The common clinician attidepartmen tude, “it’s “it’ not my responsibility,” also doesn’t help. The “source of truth documents” used by your facility doc contain a wealth of information. con Learn what they are and how to Le them. (These documents include use the details on the service that the facility subscribes to that populates their computer with drug files, etc. The docusystem w ments are used by pharmacy and revenue cycle team, as well as IT.)

A Reimbursement Lexicon APC, ambulatory payment classification; ASP, average sales price; CDM, charge description master; CMS, Centers for Medicare & Medicaid Services; CR, Change Request; CY, calendar year; EHR, electronic health record; FISS, Fiscal Intermediary Standard System; HCPCS, Healthcare Common Procedural Coding System; ICD-10, International Classification of Diseases, Tenth Revision; LCD/NCD, local coverage determination/national coverage determination; NDC, National Drug Code; OPPS, Outpatient Prospective Payment System; PA, prior authorization; SI, status indicator

The message here is that there are multiple reimbursement resources you can turn to, with CMS as a prime example; the agency supplies copious amounts of information to every hospital. If this isn’t filtering down to you, get on the CMS distribution lists for Med Learn Matters—it’s free. Most importantly, find someone who has a see LINGO HELP, page 36

Table 2. Currently Existing HCPCS Codes for Certain Drugs, Biologicals, and Radiopharmaceuticals Receiving Pass-Through Status Effective July 1, 2020 CY 2020 HCPCS Code CY 2020 Long Descriptor

April 2020 SI

July 2020 SI

CY 2020 APC

Q5116

Injection, trastuzumab-qyyp, biosimilar, (trazimera), 10 mg

9350

Q5118

Injection, bevacizumab-bvzr, biosimilar, (zirabev), 10 mg

9348

Table 3. HCPCS Codes for Certain Drugs, Biologicals, And Radiopharmaceuticals With Pass-Through Status Ending Effective June 30, 2020 CY 2020 HCPCS Code CY 2020 Long Descriptor

April 2020 SI

July 2020 SI

CY 2020 APC

J0565

Injection, bezlotoxumab, 10 mg

9490

J2326

Injection, nusinersen, 0.1 mg

9489

Table 4. CY 2020 HCPCS and CPT Code Changes for Certain Drugs, Biologicals, and Radiopharmaceuticals Retroactive for the Period Of February 23, 2020, Through June 30, 2020 HCPCS Code Q5116

Long Descriptor Injection, trastuzumab-qyyp, biosimilar, (trazimera), 10 mg

Old SI

New SI

APC

Effective Date

9350

02/23/2020

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36 Policy

Pharmacy Practice News • August 2020

Reimbursement Matters

LINGO HELP passion for this area of operations and give them this responsibility. Limited staff is no excuse; continuing to blunder through this process and not carry your financial responsibility for securing revenue will only result in suboptimal reimbursement and even less staff! A recent MLN Connects post (go.cms. gov/31RC3lY) illustrates the wealth of information that CMS provides. I’d urge you to explore the details in the lengthy bulletin that updates OPPS covering all of the outpatient areas of your facilities.

column) illustrate products that can revert from a nonpayable status to a payable one (SI K) and that this change in status can be retroactive, along with encouragement to rebill for payment. This continues through Tables 15, 16, 17 and 18, which address several retroactive changes to other biosimilars and vaccines, all of which may be resubmitted. Table 19 lists 42 new drug, biological and radiopharmaceutical HCPCS codes effective July 2020 with a variety of SIs, while Table 20 addresses new skin substitute products and their low-cost group or high-cost group assignment. (To access all of the tables referenced, visit the MLN Connects post.)

Important Code Changes

Understanding ASP Changes

Once you’ve accessed the material, go to Table 10 in the CMS document (Table 1 in this column), which lists the 11 new CY 2020 HCPCS codes, effective July 1, 2020, for drugs and biologicals receiving pass-through status (SI G). Compare these with what’s currently listed in your CDM and make any necessary changes. Pass-through status (SI G). This three-year window is updated quarterly. Move on to Table 11 (Table 2 in column) for details on two existing HCPCS codes for products that started to receive pass-through status (SI G) in July 2020, and to Table 12 (Table 3 in column) for the two HCPCS codes that lost SI G status. Note that in losing status, these two now are SI K status, which triggered 340B reimbursement at ASP minus 22.5%. More payment status changes. Tables 13 and 14 (Tables 4 and 5 in

The language that CMS uses to describe its various payment policies may sometimes sound rather convoluted, but becoming familiar with how the agency defines and updates those policies is a critical skill your revenue cycle team needs to develop. So here, verbatim, are some additional key updates from CMS, quoted directly from its July 2020 OPPS payment update. Drugs and biologicals with payments based on ASP. For CY 2020, payment for the majority of non–passthrough drugs, biologicals and therapeutic radiopharmaceuticals that were not acquired through the 340B program is made at a single rate of ASP plus 6% (or ASP plus 6% of the reference product for biosimilars). Payment for non– pass-through drugs, biologicals and therapeutic radiopharmaceuticals that were acquired under the 340B program is made at the single rate of ASP minus

continued from page 34

Reimbursement Tool Kit Reimbursement is changing at lightning speed, and if you’re not accessing the latest resources on these changes, the financial future of your health system is at stake. Fortunately, Pharmacy Practice News’ Fundamentals of Reimbursement tool kit can help you keep pace and become a financial star for your facility.

