Pharmacy Practice News (May 2020) by McMahon Group

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pharmacypracticenews.com

Medication safety pearls from ASHP MCM: optimizing IV workflow, avoiding ped errors, and more ......................... 30

Demand for Drugs ‘Unpre

Who says DOACs don’t require routine patient monitoring? .................... 35

POLICY

How to get the 20% add-on DRG payment for COVID-19 ..................

OPERATIONS & MGMT

he danger that there won’t be enough h medications to facilitate mechaniical ventilation in COVID-19 patients remains a concern as the infectionss continue to surge in hotspots around d the nation, according to a Vizientt analysis of 13 critical sedatives, opioidss and paralytic drugs. Even if the much-awaited “flattening of the curve” happens with COVID-19 cases, experts noted, the potential for a pandemic resurgence this Fall should keep ventilator drug supply chain planning a priority in the coming months. Erin Fox, PharmD, BCPS, the senior director of Drug Information and Support Services at the University of Utah Health, in Salt Lake City, said, “Hospitals are facing two to 10 times their normal ventilated population. This means that you need two to 10 times the amount of medications.

Parenteral nutrition:

Steering Clear Of Trouble From Hospital to Home

TECHNOLOGY

Telepharmacy and COVID-19: Taking the first steps to ramp up offerings ............................

CORPORATE SPOTLIGHT

American Regent See page 26.

Shortages of sedatives, opioiids and NMBAs likely to worsen

CLINICAL

A repository program repurposes costly cancer meds ...................

Volume 47 • Number 5 • May 2020

ransitioning a patient from the hospital to the home setting on parenteral nutrition (PN) can introduce a number of potential hazards. But several steps, from ensuring a safe home PN setup to identifying the appropriate PN formulation, can go a long way in protecting patients during this crucial handoff, according to a presentation at the ASPEN20 Virtual Conference. “It’s a team effort to get these patients on parenteral nutrition Continued on page 48

That is not so easy in these days of allocations and limits placed on the amounts of controlled substances you can order.” Vizient normally tracks about 200 acute and chronic “workhorse medications” used in hospitals, said Dan Kistner,

PharmD, the group senior vice president of pharmacy solutions at Vizient Inc. “About 69 drugs have our special attention because of the unusually high demand we’re seeing across the country,” he said. Continued on page 8

Preventing Medication Errors At Small and Rural Hospitals A

lmost right away, the nurse realized she had made a serious mistake. While administering medications during a shift in 2015, she gave one hospitalized patient a basal/prandial dose of insulin and then placed the pen on the top of the medication cart instead of in the patient’s medication drawer. She got distracted handling another task, then moved on to the next patient. Following the correct procedures before administering, she scanned the second patient’s wristband and the barcode on the insulin pen, and the correct dose appeared on the patient’s medication administration record (MAR). But then after administering the dose, when she opened

Special Focus:

COVID-19 Pandemic More coverage starting on page 6.

the second patient’s medication drawer, she saw their insulin pen and realized she’d used the first patient’s pen by mistake. The nurse immediately reported what had happened, and no harm came to either patient. But because insulin is a high-alert medication, the outcomes could have been much worse. Medication errors can happen at any hospital. But this one occurred at Deborah Heart and Lung Center, an 89-bed rural facility in Browns Mills, N.J. The hospital had safety checks in place in the patient’s MAR and the electronic health record (EHR), but one additional piece was missing: a patient-specific Continued on page 44

You Yo have the opportunity to

EXTINGUISH VOD E WITH RENAL OR PULMONARY DYSFUNCTION POST HSCT W Reach for Deﬁtelio, the ﬁrst and only approved treatment Re VOD=veno-occlusive disease VO

Learn more at defitelio.com Le Indication Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION Contraindications Defitelio is contraindicated in the following conditions: Concomitant administration with systemic anticoagulant or fibrinolytic therapy Known hypersensitivity to Defitelio or to any of its excipients

DEF-0232

Rev0919

Deﬁtelio was proven to improve survival at Day +100 in adult and p pediatric patients consistentlyy across 3 studies1,2 p

95% CI: 33%, 55%

60 50

95% CI: 29%, 48%

40 30 20

Survival at Day +100 post HSCT with Deﬁtelio (%) (Kaplan-Meier estimated)

Survival at Day +100 post HSCT with Deﬁtelio (%)

SURVIVAL AT DAY +100 POST HSCT WITH DEFITELIO ACROSS STUDIES IN ADULT AND PEDIATRIC PATIENTS 1,2

95% CI: 45%, 54%

50 40

Th he efficacy of Deﬁtelio was in nvestigated in 3 studies: 2 prospective clinical trials (Study 1 an nd Study 2) and an expanded acccess study (Study 3), which in ncluded 689 adult and pediatric paatients with hepatic VOD with re enal or pulmonary dysfunction fo ollowing HSCT. Patients received Deﬁtelio at a dose of 6.25 mg/kg D evvery 6 hours.1,2

20 10

0 STUDY 1

STUDY 2

STUDY 3

(n =102)

(n =75)

(n =512)

EXPECTED DAY +100 SURVIVAL WITH SUPPORTIVE CARE

21% TO 31%

Based on published reports and analyses of patientlevel data for individuals with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than Deﬁtelio.1

Warnings and Precautions Hemorrhage Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio. Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.

Hypersensitivity Reactions Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.

Most Common Adverse Reactions The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis. Please see following pages for Brief Summary of Prescribing Information. References: 1.. Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2.. Kernan NA, Grupp S, Smith AR, et al. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/ sinusoidal obstruction syndrome. Br J Haematol. 2018;181(6):816-827.

Defitelio® (defibrotide sodium) BRIEF SUMMARY OF PRESCRIBING INFORMATION: Consult the Full Prescribing Information for complete product information. Initial U.S. Approval: 2016 INDICATIONS AND USAGE Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). CONTRAINDICATIONS The use of Defitelio is contraindicated in the following conditions: • Concomitant administration with systemic anticoagulant or fibrinolytic therapy [see Warnings and Precautions] s • Known hypersensitivity to Defitelio or to any of its excipients [see Warnings and Precautions] s

Information about adverse reactions of any grade was available for all 176 patients. The most common adverse reactions (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse reactions (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported for 104 (59%) of the patients, and the events were grade 4-5 in 35 (20%). The table below presents adverse reactions independent of causality ≥10% any grade or Grade 4/5 ≥2% reported in patients treated with Defitelio. Adverse Reactionsa ≥10% or Grade 4-5 Adverse Reactions ≥2%

WARNINGS AND PRECAUTIONS Hemorrhage Defitelio increased the activity of fibrinolytic enzymes in vitro, and it may increase the risk of bleeding in patients with VOD after hematopoietic stemcell transplantation (HSCT). Do not initiate Defitelio in patients with active bleeding. Monitor patients for signs of bleeding. If patients on Defitelio develop bleeding, discontinue Defitelio, treat the underlying cause, and provide supportive care until the bleeding has stopped.