Table 5. CY 2020 HCPCS and CPT Code Changes for Certain Drugs, Biologicals, and Radiopharmaceuticals Retroactive for the Period Of March 16, 2020, Through June 30, 2020 HCPCS Code Q5113

Long Descriptor Injection, trastuzumab-pkrb, biosimilar, (herzuma), 10 mg

22.5% (or ASP minus 22.5% of the biosimilar’s ASP if a biosimilar is acquired under the 340B program), which provides payment for both the acquisition cost and pharmacy overhead costs associated with the drug, biological or therapeutic radiopharmaceutical. In CY 2020, a single payment of ASP plus 6% for pass-through drugs, biologicals and radiopharmaceuticals is made to provide payment for both the acquisition cost and pharmacy overhead costs of these pass-through items (or ASP plus 6% of the reference product for biosimilars). Payments for drugs and biologicals based on ASPs will be updated on a quarterly basis. Effective July 1, 2020, payment rates for many drugs and biologicals have changed from the values published in the CY 2020 OPPS/ASC final rule with comment period as a result of the new ASP calculations based on sales price submissions from the fourth quarter of CY 2019. In cases where adjustments to payment rates are necessary, changes to the payment rates will be incorporated in the July 2020 FISS release. Drugs and biologicals based on ASP methodology with restated payment rates. Some drugs and biologicals based on ASP methodology will have payment

Old SI

New SI

APC

Effective Date

9349

03/16/2020

rates that are corrected retroactively. These retroactive corrections typically occur on a quarterly basis. The list of drugs and biologicals with corrected payment rates will be accessible on the CMS website on the first date of the quarter at go.cms.gov/2VUZrLT. Providers may resubmit claims that were affected by adjustments to the previous quarter’s payment files. So, there you go—a bit of reimbursement lingo from CMS. Become familiar with it, communicate it to your revenue cycle team, and reap the benefits! ■

Resource Box CMS Guide on Biosimilar Modifiers go.cms.gov/3fbDnUU

CMS FAQs on 340B Changes go.cms.gov/3guSpVQ

ASP Files go.cms.gov/2O2ZxMS APhA Guide on Outpatient Fee-for-Service Billing Pharmacist.com/billing-primer

Authored by Bonnie Kirschenbaum, MS, FASHP, the tool kit covers essential pharmacy payment rules. The kit includes six modules: 1. It’s All About Coding! So Learn the Language 2. Drug Reimbursement: How Do All the Pieces Fit Together? 3. Being an Effective Prior Authorization Player 4. Injectable Drug Administration 5. Billing for Drug Waste 6. Paying for Part B Drugs—It’s Alphabet Soup!

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38 Clinical

Pharmacy Practice News • August 2020

Medication Safety

JUST CULTURE continued from page 8

successfully integrate a just culture ulture include it in every step of the way, from the onboarding process right ht through to the exit interview.”

Choose Your Response to Errors A few real-life medication errors rrors illustrate how an organization with a blame culture responds to medical errors, according to Matthew Grissinger, RPh, the director of error reporting programs at the Institute for Safe Medication Practices (ISMP), in Horsham, Pa. In a case that occurred in July 2006, a nurse accidentally administered a bag of epidural analgesia (bupivacaine) by the peripheral IV route instead of the intended penicillin to a 16-year-old woman who was giving birth (bit.ly/ 3cvR4MS). The patient experienced cardiovascular collapse. The baby was successfully delivered by cesarean, but the mother could not be resuscitated. “The organization hung [the nurse] out to dry,” Mr. Grissinger said. She “was fired and her fate was left to the justice system, where decisions are based solely on the outcome of an error, not the systemic causes of the error, which is what a just culture looks at.” Although the nurse was charged for removing bupivacaine from an automated dispensing cabinet without an order, an investigation also involving ISMP revealed a number of systemic factors that underlay her actions, suggesting they were not simply a result of risky individual behavior, Mr. Grissinger explained. “Nurses in labor and delivery at the hospital were routinely expected to be ready with all medications when they got to the delivery room,” he said. Additionally, there was only 50% compliance with barcode scanning in the labor and delivery unit; the nurse had worked two consecutive eight-hour shifts, then stayed overnight during her shift off; and worked the next day. “All of those things led to this one event.” In another case that occurred in March 2006 (bit.ly/3cyHkBu), a pharmacist dispensed a chemotherapy agent that a pharmacy technician had compounded using an incorrect strength of sodium chloride. The event led to

a child’s death; the pharmacist’s license was permanently revoked, and he was sentenced to six months in prison for involuntary manslaughter, Mr. Grissinger said. Here, too, an investigation revealed a perfect storm of factors that set the pharmacist up for an error and that an organization with a just culture would have been more interested in examining. “The pharmacist hadn’t taken breaks or eaten any meals during his shift because it was the weekend and the pharmacy was understaffed, and because maintenance had been

performed on the computer the night before, the pharmacy system was not available,” he said. Additionally, the pharmacist was asked to dispense the patient’s chemotherapy agent immediately, leaving him feeling rushed to check the technicianprepared compound, Mr. Grissinger said. The order was also among many others in a “very small and crowded checking area,” he added. “In a just culture system, there is an overarching understanding that humans make mistakes—in which case

the response should be to counsel them—and that humans also make wrong behavioral choices, which we can address by coaching them on safer ways of doing things,” Mr. Grissinger said. If there is a lesson to be learned from these cases, it may be the need for “a preoccupation with failure,” he said. “Leaders should always assume there is risk within their medication-use processes,” he said, “and they should proactively look for these weaknesses.” —David Wild The sources reported no relevant financial relationships.

The Second Victim

atasha Nicol, PharmD, is familiar with the professional and emotional fallout that can happen after a serious medication error. In 2001, Dr. Nicol, who was the director of pharmacy at McLeod Regional Medical Center, in Florence, S.C., dispensed an order for an excessive amount of potassium chloride that was administered to a 2-year-old girl—a mistake that ultimately took the child’s life. “When I got the order, we were two pharmacists filling orders for 450 patients with a six-hour turnaround time,” said Dr. Nicol, now the director of accreditation and medication safety, Innovative Solutions, Cardinal Health. “It was a complete and utter disaster waiting to happen.” Dr. Nicol entered the order, but felt too rushed to examine whether the dose was appropriate. The high level of potassium chloride led to cardiac arrest, and,