Defitelio (n=176) Adverse Reactiona

Concomitant use of Defitelio and a systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytic agents prior to Defitelio treatment, and consider delaying the start of Defitelio administration until the effects of the anticoagulant have abated [see Contraindications] s. Hypersensitivity Reactions Hypersensitivity reactions have occurred in less than 2% of patients treated with Defitelio. These reactions include rash, urticaria and angioedema. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] s • Hypersensitivity Reactions [see Warnings and Precautions] s

Any grade

Grade 4-5b

Hypotension

65 (37%)

12 (7%)

Diarrhea

43 (24%)

Vomiting

31 (18%)

Nausea

28 (16%)

Epistaxis

24 (14%)

Pulmonary alveolar hemorrhage

15 (9%)

12 (7%)

Gastrointestinal hemorrhage

15 (9%)

5 (3%)

Sepsis

12 (7%)

9 (5%)

Graft versus host disease

11 (6%)

7 (4%)

Lung infiltration

10 (6%)

5 (3%)

Pneumonia

9 (5%)

5 (3%)

Pulmonary hemorrhage

7 (4%)

4 (2%)

Infection

6 (3%)

4 (2%)

Hemorrhage intracranial

5 (3%)

4 (2%)

Hyperuricemia

4 (2%)

3 (2%)

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Defitelio was determined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who were treated with Defitelio 6.25 mg/kg every 6 hours. Patients were excluded from these trials if at time of study entry they had significant acute bleeding, active grades B-D graft-versus-host disease, or a requirement for multiple vasopressors to provide blood pressure support. For the purposes of adverse event recording in the clinical trials, events were not required to be reported if they were related to the hepatic VOD, or if they were expected to occur after hematopoietic stem-cell transplantation (HSCT), unless they were serious or Grade 4-5. The median age of the safety population was 25 years (range, 1 month to 72 years), and 63% were ≥17 years of age. A total of 60% of patients were male, 78% were white, 89% had undergone allogeneic HSCT, and the underlying diagnosis was acute leukemia for 43%. At study entry, 13% were dialysis dependent and 18% were ventilator dependent. Defitelio was administered for a median of 21 days (range: 1 to 83 days). Information about adverse reactions resulting in permanent discontinuation of Defitelio was available for 102 patients, and 35 (34%) of these patients had an adverse reaction with permanent discontinuation. Adverse reactions leading to permanent discontinuation included pulmonary alveolar hemorrhage in 5 (5%) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3%) patients; and cerebral hemorrhage and sepsis, each in 2 (2%) patients.

Cerebral hemorrhage a

Excludes events considered to be due to the underlying disease: multi-organ failure, veno-occlusive disease, respiratory failure, renal failure, and hypoxia Adverse reactions considered life-threatening or fatal c Cerebral hemorrhage has been included in the table due to clinical relevance b

DRUG INTERACTIONS Antithrombotic Agents Defitelio may enhance the pharmacodynamic activity of antithrombotic/ fibrinolytic drugs such as heparin or alteplase. Concomitant use of Defitelio with antithrombotic or fibrinolytic drugs is contraindicated because of an increased risk of hemorrhage [see Contraindications] s. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary y There are no available data on Defitelio use in pregnant women. When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, defibrotide sodium decreased the number of implantations and viable fetuses. Advise pregnant women of the potential risk of miscarriage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data Embryo-fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses. Pregnant rats were administered defibrotide sodium

Up Front

from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 mg/kg/ day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. Pregnant rabbits were administered defibrotide sodium at 0, 30, 60, or 120 mg/ kg/day from GD 6 to 18 by 2-hour infusions 4 times per day. In another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. The dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m2 basis. Subgroup 1 was dosed from GD 6 to 10, subgroup 2 was dosed from GD 10 to 14, and subgroup 3 was dosed from GD 14 to 18. An increased incidence of unilateral implantation was observed in defibrotide sodium-treated animals. Treatment with defibrotide sodium resulted in a decreased number of implantations and viable fetuses.

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Lactation Risk Summary y There is no information regarding the presence of Defitelio in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Defitelio. Pediatric Use The safety and effectiveness of Defitelio have been established in pediatric patients. Use of Defitelio is supported by evidence from an adequate and well-controlled study and a dose finding study of Defitelio in adult and pediatric patients with VOD with evidence of renal or pulmonary dysfunction following HSCT. The clinical trials enrolled 66 pediatric patients in the following age groups: 22 infants (1 month up to less than 2 years), 30 children (2 years up to less than 12 years), and 14 adolescents (12 years to less than 17 years). The efficacy and safety outcomes were consistent across pediatric and adult patients in the clinical trials [see Adverse Reactions] s. Juvenile Animal Toxicity Data A juvenile toxicity study in 21-day-old rats was conducted with intravenous bolus administration of defibrotide sodium at 40, 150, or 320 mg/kg/day for 4 weeks. A delayed mean age of preputial separation was observed at all doses, suggesting a delay in onset of male puberty. The dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m2 basis for a child. The relevance of this finding for the onset of male puberty in humans is unknown. Geriatric Use Clinical studies of Defitelio did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. OVERDOSAGE There are no known cases of overdose with Defitelio. There is no known antidote for Defitelio, and Defitelio is not dialyzable. If an overdose occurs, institute general supportive measures. PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients and caregivers that Defitelio may increase the risk of bleeding (hemorrhage). Instruct patients to immediately report any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, or altered vision) [see Warnings and Precautions] s. • Hypersensitivity Reactions: Ask patients if they have been treated with defibrotide sodium previously. Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms [see Warnings and Precautions] s.

Volume 47 • Number 5 • May 2020 • pharmacypracticenews.com EDITORIAL BOARD

TECHNOLOGY Thomas Van Hassel, RPh, Yuma, AZ

ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

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6 COVID-19 Pandemic

ome of the most severe cases of COVID-19—and many of those seen in younger patients—appear to be linked to a severe immune system overreaction called “cytokine release syndrome” or “cytokine storm,” and clinicians are scrambling to find treatments that can slow its deadly occurrence. A massive release of cytokine immune proteins produces dangerously high fevers, extreme fatigue, difficulty breathing and a sharp drop in blood pressure. Oncology pharmacists at institutions providing chimeric antigen receptor (CAR) T-cell immunotherapy for certain types of cancer are familiar with cytokine storm as a common side effect of treatment. This uncontrolled immune reaction also can occur in a variety of other conditions, including infections and autoimmune disorders. Whether the cytokine storm found in COVID-19 patients is the same phenomenon as that seen with CAR T-cell therapy and these other conditions—and can be treated the same way—remains to be determined. “Cytokine storm syndrome is a kind of umbrella term,” said Randy Cron, MD, PhD, a pediatric rheumatologist at the University of Alabama at Birmingham. “Underneath that umbrella are several

different conditions,” he said. These include a genetic/familial form called hemophagocytic lymphohistiocytosis; the macrophage activation syndrome that occurs in patients with conditions such as lupus; the cytokine release that can be triggered by CAR T-cell therapy; and virus-triggered cytokine storm. “You could put COVID in that last category,” Dr. Cron said, “but from what we’re learning on the fly, it seems to be somewhat different [from] even your typical viral-induced cytokine storm.”

Look Out for Organ Damage A distinguishing characteristic of COVID-19-associated cytokine storm is severe damage to the lungs. “Although we do see the acute respiratory distress syndrome in other cytokine storms, this seems to be worse and more focused, maybe because the virus has a predilection for the cells in the bottom of the airway,” Dr. Cron said. “On the other hand, while it definitely makes the liver unhappy, liver reaction is less than we see in other cytokine releases.

Pharmacy Practice News • May 2020

Serum ferritin is elevated in the thousands [ng/mL] range, which is significantly higher than normal, but not nearly as high as with CAR T-cell therapy, where we might see numbers in the tens or hundreds of thousands.” Nonetheless, tracking serum ferritin in COVID-19 patients still offers a useful early marker, Dr. Cron said. “We had an adult patient with serum ferritin levels at about 1,200 to 1,500 when he came into the hospital. A couple of days later, when he entered the ICU, it was up to 1,800. It’s definitely something to keep an eye on.” Kidney damage in COVID-19 patients is another concern. When researchers in Wuhan, China, conducted autopsies on people who died of COVID-19, they found that nine of 26 had acute kidney injuries and seven had particles of the coronavirus in their kidneys, the researchers reported in Kidney Internationall (doi.org/10.1016/j. kint.2020.04.003).

its patients, including interleukin (IL)-6, ferritin, C-reactive protein and D-dimer levels. “One study of 80 patients in Germany showed that IL-6 levels greater than 80 [pg/mL] were associated with patients requiring increased oxygen support, intubation and development of ARDS [acute respiratory distress syndrome],” Dr. CT imaging shows extensive inflammation (yellow areas) Proli said. “That might be a break point where in the lungs of a 59-year-old man infected with COVID-19. The patient was on a ventilator and in critical condition. people will look at treatJust days before the scan, the patient was symptom-free. ment with IL-6-directed therapies.” (The German Source: George Washington University Hospital. study was not peerreviewed; bit.ly/2xkqiYI.) Steroids a Mixed Bag Other agents being studied include Steroids have been used effectively to the IL-6 receptor blocker tocilizumab manage CAR T-cell therapy–associated (Actemra, Genentech), which the FDA cytokine storm, especially in those with An Extended Trajectory approved for the treatment of severe neurologic toxicities, but the evidence A COVID-19-triggered cytokine storm cytokine release syndrome in patients for using them in COVID-19 patients is follows a more extended trajectory than receiving CAR T-cell therapy. A case less encouraging. “Methylprednisolone that associated with CAR T-cell therapy. report from China detailed some suc- has been looked at in SARS [severe The latter typically manifests around cess in using the drug to slow cytokine acute respiratory syndrome] and MERS three to four days after infusion. “With storm in COVID-19 patients ((Blood Adv [Middle East respiratory syndrome], and it did not show a benefit and perCOVID patients, on the other hand, you 2020:14[7]:1307-1310; bit.ly/2xtkVGv). haps even had a detrimental effect in ‘We’ve had several [COVID-19] patients who were looking those patients, possibly owing to an observed decreased rate of viral clearOK to the point that we had thought about possibly ance,” Dr. Proli said ((Am J Respir Crit discharging them but decided to hold off. Then, the Care Med d 2018;197[6]:700-701). “Major bodies right now are not recommendsecond wave hit with the cytokine release [and the ing empiric steroids unless there’s accompanying] oxygen requirements and returning fever.’ a clear indication, for example, if a patient has a condition such as asthma —Anthony Proli, PharmD that is known to be steroid responsive. Other than that, the conventional have the original viral prodrome, with Other drugs being investigated in this wisdom is to avoid steroids in COVID fever, body aches and chills. Then the setting include an IL-1 blocker, anakin- patients.” viral illness seems to wane before—in ra (Kineret, Amgen), approved by the Whatever the choice of treatment, time some patients, a week or more after FDA to treat rheumatoid arthritis and is of the essence. “If it’s a cytokine storm, infection—the storm hits,” said Anthony an infantile multisystem inflammatory the sooner you treat, the better,” Dr. Cron Proli, PharmD, a clinical pharmacy spe- disease, and emapalumab (Gamifant, said. “If we wait until the patient is intucialist in bone marrow transplantation Novimmune/Sobi), already approved for bated and lung tissue has been destroyed, at Memorial Sloan Kettering Cancer hemophagocytic lymphohistiocytosis, it may be too late. So if you have a hospiCenter in New York City. “We’ve had the genetic predisposition to cytokine talized patient with evidence of cytokine several [COVID-19] patients who were storm. “There are other theoretical cyto- storm—fever, maybe some CNS [cenlooking OK to the point that we had kine-targeting agents you could use, such tral nervous system] findings, and some thought about possibly discharging as ruxolitinib [Jakafi, Incyte/Novartis], confirmatory labs like elevated ferritin, them but decided to hold off. Then, which inhibits downstream signaling of increased liver enzymes, and signs of the second wave hit with the cytokine IL-6 and other cytokines,” Dr. Cron said. coagulopathy like D-dimers being off and release [and the accompanying] oxygen The FDA has fast-tracked phase 3 platelets trending down, that’s when you requirements and returning fever.” clinical trials for all three agents in want to start your treatment of choice as The fevers that occur in patients with COVID-19 patients who develop cyto- opposed to waiting a few days until they COVID-19 and CAR T-cell–related cytokine storm. “There are lots of potential are really sick.” kine storm “are probably relatively simi- options; we’re desperately hoping one Dr. Cron declined to say which agent lar, in that the patients will spike for hours or more of these trials gives us the infor- his hospital deems first-line for treating without any relief from [acetaminophen] mation we need,” Dr. Cron said. “But COVID-19. Dr. Proli said Sloan’s protocol or other medications,” Dr. Proli added. it’s very hard to say anything without is still in development. data, and we don’t yet know which ones —Gina Shaw Tracking Via Biomarkers will be valuable. If any of them are, or if Memorial Sloan Kettering is track- several are, will we have enough to go The sources reported no relevant ﬁnancial relationships. ing a variety of disease biomarkers in around? That’s the next question.”

PHARMACY WORKFLOW MANAGER

DRIVING INCREASED DRUG PREPARATION SAFETY 30% of hospitals have experienced a patient event involving a compounding error in the past 5 years1, yet only 33% of hospital facilities use IV workflow technology to help prevent dose preparation errors.2 A recent study found that hospitals using IV workflow technology detected 14 times more medication preparation errors than hospitals performing manual IV workflow.3

4.2%

~2,800

~42%

OF ALL DOSES COMPOUNDED

COMPOUNDING ERRORS

INCORRECT DRUG ERROR

in 2019 by facilities using the DoseEdge System experienced an error intercepted by the system4

were intercepted by the the average hospital facility in 2019 using the DoseEdge System4

was the most common compounding error intercepted by the DoseEdge System in 20194

Help ensure doses in your pharmacy are prepared safely and accurately Call 888-229-0001 to ﬁnd your local Dose Management Specialist and choose the DoseEdge System today Fo or th the e safe and nd pro rop perr us pe p u e of the device, reffer to the approp pri ria ate use err’ss gui uide de. 1. Insti Institute tute te for or Sa Safe M Medica dication tion Pra Practic cticces (ISMP). ( ISMP Guidelines for Safe Preparation of Compounded Steril rile e Pre Preparatio tions; 2 2016.. www.is 201 www mp.o m rg/guide ideline es/st s/steril erile-co e-com mpounding 2 “IV 2. “IIV V Workf orkfl kfllow.” P kf Ph Phar harmacy Pur P chasing Purchas h ing i g & Products P d t ,M Mar. 2020, 2020 p. 12. 12 https://www.p htt // pppmag.com/digitalmag/Ma /di it l /M Main.p i hp?Mag in.ph ?MagNo=2 N 2 261&P 261&Pag 261 &P eN &PageNo= N 1#page/1 1# /1 3 Step 3. Sttephen hen F Eckel, ke Jor Jordyn dyn P Higgin Higgins, s Elizabeth Hess, Thomas Cerbone, Jennifer B Civiello, Christian Conley ey,, Nilofa Nilof r Ja afa fari, Shaill aillyy S Shah, Stephen en L Speth, Speth, Lynn n Thornt Thorn on on, Multicenter study to evaluatte tthe benefiits of techn technolog gy-as y-assist sisted ed workf workflow low on i.v. room efficiency, costs, and safety, Ameriican Journal of Health-Syste ystem m Pharmacy Ph cy, Volu ume 76, 7 Issue 12, 15 June ne 201 2019, Pag Pages es 895–9 8 901, https://doi.org/10.1093/ajhp aj /zxz067 06 4. Baxte Baxterr Intern In ernal al Data Data on File File. DoseEdge System 2019 Safety Statistics