Being part of a medical error with severe consequences ‘changes you from the roots in every way.’ —Natasha Nicol, PharmD after undergoing two hours of resuscitation attempts, the child died. “I haven’t entered another order for a baby, and I never will again,” Dr. Nicol said. “I’m even terrified to dose my own kids’ Tylenol [Johnson & Johnson/McNeil], and they’re now 120 pounds!” According to Dr. Nicol, while patients and their families should be the priority of an institution’s response to a medical error, oftentimes the practitioners involved in an error—the “second victims”—are ignored. Being part of a medical error with severe consequences “changes you from the roots in every way,” she said. “Even in cases that don’t lead to harm, people often have fears of what could have happened.” Robert D. Warhurst, PharmD, a system pharmacy program manager at Indiana University Health (IUH), in Indianapolis, was on call at the university’s Methodist Hospital in September 2006, when three premature infants in the neonatal ICU (NICU) died after receiving a 1,000-fold

higher heparin dose than what they were supposed to have received as a line flush (bit.ly/2X24jhF). According to Dr. Warhurst, the errors occurred because an automated dispensing cabinet (ADC) was stocked with 1-mL vials of 10,000 units/mL instead of 1-mL vials of 10 units/mL, due to their “nondistinct ‘look-alike’ labels. “Although I was not involved in causing the error, I helped ensure that no other ADCs were incorrectly stocked and provided the NICU team with treatment options to reverse the overdoses,” Dr. Warhurst said. IUH leadership offered front-line staff crisis counseling and were forthcoming with “as much information as they could publicly disclose the very next day, so that not only our staff but other organizations could understand why this happened and how it could be prevented,” Dr. Warhurst said. The hospital’s nonpunitive response ultimately improved the organization’s culture of safety, he noted. Additionally, IUH implemented barcoding technology, double independent verifications, and use of different dosage forms for different indications. Dr. Warhurst said he went through “the first phases of grieving” during the first few days and months after the incident. Although he still lives with the pain of that day, he said he has “fairly recently” began accepting the event through journaling. “By writing, I finally dealt with feelings of anger, guilt, betrayal and failure.” Although failure “is not easy to accept, especially when it’s lethal,” he urged institutions to analyze and take action on “‘little failures’ to avoid catastrophic events.” —D.W.

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Role of Specialty Pharmacists in

Treating Patients With HIV JAMES ZHANG, PHARMD, CSP Clinical Program Manager Clinical Services AllianceRx Walgreens Prime Frisco, Texas

n February 5, 2019, in the State of the Union Address, President Donald Trump announced a goal to end the HIV

epidemic in the United States within 10 years.1

The Ending the HIV Epidemic: A Plan for America initiative was created with the goal of reducing new HIV infections in the United States by 75% in 5 years and 90% by 2030. Collaboration among federal, state, and local health departments, and health care providers is needed to reach this target. Specialty pharmacists also have a role to play to help ensure that goal is reached, starting with understanding HIV guidelines and how specialty pharmacists can facilitate and optimize the care of HIV patients.

Table 1. TDF Combinations and Corresponding TAF Productsa

TDF Regimen

TAF Regimen

Emtricitabine-TDF (Truvada)

Emtricitabine-TAF (Descovy)

Cobicistat-elvitegravir-emtricitabine-TDF (Stribild)

Cobicistat-elvitegravir-emtricitabine-TAF (Genvoya)

Emtricitabine-rilpivirine hydrochloride-TDF (Complera)

Emtricitabine-rilpivirine hydrochloride-TAF (Odefsey)

All products are marketed by Gilead.

TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate

Treatment Guideline Recommendations First-Line Antiretroviral Treatment (ART) for Treatment-Naive Adults and Adolescents2 • Bictegravir-emtricitabine-tenofovir alafenamide (BIC/FTC/TAF; Biktarvy, Gilead) • Abacavir (ABC), dolutegravir (DTG), lamivudine (3TC) (only if patient is HLA-B*5701-negative and does not have chronic hepatitis B virus [HBV] coinfection) – Available in 3-drug combination (Triumeq, ViiV Healthcare) or separately • DTG plus 3TC (except for those with more than 500,000 copies/mL of HIV RNA, no HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available) – Available in combination (Dovato, ViiV) or separately • DTG plus (FTC or 3TC) plus TAF or tenofovir disoproxil fumarate (TDF) • Raltegravir (RAL) plus FTC or 3TC, plus TAF or TDF • Generally, HIV guidelines recommend 1 integrase strand inhibitor (INSTI) and 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination as first-line therapy. – Other regimens, such as 1 boosted protease inhibitor (PI) plus 2 NRTIs or 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) plus 2 NRTIs, could be preferred

in certain situations, such as in females of childbearing potential, and may be patient specific. One boosted PI regimen, a darunavir (DRV)-based regimen, may be used if resistance testing is not available or delayed and treatment must be started immediately, because it is associated with a low likelihood of resistance. – See AIDSinfo Clinical Guidelines for more details.2 Treatment-Experienced Patients2 • Drug resistance testing is recommended for a patient on a failing regimen or within 4 weeks of discontinuation. • Use of 2 to 3 active agents with uncompromised activity based on ART history or drug resistance test results, possibly with new mechanism of action, is recommended. • Adding a single agent to a current regimen generally is not recommended. • For highly ART-experienced patients, continue treatment with a regimen that will minimize adverse effects (AEs) while maintaining CD4 counts to delay disease progression. Patients With Coinfections2 • Hepatitis C virus (HCV) infection2,3 – Screen all HIV patients for HCV. – ART may help preserve liver function and

should be started immediately, regardless of CD4 count. – Prescribers should collaborate to prevent drug interactions between HCV and HIV regimens. * If HCV treatment is not being implemented, start HIV ART as recommended for patients without HCV. – See HCV guidelines for more details.3 • HBV infection2 – Screen all HIV patients for HBV. – FTC, TAF, TDF, and 3TC have dual activity against HBV and HIV and are recommended. – Certain HBV regimens may not be recommended due to potential HIV resistance. – Discontinuation of dual-activity HIV/HBV drugs increases risks for liver damage and HBV reactivation and should be avoided if possible. If these agents are discontinued, patients should have frequent liver function tests and take entecavir to prevent flare-ups. • Tuberculosis (TB)2 – Due to the risk for drug interactions, ART regimens should be carefully evaluated. – All patients with active TB and HIV (especially those who have CD4 counts <50 cells/mm3 and/or who are pregnant)

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should start ART as soon as possible. – See HIV guidelines for more recommendations.