Baxter Bax ter an a d Dose os Ed Edge are registeered trademarks r of Baxteer Internation nal Inc., or its subssidi idiari aries. e USMP/M USM P/MG84/2 /20-0007 4/20

Baxter Healthcare Corporation One Baxter Parkway O Deerﬁe Dee rﬁeld, ld, IL 60 6 015 www.ba www baxte xter.c r com

8 COVID-19 Pandemic

Pharmacy Practice News • May 2020

continued from page 1

For this analysis, Vizient focused on 13 of the hardest hit—each often administered to facilitate mechanical ventilation and patient comfort throughout the course of therapy. The study used purchase order data from Vizient’s health-system members to calculate customer demand and fill rate trends for the 13 agents in March, with some data updates done in April. They were divided into three groups: sedatives or anesthetics (six); opioid analgesics (three); neuromuscular blocking agents (four). In the sedative/anesthetic group— which included propofol, dexmedetomidine and lorazepam—the April fill rate was down to 47%, just as demand was increasing by 272%, according to the Vizient report. For the three opioids studied—hydromorphone, fentanyl and morphine—April demand rose 104% while the medication fill rate decreased to 69%. The trend was the worst for the four neuromuscular blockers studied: Demand was up by 508% as the fill rate declined to 41%. “We are continuing to monitor these drug classes daily and the heightened demand is not waning, but staying steady,” Dr. Kistner said. “In fact, when comparing the run rate in April to March, the demand is even higher and fill rates have fallen from 72% overall [in] March to 55% so far in April. The unprecedented demand for these drug classes appears to be consistent with the overall need for ventilators in this country as supply is simply not able to meet the current level of demand. We can’t lose sight that ventilators, and the medications necessary for those patients, is a 1:1 equation.”

Shortages Likely to Worsen John W. Devlin, PharmD, a professor of pharmacy at Northeastern University, in Boston, and the chair of the Society of Critical Care Medicine’s 2018 “Guidelines for the Prevention and Management of Pain, Agitation/ Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU,” said the shortages of sedatives, opioids and neuromuscular blocking agents are only likely to worsen as new COVID-19 cases surge across the country. “In the Boston area, we are seeing an ever-increasing prevalence of COVID19-associated acute respiratory distress syndrome (ARDS),” he said. “The complex ventilator settings and proning required to treat the severe hypoxemia found in these ARDS patients sometimes requires deep sedation to reduce oxygen consumption, highdose opioids to reduce respiratory drive, and neuromuscular blockers to reduce airway pressure and optimize ventilator compliance.” Dr. Devlin recalled the critical propofol shortage that occurred during the 2009-2010 H1N1 pandemic, which caused problems but was obviated by the increased use of benzodiazepines such as midazolam. The current situation is far more difficult, he said, because the shortages “are really across the board.” In the face of the shortages, Dr. Devlin highlighted six strategies to reduce the daily use of IV sedatives, opioids and neuromuscular blockers in mechanically ventilated patients with COVID-19: 1. Be judicious with deep sedation. Dr. Devlin said ICU clinicians are

6 Strategies For Conserving Ventilator Rx 1. Be judicious with deep sedation 2. Be ready with IV boluses 3. Adjust ventilator first; prescribe second 4. Follow the data on what works, what doesn’t 5. Use oral meds when appropriate 6. Consider nonopioid analgesics Source: John W. Devlin, PharmD.

striving to minimize their time at the bedside and, thus, are likely to keep patients with COVID-19 more deeply sedated than usual. But he noted that not all COVID-19 patients require deep sedation throughout the course of mechanical ventilation. “The ICU team should evaluate sedation goals at least daily,” he advised, “and continuously infused sedation should be interrupted or decreased in patients who are excessively sedated.” 2. Be ready with IV boluses. Dr. Devlin further suggested that acute episodes of agitation or pain generally can be treated with IV boluses of opioids and/or sedatives; increases in the infusion are not always needed. 3. Adjust ventilator first; prescribe

FDA Turns to Compounders for Help T he FDA eased its restrictions on 503A state-licensed pharmacies and 503B outsourcing facilities to allow them to supply hospitals with compounded medications that are in critically short supply for COVID-19 patients. The agency said the new temporary policy is a response to “the unprecedented disruptions to, and demands on, the global pharmaceutical supply chain as a result of the COVID-19 pandemic.” Shortages are particularly severe for drugs administered to calm or immobilize ventilated patients in acute respiratory distress. They include propofol, dexmedetomidine, fentanyl and succinylcholine. Vizient’s latest tracking studies show that demand for these and other sedating and paralyzing agents soared through April as supplier fill rates plummeted. (See accompanying story) The policy is intended to provide relief to hospitals in coronavirus hot spots for the duration of the pandemic. Outsourcing facilities now will be able to compound and supply hospitals with products that are essentially copies of approved drugs, but only when the approved drugs are unobtainable from wholesalers or manufacturers. Restrictions also have been relaxed for United States Pharmacopeia-compliant 503A

pharmacies, which under normal policy are only permitted to compound medications for individual patients. These smaller state-licensed pharmacies now can compound and supply hospitals with copies of commercially available drugs without patient-specific prescriptions. They don’t have to fear the agency will take action against them, the FDA said. The new policy also applies to federal facilities. Eric Kastango, MBA, RPh, the president and CEO of Clinical IQ and CriticalPoint, said: “The recent easing on the limitations placed on 503A compounding pharmacies by the FDA is an important strategy in supporting the hospital’s ability to procure critical medications needed to treat COVID-19 patients. Although the FDA has been very concerned about the quality of compounded medications from bad operators, the agency recognizes the vital role that compounding plays to meet the clinical needs of patients.” He added: “Now, more than ever, the pharmacy profession needs to bring its compounding expertise to meet the demand for medications that are in shortage. Compounding is and will continue to be a differentiating skill set and a cornerstone of our professional mission.” —B.B.

second. Ventilator dyssynchrony should be managed with ventilator adjustments before more sedation is administered. 4. Follow the efficacy data. “The recent ROSE-PETAL [randomized controlled trial] demonstrated that the routine administration of continuous IV neuromuscular therapy does not improve outcomes in patients with ARDS,” Dr. Devlin noted. Therefore, “neuromuscular blockers should be administered on an intermittent ‘as-needed’ IV push basis.” ((N Engl J Med d 2019;380[21]:1997-2008.) 5. Use oral meds when appropriate. For patients with functional nasogastric or enteral access, Dr. Devlin said clinicians should consider administering oral opioids, such as oxycodone or methadone, and/or sedatives such as lorazepam, to reduce continuous IV infusions. In the absence of first-line sedatives, clinicians can consider using other classes of medications (either oral or IV) known to have sedating properties, including phenobarbital, valproic acid, haloperidol, quetiapine or ketamine. 6. Consider nonopioid analgesics. Administering these medications in a multimodal approach that’s often used in postsurgical patients—for example, acetaminophen, lidocaine and ketamine—may help reduce opioid requirements in COVID-19 patients requiring mechanical ventilation in the ICU. For details on how Ochsner Health addresses ventilator drug shortages, see article, page 25. —Bruce Buckley The sources reported no relevant ﬁnancial relationships.

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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

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Please see Important Safety Information and brief summary of Prescribing Information for n. HyperRAB on adjacent pages, or visit www.HyperRAB.com for full Prescribing Information. 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.

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10 COVID-19 Pandemic

ith shortages of smart infusion pumps rising in hospitals besieged by COVID-19 admissions, the Institute for Safe Medication Practices (ISMP) issued a set of strategies designed to reserve supplies of the pumps for the most critically ill patients, including those on mechanical ventilation. The conservation measures are featured in the second pandemicfocused edition of the ISMP Acute Care Safety Alert! newsletter (bit.ly/3cgmpTk).

Pharmacy Practice News • May 2020

In a separate webinar, ISMP issued guidelines on how to use smart pumps safely during the COVID-19 pandemic, including keeping the pumps outside of patients’ rooms to prevent viral exposure.

Conserving a Limited Resource “What we’re learning is that the [smart pump] situation is very dynamic as these [COVID-19] surges impact individual organizations,” said Michelle Mandrack,

MSN, RN, the director of consulting services at ISMP. “These strategies are what we think offer the best use of limited resources.” They include reserving the use of smart pumps for high-alert medications and critical patients and, in certain cases, considering infusion delivery via IV push instead of continuous infusion (bit.ly/2REYuVG). Another suggested option is to revive the use of gravity flow infusion for

medications that can be safely managed without the alerts built into the smart pumps. These cases might involve infusions of IV hydration and some IV antibiotics. Ms. Mandrack pointed out, however, that “on the critical care units, we’re not used to running infusions by gravity. We’re used to having smart pumps with dose error reduction software to safely manage intensive care patients who are receiving many high-alert drugs. So,

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.

COVID-19 Pandemic 11

Pharmacy Practice News • May 2020

iitt’s it’s ’ cru ruci cial all to co ontin nttinue ue the he use of sm s arrt pumps for medi dicati di tion inffusio ti i ns in [t [th he]] ICU. At the ICU th same time, ti to t preserve pumps and dedicated sets, have a plan to convert to gravity infusion elsewhere as the circumstances begin to dictate.” The newsletter also suggested converting some IV patients to oral therapy as soon as possible while following facilities’ specific IV-to-oral protocols, and weighing the use of either syringe pumps, if available, or subcutaneous infusion delivery for hydration and low doses of potassium chloride.

Firs Fi rst St rs Step eps ep s One off the h firstt stteps for deall iing with ith an active ti or looming l i smart pump shortage, according to ISMP, is to inventory all available supplies of the devices, with an eye towards underrecognized locations. “They may be sitting underutilized in interventional radiology, for example, or in perioperative areas, surgery centers and outpatient settings,” Ms. Mandrack said. Another step is to develop a list of

Photo courtesy Phot urte t sy y of Le Lehigh hig Val high Va ley Heal ealth lth Netwo Netwo etwork, t rk, k, Alle Allentow All ntown, ntow t n,, P Pa. a

i l d IV vasopressors, antiarinclude ti rhythmic agents, opioids, sedation and anesthetic agents, neuromuscular blockers, antithrombotics and insulin. Unfortunately, several of these agents are in short supply (see page 1).

medications that “absolutely require” smart pump delivery. At a minimum, the newsletter stated, the list would

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 prophylaxis, 20 IU/kg as possible after along with body weight exposure, preferably rabies OR at the time of the first vaccine, after 0.0665 mL/kg rabies vaccine dose. suspected body weight • Infiltrate the full 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

Keeping Pumps Outside Of Rooms Even when smart pumps are available, COVID-19 has necessitated workflow changes to ensure safety. Specifically, some hospitals are stationing the pumps outside the rooms of critically ill patients with COVID-19. Doing so can reduce the number of times health care workers enter patient rooms, preserving personal protective equipment and cutting the risk for SARS-CoV-2 exposure. However, as experts from ECRI and ISMP said during the webinar, with new workflows come new concerns. ECRI has tested the five most common smart infusion pump brands using up to 20 feet of microbore extension, which many organizations have opted to use because of the smaller priming volume, noted Erin Sparnon, MEng, a senior engineering manager at ECRI. Ms. Sparnon said the pumps performed as they typically do at the bedside for flow rates ranging from roughly 5 to 300 mL per hour, flow rates that are sufficient for most infusions, she noted. “However, at both ends of the spectrum is where we get problems, specifically with alarms.” At flow rates below 5 mL per hour and with long tubing sets, she explained, pumps were slow to detect occlusions close to the patient, thus delaying alarms. On the other hand, with flow rates above 300 mL per hour, fluid pushed through the low-volume and small-diameter microbore tubing, leading to higher downstream resistance and more frequent occlusion alarms. “At either end of the spectrum, there’s the risk of the patient not getting the medication they need,” she said, noting that it is impractical for busy nurses to attend to frequent alarms. A challenge that comes with using microbore extension sets is that when small-volume infusions are administered, much of the drug can remain in the tubing and needs to be flushed when the infusion is complete, according to Ms. Mandrack. “It’s really important to know the total volume of the bag to make sure you get all the drug to the patient access site,” she stressed. Using extension sets also can affect infusions that require titration, she said, noting that “if titrations are done more proximal to the pump in the hallway and there is a long extension of see SMART PUMPS, page 12

12 COVID-19 Pandemic

SMART PUMPS continued from page 11

tubing, there can be delays in the effect of the titration. So you might consider placing these types of infusions closer to the patient.” Perhaps one of the most important consequences of placing infusion pumps in the hallway is the potential to compromise the safety of the medication administration process, Ms. Mandrack said. “The independent double-check process for high-alert

Pharmacy Practice News • May 2020

mee di d ca cati tii on ons ha h s de d e fi fini nii tely tee l y b ee een n impactted d by th his practtice,”” sh he said id d. “The separation “Th ti off iinfusion f i pumps from the patient at their bedside has frequently limited these double checks to verifying the medication, concentration and dose, and pump setting but not the patient’s barcode bracelet.” A number of hospitals are labeling the pump itself with the patient’s name and date of birth as well as scanning a “proxy bracelet”; a duplicate patient-barcoded bracelet that two nurses have verified is an exact match to the bracelet the patient

i weari is ring ingg, Ms Ms.. Ma M nd drack k not oted ed d. Ho oww ever, sh he cauti tioned d th hatt “th his i proxy situation ti carries i its it own risks, i k particularly ti l l when you’re using mobile infusion poles and the bracelet may be accidentally left on the pole after it’s been transferred for use for another patient.”

Nurse-to-Nurse Communication There is at least one novel approach to mitigating the risk for wrong-patient drug administration: having a nurse in the patient room communicate with another nurse in the hallway, as one hospital told

IS SMP M . Ms M . Ma Mand nd draack k said aiid tth he cr crit i ic it i all car aree rooms at thi his partticullar hospit hi ital are gllass enclosed, l d which hi h allows ll a nurse llocatt ed inside the room to scan the patient’s bracelet and a second nurse in the hallway to scan the infusion bag through the glass, she explained. Other organizations reported wrestling with the possibility of allowing nurses to override hard stops that typically require independent double checks before a medication can be administered, she noted. Although Ms. Mandrack acknowledged there can be “really tough conversations” around these topics, ISMP believes health systems can implement workflow modifications to preserve the independent double-check process as much as possible. For example, with some electronic health record (EHR) systems, two nurses can independently double-check the medication and pump settings in the hallway. With the order pending in the EHR, the patient’s nurse can then enter the room to complete the process through the medication administration record on the computer and scanning the patient’s bracelet, she explained. Ms. Mandrack urged organizations that are using infusion pump extension sets to clearly label lines both inside and outside the room, particularly when there are multiple sets running from the pump. “Once you have two or three different patient infusion pump setups outside a single room, the potential for wrong patient drug administration becomes a real safety hazard.”