Pre-Exposure Prophylaxis The FDA has approved 2 drugs for pre-exposure prophylaxis (PrEP): FTC/TDF (Truvada, Gilead) and FTC/TAF (Descovy, Gilead). FTC/ TDF is indicated to prevent HIV in people at risk through sexual activity or injection drug use. FTC/TAF is recommended for people at risk through sex but not those at risk through receptive vaginal sex. There have been insufficient studies supporting HIV prevention in those engaging in receptive vaginal sex. When taken daily, PrEP has been shown to decrease the risk for contracting HIV via sex by approximately 99% and via injecting drugs by approximately 74%.4 Gilead announced in May 2019 that a generic version of FTC/TDF would be available in September 2020, 1 year earlier than expected.5 Gilead had previously reached an agreement with Teva to allow early launch of a generic. The release of a generic generally allows for lower pricing of the drug, but there are concerns related to affordability associated with having only 1 generic manufacturer. Teva will have approximately 1 year of exclusivity until the patent on FTC/TDF expires in September 2021. As with many other diseases and conditions, prevention and education are the preferred methods of controlling spread. As specialty pharmacists, we can educate patients about who is at risk for contracting HIV and about recommendations for starting PrEP, as necessary.

Table 2. Selected Recently Approved HIV Drugs Generic Name(s) (Brand name, Manufacturer)

Drug Class(es)

Fostemsavir (Rukobia, Viiv)

gp120 attachment inhibitor

FDA Approval Date

Significance

7/2/20

• First drug in class • Indicated for use in combination with other ART in HTE adults with multi-drug resistant HIV-1 • Granted FDA Fast Track, Priority Review, and Orphan Drug Designations

Doravirine-lamivudine-TDF (Delstrigo, Merck)

NNRTI/ NRTI

8/30/2018

• New NNRTI-based combination

Darunavir-cobicistatemtricitabine-TAF (Symtuza, Janssen)

PI/NRTI

7/17/2018

• First and only darunavir-based, single-tablet regimen

Dolutegravir-lamivudine (Dovato, ViiV)

INSTI/NRTI

4/8/2019

• First single-tablet, 2-drug regimen approved for treatment-naive adults

Bictegravir-emtricitabine-TAF (Biktarvy, Gilead)

INSTI/NRTI

2/7/2018

• First and only complete 3-drug, INSTI-based, single-tablet regimen

Ibalizumab-uiyk (Trogarzo, Theratechnologies)

Postattachment inhibitor

3/6/2018

• First drug approved in new drug class

• Favorable lipid profile and less neuropsychiatric adverse effects (sleep disorders/disturbances, dizziness, and altered sensorium) compared with efavirenzemtricitabine-TDF (Atripla, Gilead)

• IV administration and treats patients with multidrug resistance • Granted FDA Fast Track, Priority Review, and Orphan Drug Designations

ART, antiretroviral therapy; HTE, heavily treatment experienced; INSTI, integrase strand inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil Based on reference 2.

PrEP for Men Who Have Sex With Men (MSM)4 • For adult HIV-negative men, who have had any male sex partners in the past 6 months, are not in a monogamous partnership with a recently tested, HIV-negative man, and for whom at least 1 of the following is true: – They have had any anal sex without condoms (receptive or insertive) in the past 6 months. – They have had a bacterial sexually transmitted infection (STI) (syphilis, gonorrhea, chlamydia) diagnosed or reported in the past 6 months. PrEP for Heterosexually Active Adults4 • For HIV-negative adults, who have had any sex with opposite sex partners in the past 6 months, are not in a monogamous partnership with a recently tested HIV-negative partner, and for whom at least 1 of the following is true: – They are behaviorally bisexual (see MSM guidelines). – They infrequently use condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk for HIV infection. – They are in an ongoing sexual relationship with an HIV-positive partner. – They have had a bacterial STI (syphilis, gonorrhea, chlamydia) diagnosed or reported in past 6 months. PrEP for People Who Inject Drugs4 • For adults without acute or established HIV

infection who have injected any drugs not prescribed by a clinician in the past 6 months for whom at least 1 of the following is true: – They have shared injection or drug preparation equipment in the past 6 months. – They are at risk for sexual acquisition. (See above guidelines and MSM guidelines.)

Trends in Prescribing TAF in Place of TDF TDF has a risk for nephrotoxicity.11 Dose adjustments are recommended in patients with a creatinine clearance (CrCl) of less than 50 mL/min, which can be challenging for a fixed combination tablet. TAF does not require dose adjustments at a CrCl less than 50 mL/min, although neither product is recommended for a CrCl less than 30 mL/min. In a pooled analysis of 26 clinical trials, TAF caused fewer renal events and had an overall more favorable renal profile than TDF.12 A total of 5 combination products containing TAF have come on the market since TAF was initially released in 2015. Three of these products use TAF in place of TDF in combination products (Table 1), whereas the other 2—cobicistat-DRV/FTC/TAF (Symtuza, Janssen) and BIC/FTC/TAF—are novel TAF combinations. 2 Given TAF’s proven better renal and bone safety profile, more prescribers are switching to TAF-containing regimens over TDF-containing regimens.11-13

Single-Tablet Regimens Another trend is higher prescribing of singletablet regimens. As more people are diagnosed with HIV, having more options to improve adherence is always better for the patient. Most new HIV drugs released to the market are new combinations of already FDA-approved medications or combinations of new drugs. A retrospective study in 2018 showed that single-tablet regimens led to higher rates of retention in care and favorable virologic outcomes.14 Another meta-analysis from 2015 showed that the odds for adherence among patients on a single-tablet regimen was 2.37 times higher than among those on a multiple-tablet regimen.15

On the Horizon Looking ahead at the pipeline, cabotegravirrilpivirine (ViiV) is a long-acting injectable that shows promise. This once-monthly intramuscular injectable combination drug has completed phase 3 trials and is awaiting FDA approval. If approved, it would be the first and only oncemonthly, long-acting regimen for treatment of HIV-1. It received approval for use in Canada on March 20, 2020, as Cabenuva.16