Conservation Measures With the demand for extension sets having “skyrocketed,” some organizations have experienced shortages of these sets and moved pumps back to the bedside, said Mike Cohen, RPh, the president of ISMP. “From our discussions with manufacturers, they are working overtime to meet demand for extension sets,” he noted during the webinar. Until ample supply is secured, Mr. Cohen said organizations can turn to a number of strategies to conserve pump-related inventory. For example, he urged organizations to create a list of medications they believe must “absolutely” be administered through infusion pumps, and switch appropriate patients from IV to oral medications and hydration as early as possible. He said organizations also should maximize the length of time they use tubing sets, while still adhering to standards issued by organizations such as the CDC (bit.ly/3bjRzZZ). Finally, he suggested administering medications through IV push and gravity infusion when possible. —Bruce Buckley, David Wild The sources reported no relevant ﬁnancial relationships.

COVID-19 Pandemic 13

Pharmacy Practice News • May 2020

elivering appropriate nutrition for very sick adults with COVID-19 remains an important consideration for optimizing outcomes, but it also involves some unique challenges, including dealing with looming shortages of nutrition products, according to a presentation at the ASPEN20 Virtual Conference. “We’re assessing and treating patients with COVID-19 just like any other patient in the ICU with acute respiratory distress syndrome (ARDS), with the exception of exposure issues,” said Robert Martindale, MD, a professor of surgery and an expert in digestive health at Oregon Health & Science University, in Portland. Dr. Martindale and other session presenters highlighted the importance of choosing and timing the provision of nutrition products while also protecting health care workers. He suggested using enteral nutrition if it can be successfully given via a gastric feeding tube, and then considering supplementation with parenteral nutrition (PN) if the enteral route is unsuccessful. In April, the Society of Critical Care Medicine and ASPEN released COVID-19 nutrition recommendations that include discussion of early conversion to PN if the enteral mode requires significantly more health care worker exposure (sidebar). “I never thought I’d say that,” Dr. Martindale said. This strategy, however, should

Experts are warning against the use of propofol in COVID-19 patients: The anesthetic is suspended in a 100% soybean oil–based emulsion that is known to be proinflammatory.

decrease the need to check patients’ bellies, place distal feeding tubes and other potential routes of exposure for health care providers. “How do we deliver the same nutrition support without having too much health care worker exposure to the [causative SARS-CoV-2] virus?” Dr. Martindale said. “That is a big issue.” When it comes to PN, if using IV lipid emulsions, he recommended opting for lipid injectable emulsions that are lower

Still, in contrast to other critically ill patients, the threshold for switching to PN may need to be lower for a patient with COVID-19. “Use of PN in these patients, especially those with severe septic shock or when high-pressure respiratory support is required, may help lessen the risk for ischemic bowel and reduce droplet aerosol transmission to healthcare providers.”That risk is reduced, they noted, “by avoiding procedures involved in the initial [EN] placement and the nursing care required to maintain an enteral access device.” The authors noted that these new recommendations are based on indirect evidence from critically ill patients. However, anecdotal “lessons from the field” suggest further COVID-19 considerations, such as a potential shortage of enteral pumps. “Enteral pump distribution priority should be given to patients with small bowel feeding or those with symptoms of intolerance, and continuous gravity feeding be attempted for those not able to have a pump,” the authors wrote. They also noted that, based on these on-the-ground experiences, the use of multichamber bag PN products could decrease pharmacist compounding time for PN preparation. The guidelines also offer strategies to reduce how often health care providers interact with patients, minimize contamination of additional equipment, and avoid transport out of the ICU. Toward that end, they recommend using continuous rather than intermittent or bolus infusion, calculating energy requirements by weight-based equations rather than indirect calorimetry, and reducing the need for endoscopic or fluoroscopic techniques for feeding tube placement.

“We no longer have to use 100% soybean oil,” Dr. Martindale added. “Now that we have a potentially less inflammatory oil, we should use it.” More specifically, he noted that fish oils produce metabolites called specialized pro-resolving mediators (SPMs). An inflamed cell turns on production of SPMs, which are made from the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid by the body. “Those go on to stimulate resolution of inflammation,” Dr. Martindale said. Based on evidence from flu and other viruses ((N Engl J Med d 2013;369[2]:191193), “SPMs might enhance viral clearance,” he added. “But that’s pure speculation at this point for COVID-19.” In addition, “you need to follow the lipid profiles of COVID-19 patients,” Dr. Martindale said. “For the subpopulation of patients who get rapidly sick—and need a ventilator within 12 to 24 hours— you need to be especially careful with lipids. Their serum lipids seem to rapidly rise for unexplained reasons.” Joseph Boullata, PharmD, a nutrition specialist at the Hospital of the University of Pennsylvania, in Philadelphia, emphasized the outcome benefits of new lipid emulsions over the traditional 100% soybean oil products during the presentation. He added a warning about the use of propofol in COVID-19 patients: The anesthetic is suspended in a 100% soybean oil–based emulsion that, again, is known to be proinflammatory. Another product that may benefit COVID-19 patients is probiotics, according to Dr. Martindale. He noted he would consider providing probiotics to these patients on admission to the ICU. “I believe strongly that probiotics are important for everybody, especially those with viral infections,” he said.

—Lynne Peeples

see COVID-19 FEEDING, page 18

in proinflammatory soybean oil and using mixed lipid emulsions that contain fish oil and olive oil. Historically, the only lipid injectable emulsions available in the United States were 100% soybean oil. Additional products have been developed in recent years, including Fresenius Kabi’s Smoflipid—combination of soybean oil, medium-chain triglycerides, olive oil and fish oil—and Omegaven—an injectable emulsion of fish oil triglycerides.

New Joint ICU Feeding Guidelines Issued

n April 1, in response to ICUs becoming overwhelmed with COVID-19 patients, the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition coreleased guidelines for nutrition therapy in patients with the disease (bit. ly/3bsdzlb). “The nutritional management of the ICU patient with COVID-19 is in principle very similar to any other ICU patient admitted with pulmonary compromise,” the guideline authors wrote. But they underscored some unique considerations with the contagion and posited three guiding principles: 1. bundling care to limit exposures; 2. adhering to CDC recommendations on hand hygiene and personal protective equipment (PPE); and 3. preserving PPE by limiting the number of staff providing care. In addition, they detailed eight specific recommendations for this patient population—from the timing, route and dose of nutrition delivery to strategies for patients undergoing prone positioning or on extracorporeal membrane oxygenation. Among the key goals is to initiate early enteral nutrition (EN) within 24 to 36 hours of admission to the ICU or within 12 hours of intubation and placement on mechanical ventilation. “Like most ICU patients, COVID-19 patients are expected to tolerate EN and benefit from the favorable physiologic response to bathing the intestinal mucosa with luminal nutrients,” the authors wrote. They added that early parenteral nutrition (PN) should be initiated as soon as possible in the high-risk patient for whom early gastric EN is not feasible.

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In cUTI caused by susceptible Gram-negative microorganisms

OUTSMART RESISTANCE Fetroja outsmarts pathogens by using iron to gain cell entry, like a Trojan horse.1,2

Fetroja—the world’s only siderophore cephalosporin—overcomes Gram-negative antibacterial resistance1

Sta S Stable ab e in vitro against all known classes of ϐ-lactamases, including serine-carbapenemases i rbapenemases (such as KPC and OXA) and metallo-ϐ-lactamases (such as VIM and NDM)1 Active against some pathogens with porin channel deletions1

INDICATION Fetroja® (cefiderocol) is indicated in patients 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. Approval of this indication is based on limited clinical safety and efficacy data for Fetroja. USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja. WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients With CarbapenemResistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically-ill patients with carbapenemresistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including nonfermenters such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. The safety and efficacy of Fetroja has not been established for the treatment of nosocomial pneumonia, bloodstream infections, or sepsis. Reserve Fetroja for use in patients who have limited or no alternative treatment options for the treatment of cUTI. Closely monitor the clinical response to therapy in patients with cUTI. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving betalactam antibacterial drugs. Hypersensitivity was observed in Fetroja clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens.

Fetroja antimicrobial spectrum1 Fetroja is active both in vitro and in clinical infections against: Enterobacteriaceae (E coli, E cloacae complex, K pneumoniae, and P mirabilis) and P aeruginosa

Fetroja is highly active in vitro vs Gramnegative carbapenem-NS pathogens3 In vitro activity does not necessarily correlate with clinical efficacy. Fetroja in vitro susceptibility (US isolates)

Fetroja demonstrated significantly higher efficacy vs high-dose imipenem/cilastatin at TOC1,6‡ Primary endpointc: Composite clinical response and microbiological eradication at TOC 100

Susceptibility rates using FDA-approved breakpoints for pathogens in which Fetroja demonstrated both in vitro and clinical activitya

Enterobacteriaceae carbapenem non-susceptible P aeruginosa overall

99%

(n=10,186)

91%

PERCENT

Enterobacteriaceae overall

(n=162)

98% (n=2445)

P aeruginosa carbapenem 97% non-susceptible (n=468) Susceptibility rates using CLSI investigational breakpoints for pathogens in which Fetroja demonstrated in vitro activityb

96% (n=548)

99% (n=596)

In vitro susceptibility study design Clinical isolates of Gram-negative bacteria were collected in the United States from 2014-2018 for one study that included Enterobacteriaceae* and non-fermenter strains. The Proteeae† study isolates were collected from 2013-2016 and were tested centrally (IHMA Inc., Schaumburg, IL, USA). Fetroja MICs were determined by microbroth dilution using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as approved by the Clinical and Laboratory Standards Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. FDA breakpoints were used for Enterobacteriaceae MIC ≤2 μg/mL and P aeruginosa MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for A baumanniii and S maltophilia MIC ≤4 μg/mL. Carbapenem non-susceptible strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae (including Proteeae) strains and MIC ≥4 μg/mL for P aeruginosa and A baumannii.3 a FDA breakpoints used for Enterobacteriaceae MIC ≤2 μg/mL and P aeruginosa MIC ≤1 μg/mL. b CLSI investigational breakpoint used for A baumannii and S maltophilia MIC ≤4 μg/mL. *Escherichia coli, Klebsiella pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. † Morganella morganii, Proteus mirabilis, Proteus vulgaris, and Providencia rettgeri.

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) Hypersensitivity Reactions (continued) There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs. Clostridioides difficile-Associated Diarrhea (CDAD) Clostridioides difficile-Associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

54.6%

(n=1049)

A baumannii carbapenem non-susceptible S maltophilia overall (inherently carbapenem-resistant)4,5

18.6%

(95% CI, 8.2, 28.9) [P=0.0004]

98%

A baumannii overall

TREATMENT DIFFERENCE

72.6%

Fetroja (n=183/252)

Imipenem/cilastatin (n=65/119)

Microbiological intent-to-treat (micro-ITT) population, which included all patients who received at least a single dose of study medication and had at least 1 baseline Gram-negative uropathogen.

‡

Study Design

Multinational, double-blind, non-inferiority (margin of 15%) trial in 448 adults hospitalized with cUTI (including pyelonephritis) randomized 2:1 to receive Fetroja (2 grams IV every 8 hours§) vs high-dose imipenem/cilastatin (1 gram/1 gram IV every 8 hours) both infused over 1 hour for 7-14 days. Carbapenem-resistant pathogens were excluded as ethical necessity due to carbapenem comparator. Primary efficacy endpoint was composite of microbiological eradication (defined as all Gram-negative uropathogens found at baseline at ≥105 CFU/mL were reduced to <104) and clinical response (defined as resolution or improvement of cUTI symptoms and no new symptoms assessed by the investigator) at TOC visit 7±2 days after last dose of study drug.1,6 § Recommended dosing of Fetroja is 2 grams every 8 hours by IV infusion over 3 hours in patients with creatinine clearance [CLcr] ≥60 to <120 mL/min.1 A baumannii=Acinetobacter = baumannii; E cloacae complex=Enterobacter cloacae complex; E coli=Escherichia coli; K pneumoniae=Klebsiella pneumoniae; P mirabilis=Proteus mirabilis; P aeruginosa=Pseudomonas aeruginosa; S maltophilia=Stenotrophomonas maltophilia; TOC=test of cure.

Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued. Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and may increase the risk for development of drug-resistant bacteria. ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in clinical trials were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%).

Please see a Brief Summary of Prescribing Information on following page. References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019. 2. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant g Gram-negative bacilli. Drugs. 2019;79(3):271-289. 3. Data on file. 4. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pp pathogen. p g Clin Microbiol Rev. 2012;25(1):2-41. 5. Ruppé E, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care. 2015;5(1):61. doi: 10.1186/s13613-015-0061-0. 6. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin p for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. © 2020 Shionogi g Inc. Florham Park, NJ 07932. All Rights g Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. USCEF-0222 03/20

16 COVID-19 Pandemic

bnormal clotting, apparently resulting from endothelial damage, has been described in patients with severe COVID-19 disease, and Chinese clinicians recommend initiating prompt anticoagulation therapy in such patients. Bin Cao, MD, with the National Clinical Research Center for Respiratory Diseases in Beijing, described “clots in the small vessels of all organs, not only the lungs but also ... the heart, the liver and

Pharmacy Practice News • May 2020

the kidney," during a March 19 webinar on the disease cosponsored by the Chinese Cardiovascular Association and the American College of Cardiology. High D-dimer levels seen in these patients, Dr. Cao said, point to abnormal coagulation throughout the body. “The virus can bind to the endothelial cells and may cause damage to the blood vessel, especially the microcirculation of the small blood vessels.”