Role of the Specialty Pharmacist Reviewing Regimens It is important for specialty pharmacists to help ensure patients receive complete and see HIV, page 42

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HIV continued from page 41

recommended regimens. With new drugs often coming to the market, it is important to stay up-to-date with new drugs and guideline recommendations. Guidelines generally are updated annually and include revisions based on new drug releases or studies. Table 2 lists selected HIV drugs approved since 2018 that have significantly improved HIV treatment. Facilitating Adherence Adherence is the most important factor in achieving viral suppression.17 The job of a specialty pharmacist is to help ensure new fills or refills are processed in a timely manner and any processing issues are resolved to avoid missed doses. Adherence levels of at least 95% generally are accepted benchmark standards for achieving successful virologic outcomes, although some studies show a more lenient range.18 Understanding the importance of patient adherence will allow specialty pharmacists to educate patients about not missing doses. A study on pharmacist adherence interventions showed that a pharmacist-led adherence clinic helped HIV-infected patients achieve viral suppression, significant prevention of HIV transmission to secondary partners, and cost savings of nearly $3 for each dollar spent on adherence intervention.19 The interventions include monitoring refills and reaching out to patients and doctors’ offices to provide additional education as needed. Not all specialty pharmacies have adherence programs, but the study showed there is value in pharmacist intervention to improve adherence of HIV patients.19 If patients are taking multiple drugs for HIV, it is also important that they receive their complete regimen and not a partial regimen because that may lead to drug resistance.2 A partial regimen can occur if 1 of the drugs is out of stock or is rejected by a payor. Pharmacists can work with the prescriber to determine an appropriate course of action and follow up with the patient so they can receive a complete therapeutic regimen. Managing Drug Costs With high drug costs for HIV treatment, the specialty pharmacy should explore all options to find affordable care for patients. This search includes reaching out to various drug foundations or copay assistance programs and assisting patients through enrollment processes. If a prior authorization is required, diligent efforts to initiate the process and educate the patient on next steps will allow for a smoother process. Many specialty pharmacies offer resources for patients to use to explore various patient assistance programs.

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or mail-order pharmacy. Specialty pharmacists can refer to HIV guidelines for complete listing of drug– drug interactions or use drug databases, such as Clinical Pharmacology or LexiComp, to verify.2 Managing Adverse Effects It is important to counsel patients at the time of their initial dispense and as necessary afterward. Helping patients set expectations about potential AEs, and providing counseling and guidance when they occur, will greatly improve adherence and virologic outcomes.19 Managing Therapy Interruptions If a patient misses doses or has an upcoming medical procedure, it is important to be aware of guidelines on managing therapy interruptions. Notifying the prescriber should be the first course of action, but it also is important to educate the patient. Planned short-term interruptions can last up to 2 weeks.2 Drugs that have similar half-lives should be stopped at the same time. All drugs that are part of a regimen should be stopped if the interruption will only be for 1 or 2 days, regardless of half-life.2 NNRTIs may have longer half-lives; thus, it is recommended that they be stopped earlier, but there are no clear guidelines stating so. Specialty pharmacists can play a large role in achieving the goal of ending the HIV epidemic by 2030. Whether it is reaching out to a patient who consistently refills late, taking extra time to review HIV guidelines, or helping a patient find copay assistance to start their regimen, all these activities help create better outcomes for those patients. Specialty pharmacists helping patients one by one is how we can help achieve this goal.

References 1.

Department of Health and Human Services. What is ‘Ending the HIV epidemic: a plan for America’? HIV. gov. Updated February 26, 2020. www.hiv.gov/federalresponse/ending-the-hiv-epidemic/overview. Accessed June 29, 2020.

2. Department of Health and Human Services, Clinical Guidelines. AIDSinfo. Updated April 7, 2020. aidsinfo.nih. gov/guidelines. Accessed June 29, 2020. 3. American Association for the Study of Liver Diseases/ Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing and treating hepatitis C. Patients with HIV/HCV coinfection. Updated November 6, 2019. www.hcvguidelines.org/uniquepopulations/hiv-hcv. Accessed June 29, 2020. 4. CDC. HIV basics. www.cdc.gov/hiv/basics/index.html. Accessed June 29, 2020. 5. Fitzsimons T. Generic HIV prevention drug coming in 2020, Gilead says. NBC News. May 8, 2019. www.nbcnews.com/ feature/nbc-out/generic-hiv-prevention-drug-coming2020-gilead-says-n1003391. Accessed June 29, 2020.

Monitoring Drug Interactions

6. Merck. FDA approves Merck’s DELSTRIGO (doravirine/ lamivudine/tenofovir disoproxil fumarate), a once-daily fixed-dose combination tablet as a complete regimen and PIFELTRO (doravirine), an NNRTI, both for the treatment of HIV-1 in appropriate patients. August 30, 2018. bit.ly/3eMflhZ. Accessed July 20, 2020.

It is important to maintain current medical profiles of allergies, medications, and conditions. Many HIV drugs have interactions with other medications that a patient may be getting from a retail

7. Janssen Global. Janssen announces U.S. FDA approval of SYMTUZA (D/C/F/TAF), the first and only complete darunavir-based single-tablet regimen for the treatment of HIV-1 infection. July 17, 2018. bit.ly/2OEthAb. Accessed July 20, 2020.

8. ViiV Healthcare. US FDA approves ViiV Healthcare’s Dovato (dolutegravir/lamivudine), the first, once-daily, singletablet, two-drug regimen for treatment-naïve HIV-1 adults. April 8, 2019. bit.ly/2ZIK0IT. Accessed July 20, 2020. 9. Gilead. U.S. Food and Drug Administration approves Gilead’s Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) for treatment of HIV-1 infection. February 7, 2018. bit.ly/3eQcp3P. Accessed July 20, 2020. 10. FDA. FDA approves new HIV treatment for patients who have limited treatment options. March 6, 2018. www.fda. gov/news-events/press-announcements/fda-approvesnew-hiv-treatment-patients-who-have-limited-treatmentoptions. Accessed July 21, 2020. 11. Venter WDF, Fabian J, Feldman C. An overview of tenofovir and renal disease for the HIV-treating clinician. South African J HIV Med. 2018;19(1):817. doi. 10.4102/sajhivmed. v19i1.817. Accessed June 29, 2020. 12. Gupta SK, Post FA, Arribas JR, et al. Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate, a pooled analysis of 26 clinical trials. AIDS. 2019;33(9):14551465. doi. 10.1097/QAD.0000000000002223. Accessed June 29, 2020. 13. Surial B, Cavassini M, Calmy A, et al. Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort. BMC Infect Dis. 2019;19:834. doi. 10.1186%2Fs12879-019-4454-9. Accessed June 29, 2020. 14. Hemmige V, Flash CA, Carter J, et al. Single tablet HIV regimens facilitate virologic suppression and retention in care among treatment naïve patients. AIDS Care. 2018;30(8):1017-1024. doi. 10.1080/09540121.2018.1442554. Accessed June 29, 2020. 15. Clay PG, Nag S, Graham CM, et al. Meta-analysis of studies comparing single and multi-tablet fixed dose combination HIV treatment regimens. Medicine. 2015;94(42):e1677. doi. 10.1097/MD.0000000000001677. Accessed June 29, 2020. 16. Johnson & Johnson. Janssen announces Health Canada approval of CABENUVA, the first long-acting regimen for the treatment of HIV. March 20, 2020. www.jnj.com/ janssen-announces-health-canada-approval-of-cabenuvathe-first-long-acting-regimen-for-the-treatment-of-hiv. Accessed June 29, 2020. 17. Machtinger EL, Bangsberg DR. Adherence to HIV antiretroviral therapy. HIV InSite. Published May 2005. Updated January 2006. http://hivinsite.ucsf.edu/ InSite?page=kb-03-02-09. Accessed June 29, 2020. 18. Bezabhe WM, Chalmers L, Bereznicki LR, et al. Adherence to antiretroviral therapy and virologic failure: a meta-analysis. Medicine. 2016;95(15):e3361. doi. 10.1097%2FMD.0000000000003361. Accessed June 29, 2020. 19. Dilworth TJ, Klein PW, Mercier RC, et al. Clinical and economic effects of a pharmacist-administered antiretroviral therapy adherence clinic for patients living with HIV. J Manag Care Spec Pharm. 2018;24(2):165-172. doi. 10.18553/jmcp.2018.24.2.165. Accessed June 29, 2020.

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Pandemic Offers Lessons for Payors, Health Plans

he COVID-19 pandemic has had a major economic impact on the health care system but also offers a number of lessons that health systems and payors can take forward in preparing for future epidemics or a resurgence of COVID-19, experts said during a webinar sponsored by Impact Education. “There is a lot of opportunity to be optimistic about how our health system will improve as a result of COVID,” said

Peter Watson, MD, the vice president of care management, quality and outcomes for the Health Alliance Plan, a nonprofit plan based in Michigan. Many areas within health care systems struggled with the unexpected during the pandemic surge this spring; all can be looked at as opportunities for improvement going forward, he said. Hospitals had a lot of extended waits for COVID-19 test results in the beginning

of the pandemic. As a result, they had to act in a manner that presumed patients were positive and use personal protective equipment, and it was difficult to cohort infected and noninfected patients because it was unclear who was who, said Dr. Watson, who also is an attending staff hospitalist at Henry Ford Medical Group, in Michigan. There also were issues with shortages of specialized providers needed to

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Director, Clinical Microbiologist AdventHealth Orlando, FL

Thomas Lodise, PharmD, PhD Supported by an independent educational grant from Shionogi, Inc. This activity is distributed via Infectious Disease Special Edition, Pharmacy Practice News, and CMEZone.

Professor Albany College of Pharmacy and Health Sciences Albany, NY 1.0 AMA PRA Category 1 Credit™ 1 ACPE Contact hour Universal Activity Number: JA4008162-9999-19-891-H01-P Type of activity: knowledge

manage patients. At Henry Ford, the graduate medical education director repurposed all training staff to care for COVID-19, which demonstrated that health systems can be nimble. “As payors, we have to be very supportive of our health systems that are trying to react very quickly in these situations,” he said. Hospitals also faced shortages of certain equipment, such as ventilators and infrared thermometers. “These are things all facilities are now rethinking, and as health plans we will have to partner with our facilities to make sure they have the resources they need to take care of our membership,” Dr. Watson said. In addition, health systems have been working to try to stay financially viable, he said, continuing to provide needed care and working to try to make sure staff were paid and deployed properly. Many had to make changes in their lines of credit or apply for government or other loans. Some hospital groups have since started working together to pool supplies and make sure they have enough inventory on hand for the next epidemic. The pandemic opened discussions about fair allocation of resources, Dr. Watson said. While much of that had to do with ventilators, it opens the door for conversations about how COVID-19 vaccines should be distributed if and when they are approved and appropriate. “Getting the vaccine is just one step,” he said. “Getting the vaccine to the people who need it will be an entirely different issue. As health plans, we will have to partner with health care organizations to make sure it’s done fairly and appropriately for our population.”

Multiple Points of Support The virus shed light on other areas health plans can be involved in, he said, including testing for their members and the broader community, and supporting member needs outside of clinical care, such as providing food benefits. It also highlighted opportunities for health plans to partner with clinical systems to address risky chronic conditions—such as obesity, hypertension and diabetes— that exacerbated COVID-19 clinical outcomes and deaths, Dr. Watson said. “These should be areas of intense focus as we prepare for future epidemics.” —Karen Blum Dr. Watson reported no relevant financial relationships.

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The Price of Delay continued from page 1

Dr. Kesselheim and his colleagues reviewed patent term restoration data from the U.S. Patent and Trademark Office to identify a cohort of drugs with key patents expiring in 2010 to 2015, adding six months to the exclusivity period in cases for which the manufacturer was asked to conduct pediatric clinical trials. They also studied Medicaid State Drug Utilization files to tally use of these products by National Drug Code identifiers to find when generic entry actually did happen. For each drug, they estimated the difference between the expected and actual quarter-year of generic drug entry, defined as the first appearance of a prescription for a generic equivalent in Medicaid claims. The researchers then searched sources including press reports and other industry patent databases to identify reasons for delay. The study identified darunavir (Prezista, Janssen) as the product associated with the highest share of excess Medicaid spending due to delays in generic entry. Although a generic was expected by the first quarter of 2015,

the brand-name drug, he also advocated for better systems of ensuring that “frivolous or otherwise inappropriately granted patents are not granted or are easier to overturn. “There are a lot of different strategies to try to fix this problem, because GENERIC PRESCRIPTIONS there [is] a multitude of FILLED IN 2018 strategies manufacturers use to delay generic entry,” Dr. Kesselheim said. He OF GENERIC PRESCRIPTIONS ARE recommended more fundFILLED AT $20 OR LESS ing at the FDA level “to provide guidance as to the AVERAGE GENERIC AVERAGE BRANDtypes of studies needed to COPAY: NAME COPAY: get generics on the market so we have a competitive market ready to go at the time when exclusivity is Source: Iqvia 2019. expiring.”

4 Billion

95%

$5.63

$40.65

spending, researchers found. For 12 products (80%), patent litigation was the most common reason; nine of the 12 cases in which litigation was a contributor were settled out of court. Manufacturers filed citizen petitions with the FDA for 10 products (67%) that also might have delayed approval of the generic. For example, generic manufacturers of bosentan (Tracleer, Actelion) cited

‘Delaying generic entry is one of the key strategies that pharmaceutical manufacturers use to maintain their high revenue streams.’ —Aaron S. Kesselheim, MD, JD, MPH

none was detected during the study period, yielding an estimated excess spending of $137 million. Generic versions of paliperidone (Invega Trinza, Janssen), atorvastatin and olopatadine (Pataday, Alcon) were delayed for three, 1.75 and 4.5 years, respectively, and were associated with estimated excess Medicaid spending of $126 million, $62 million and $100 million. Because Medicaid serves only 23% of the total U.S.-insured population, and commercial insurers and Medicare plans typically have much lower brand-name rebates, excess spending in other parts of the health care system is likely much higher, Dr. Kesselheim said. Often, more than one reason was associated with delays to market entry for the top 15 brand-name products by Medicaid

issues in obtaining brand-name is samples for bioequivalence testing. Disputes over patents for atorvastatin (Lipitor, Pfizer) and pioglitazone (Actos, Takeda) were settled out of court after delaying generic entry by approximately 1.75 and 1.5 years, respectively. The study authors pointed out some policy recommendations that could overcome these issues. One of the most important aspects is having clear expected generic entry dates for brand-name products, noted Dr. Kesselheim, who is also the director of the Program On Regulation, Therapeutics And Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacogenomics at Brigham and Women’s Hospital, in Boston. Such entry dates could be used to alert authorities—such as the Federal Trade Commission or FDA—to investigate when a generic alternative does not hit the market. Because reasons for delays often include litigation over patents on

Patent Is the Key There are sometimes legal delays in new generics being released, but generally once a patent’s time is up, a generic product is approved, said Howard Wild, BSPharm, RPh, the vice president of generic strategies at MedImpact, a pharmacy benefit manager. He noted that the data used in this study were several years old. Dr.

Kesselheim said his team wanted to allow enough time between the end of the study and present day to calculate spending. Another tactic that manufacturers use is to work with a specific generic drugmaker to release an authorized generic identical to the brand-name product earlier and at a higher cost than other generics scheduled for release, Mr. Wild said. This strategy allows the manufacturer to share in the revenue, and often limits the release of other generic versions due to the size of the market. Some additional hurdles faced by generic manufacturers include sourcing raw materials, conducting bioequivalence studies, production capability and quality control in the manufacturing plant, Mr. Wild said. Another factor he pointed to that could drive increased Medicaid spending is that while pharmacy benefit managers and others initiate maximum allowable cost (or MAC) pricing within days of the release of a new generic, government programs might not list a generic for months. —Karen Blum The sources reported no relevant financial relationships.

46 Technology

Pharmacy Practice News • August 2020

Supply Chain

Can Patients Be Part of the Drug Shortages Solution?

ecause patients lack the resources that hospitals have to search for clinical, cost-effective alternatives when prescribed drugs are out of stock or too costly, Scripta Insights has made its drug substitution search tool free for anyone to use during the COVID-19 pandemic. At first glance, it may seem strange to enlist patients in efforts to navigate drug shortages. But that’s exactly what the website (drugfinder.scriptasaurus.com) is set up to do—albeit with the initial help of pharmacists. In a typical scenario, a health-system pharmacist will educate an inpatient about the new search tool at discharge during medication review, explained Scripta CEO Eric Levin. With the knowledge gained from the website, patients “can have better-informed discussions with outside physicians and pharmacists” about therapeutic alternatives when drugs they need are in short supply, “or [when the drugs are] too expensive even after insurance coverage, rather than just feeling despair,” Mr. Levin told Pharmacy Practice News. The artificial intelligence tool—conceived in 2018 for Scripta’s main business to help self-insured employers save on their workers’ health care costs—maps more than 3,000 of the most used drugs by the disease states they treat. The price of the medications updates daily, and can be tied to a patient’s prescription history. A drug query could yield a list of zero to eight options, depending on a patient’s comorbidities and potential drug interactions. The doctor and pharmacist would then decide which choice is best, Mr. Levin noted. Including cost in such discussions is critical, given the strong link between affordability and adherence. A 2019 KFF Health Tracking Poll, for example, found that 29% of adults said cost caused them not to take their medicines as prescribed at some point in the past year (bit.ly/2M8n3Hq). Asked to comment on Scripta’s drug substitution search tool, Michael Ganio, PharmD, ASHP’s senior director of pharmacy practice and quality, said, “Whenever a patient can do his or her own research to be informed, it’s always helpful.” But enlisting a patient “isn’t necessary in an actual pharmacy setting because of the pharmacist’s training and expertise.”

The Most Vulnerable Drug Classes As for more straightforward, hospital-based drug shortage strategies, the first step is to focus on the medications that have been most vulnerable during COVID-19, Dr. Ganio noted. Those

include albuterol inhalers, which have been under supply pressure because of their increased use for COVID-19 patients with respiratory issues. The inhaled medication also has become a more frequent choice because there is a concern that nebulizers used on patients with COVID-19 in the hospital could spread the virus and place other patients and caregivers at risk. Such concerns “mean that if we suspect a

patient is positive, we prefer to use albuterol meter-dose inhalers despite their higher cost,” he explained. The hype over hydroxychloroquine as a potential COVID-19 “cure” has triggered another supply chain headache for pharmacy, leading to shortages of the drug for patients with lupus, rheumatoid arthritis and other more established indications. Azithromycin, often used in combination with

hydroxychloroquine for COVID-19, also has been in short supply. And then there are all of the medications used to manage patients on ventilators. A recent ASHP practice survey found that five medications used to sedate or immobilize intubated COVID-19 patients on mechanical ventilation were cited most often by U.S. hospital pharmacy leaders as being in critically short supply. The five IV drugs—cisatracurium,

Indication and Usage HYPERRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies. Limitations of Use Persons who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine. For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis. Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred. Important Safety Information For infiltration and intramuscular use only. Severe hypersensitivity reactions may occur with HYPERRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur. HYPERRAB is made from human blood and may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The most common adverse reactions in >5% of subjects during clinical trials were injection-site pain, headache, injection-site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain. Do not administer repeated doses of HYPERRAB once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine. Other antibodies in the HYPERRAB preparation may interfere with the response to live vaccines such as measles, mumps, polio, or rubella. Defer immunization with live vaccines for 4 months after HYPERRAB administration. Please see brief summary of Prescribing Information on adjacent page or visit HyperRAB.com for full Prescribing Information.

Technology

Pharmacy Practice News • August 2020

Supply Chain fentanyl, ketamine, vecuronium and midazolam—were part of a list of ICU medications that respondents were asked to rate by current inventory status and availability from suppliers, as previously reported in Pharmacy Practice News (bit.ly/2ZPwwvt). Dr. Ganio urged practitioners to visit the ASHP’s Current Drug Shortages websites for updates on drugs that are in short supply (bit.ly/3gAMcZh), as well as the FDA’s drug shortages website (bit.ly/3cd1hNq). But the work doesn’t end at simply

tracking drug shortages; finding alternatives for inpatients is another key task, Dr. Ganio noted. Fortunately, hospital pharmacy and therapeutics committees

“can e-vote quickly on substitution plans during emergencies after discussing complex issues, such as allergies and chronic conditions,” he said. “More

HyperRAB®

-----------DOSAGE FORMS AND STRENGTHS---------300 IU/mL solution for injection supplied in 1 mL, 3 mL and 5 mL single-dose vials.

HIGHLIGHTS OF PRESCRIBING INFORMATION

--------------------CONTRAINDICATIONS--------------------None.

Rabies Immune Globulin (Human) These highlights do not include all the information needed to use HYPERRAB® safely and effectively. See full prescribing information for HYPERRAB. HYPERRAB [rabies immune globulin (human)] solution for infiltration and intramuscular injection Initial U.S. Approval: 1974 ----------------INDICATIONS AND USAGE------------------HYPERRAB is a human rabies immune globulin indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies. Limitations of Use Persons previously immunized with rabies vaccine that have a confirmed adequate rabies antibody titer should receive only vaccine. For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis. Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred. --------------DOSAGE AND ADMINISTRATION------------For infiltration and intramuscular use only. Administer HYPERRAB within 7 days after the first dose of rabies vaccine. Postexposure HYPERRAB • Administer as soon as possible after 20 IU/kg prophylaxis, exposure, preferably body weight along with at the time of the first OR rabies vaccine, after 0.0665 mL/kg rabies vaccine dose. body weight • Infiltrate the full suspected exposure to dose of HYPERRAB Single dose rabies thoroughly in the area around and into the wound(s), if anatomically feasible. • Inject the remainder, if any, intramuscularly.

-------------WARNINGS AND PRECAUTIONS-------------• Severe hypersensitivity reactions, including anaphylaxis, may occur with HYPERRAB. Have epinephrine available immediately to treat any acute severe hypersensitivity reactions. • HYPERRAB is made from human blood; it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. --------------------ADVERSE REACTIONS--------------------The most common adverse reactions in >5% of subjects in clinical trials were injection site pain, headache, injection site nodule, abdominal pain, diarrhea, ﬂatulence, nasal congestion, and oropharyngeal pain. To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics LLC at 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------DRUG INTERACTIONS------------------• Repeated dosing after administration of rabies vaccine may suppress the immune response to the vaccine. • Defer live vaccine (measles, mumps, rubella) administration for 4 months.

Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871

3054805 Revised: 11/2019

challenging is the operationalizing that happens after choosing a substitute, particularly with injectable drugs.” That process, he noted, requires “updating the electronic health records and IV pumps,” as well as “procedural changes for technicians making the preparations. It’s also sometimes a cost challenge to substitute when a desired substitute is not a preferred drug.” —Al Heller The sources reported no relevant financial relationships.

Introducing greater dosing convenience with a new 3-mL (900-IU) vial

When protecting your patients with HRIG

DELIVER MORE OF THE TOTAL DOSE AT THE WOUND SITE. HyperRAB® (rabies immune globulin [human]) 300 IU/mL The ﬁrst and only high-potency human rabies immune globulin (HRIG) that offers:

the volume of medication administered in a total dose, potentially resulting in fewer injections the concentration of rabies antibodies per mL at the wound site

HIGH-POTENCY FORMULA

REDEFINING HRIG ADMINISTRATION REDEFINING HRIG ADMINISTRATION

LOWEST VOLUME PER DOSE

MORE RABIES ANTIBODIES PER mL

Please see Important Safety Information and brief summary of Prescribing Information for HyperRAB on adjacent pages, or visit www.HyperRAB.com for full Prescribing Information. n. HyperRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies. HyperRAB is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products.

#1 Prescribed HRIG in the US

March 2020

US-HB3-2000016