In a Mar arch ch h 11 sttud dy in i La L ancett i nvol oll ving i g 191 911 COVID-19 COVID 19 patients in Wuhan, Wuhan Dr. Cao and colleagues reported that D-dimer levels over 1 mcg/L at admission predicted an 18-fold increase in the odds of death before discharge ((Lancet 2020;395[10229]:1054-1062). However, American clinicians advised caution in interpreting these data. “Elevation of D-dimers may be a VTE [venous thromboembolism] risk signal to consider,” said William Dager, PharmD, a pharmacist specialist at UC Davis Medical

FETROJA (cefiderocol) for injection, for intravenous use BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis FETROJA® is indicated in patients 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacaee complex. Approval of this indication is based on limited clinical safety and efficacy data for FETROJA [see Clinical Studies (14.1) in the full prescribing information]. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients With Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically-ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. The safety and efficacy of FETROJA has not been established for the treatment of nosocomial pneumonia, bloodstream infections, or sepsis. Reserve FETROJA for use in patients who have limited or no alternative treatment options for the treatment of cUTI [see Indications and Usage (1.1)]. Closely monitor the clinical response to therapy in patients with cUTI. 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs. 5.3 Clostridioides difficilee-Associated Diarrhea (CDAD) Clostridioides difficilee-Associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficilee produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficilee cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficilee may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. 5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA

Ceent nter er,, in er i Sac acrrame rament nto. to “Bu B t mo more re [da data t ta are]] neede d d to t know th he si siggniffic icance off this association alone to drive initiating antithrombotic prophylaxis that otherwise would not be considered.” Dr. Dager added that due to the rapid pace of COVID-19 developments, “we are learning so much as we go. But it would be difficult to provide much more comment than this: There are notable signals suggesting an increased risk for thromboembolism in patients being managed for COVID-19.” As for the causes of the abnormal

dosing based on creatinine clearance [see Dosage and Administration (2.2) in the full prescribing information]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued. 5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and may increase the risk for development of drug-resistant bacteria [see Indications and Usage (1.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients With Carbapenem-Resistant GramNegative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficilee-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience p in cUTI,, includingg Pyelonephritis y p FETROJA was evaluated in an active-controlled clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose) and 148 patients were treated with imipenem/cilastatin 1 gram/1 gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were white, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days. Serious Adverse Reactions and Adverse Reactions Leadingg to Discontinuation In Trial 1, a total of 14/300 (4.7%) patients treated with FETROJA and 12/148 (8.1%) of patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%). Common Adverse Reactions Table 3 lists the most common selected adverse reactions occurring in ≥ 2% of patients receiving FETROJA in the cUTI trial. Table 3 Selected Adverse Reactions Occurring in ≥2% of Patients Receiving FETROJA in the cUTI Trial FETROJAa Imipenem/Cilastatinb Adverse Reaction (N = 300) (N = 148) Diarrhea 4% 6% Infusion site reactionsc 4% 5% Constipation 3% 4% Rashd 3% <1% Candidiasise 2% 3% Cough 2% <1% Elevations in liver testsf 2% <1% Headache 2% 5% Hypokalemiag 2% 3% Nausea 2% 4% Vomiting 2% 1% cUTI = complicated urinary tract infections a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function) b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight) c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. d Rash includes rash macular, rash maculopapular, erythema, skin irritation. e Candidiasis includes oral or vulvovaginal candidiasis, candiduria. f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. g Hypokalemia includes blood potassium decreased. Other Adverse Reactions of FETROJA in the cUTI Trial The following selected adverse reactions were reported in FETROJA-treated patients at a rate of less than 2% in the cUTI trial: Blood and lymphatic disorders : thrombocytosis Cardiac disorders : congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders : abdominal pain, dry mouth, stomatitis

COVID-19 Pandemic 17

Pharmacy Practice News • May 2020

clotti clot ting ti ngg, “i “itt mayy be multi ulltiifa fact ctor oria ial, l, fro rom m b ing sed be denttary to t the impactt off managementt approaches h iin these th more critiiti cally ill [patients],” said Dr. Dager, who is also a clinical professor of medicine at UC Davis School of Medicine and clinical professor of pharmacy at UC Davis College of Pharmacy. Anthony Proli, PharmD, a clinical pharmacy specialist in bone marrow transplantation at Memorial Sloan Kettering Cancer Center in New York City, agreed that handling clotting issues in COVID-19 patients is far from straight-forward.

“Che “C hecck he kin i g DD-diime m r le leve vels l and ls d fib briino no-gen and d th then h iniitiati ting anti ticoaggullattio i n iis controversial, t i l b based d on th the A American i Society of Hematology [ASH] guidelines,” Dr. Proli said. (For more on the ASH recommendations, see sidebar.) “Still, in our ICU, when D-dimers are elevated in COVID-19 patients, we initiate full-dose anticoagulation. Some of our hematologists are even wondering if there’s a potential for defibrotide [Defitelio, Jazz Pharmaceuticals] in these patients who have potential to go into hypercoagulable DIC [disseminated

General system disorders : pyrexia, peripheral edema Hepatobiliary disorders:: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders : drug hypersensitivity Infections and infestations : Clostridioides difficilee infection Laboratory Investigations : prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders : decreased appetite, hypocalcemia, fluid overload Nervous system disorders : dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders : dyspnea, pleural effusion Skin and subcutaneous tissue disorders:: pruritis Psychiatric disorders : insomnia, restlessness 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summaryy There are no available data on FETROJA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 1.4 times (rats) or 2 times (mice) higher than the average observed in cUTI patients receiving the maximum recommended daily dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 1.4 times (rats) and 2 times (mice) the daily mean plasma exposure in cUTI patients that received 2 grams of cefiderocol infused intravenously every 8 hours. In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed. In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (<0.5%) of the dose. 8.2 Lactation Risk Summaryy It is not known whether cefiderocol is excreted into human milk; however, cefiderocolderived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production.

i tr in t av avas ascu culla lar co coag agulopatthy hy]. ].”

More on Mechanisms Katelyn Sylvester, PharmD, the pharmacy manager for anticoagulation services at Brigham and Women’s Hospital, in Boston, said there are multiple possible underlying mechanisms for abnormal clotting and cardiac damage in COVID-19. “It’s interesting to consider the direct damage they’re seeing in endothelial cells,” Dr. Sylvester said. “Is the virus attacking those cells and causing microvascular damage, and is that leading to

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition. Data Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level. 8.4 Pediatric Use Safety and efficacy of FETROJA in pediatric patients younger than 18 years of age have not been established. 8.5 Geriatric Use Of the 300 subjects treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min. Patients with CLcr Less Than 60 mL/min Dose adjustment is required in patients with CLcr 15 to 59 mL/min, and in patients with end-stage renal disease or who are receiving hemodialysis (HD). In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy. Patients with CLcr 120 mL/min or greater g CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy. 8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function. 10 OVERDOSAGE There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered. Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3) in the full prescribing information]. Manufactured byy Shionogi & Co., Ltd. Osaka 541-0045 Japan Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932 FET-BS-01 USFET-0003 Revised: 11/2019

so ome of th thee accutte co coro rona nary syn y dr d om omes es bein i g reportted d in th these pati tiients t ? Do D es thatt suggestt that th th t we need d to t consider id therapeutic anticoagulation versus prophylaxis? Although we are seeing endothelial tissue damage, so far there are not a lot of VTE events being reported.” see COVID-19 CLOTTING, page 18

Guidelines On COVID-19 And Coagulation

n late March, the International Society on Thrombosis and Haemostasis (ISTH) issued an interim guidance document, recommending that all hospitalized COVID-19 patients get prophylactic-dose lowmolecular-weight heparin (LMWH), unless they have contraindications (active bleeding, platelet count <25x109/L) (bit.ly/2VhBgG7). An American Society of Hematology (ASH) FAQ document on COVID-19 and coagulopathy reiterated the recommendation for prophylactic LMWH but also noted that therapeutic anticoagulation should be reserved for patients who have active bleeding, require an invasive procedure, or are otherwise at high risk for bleeding complications (bit.ly/2y5WXRO). “In patients with CAC/DIC who are nott bleeding, there is no evidence that correction of laboratory parameters with blood products improves outcomes,” the ASH document stated. “Replacement might worsen disseminated thrombosis and further deplete scarce blood products.” Other key points from the ISTH guidance include: • D-dimers: Patients with marked (three- to fourfold) elevations in D-dimers should be considered for hospital admission, even absent other signs of disease severity. • Low platelets: Some data suggest that thrombocytopenia may be predictive of mortality, but this finding has not been consistent. • Routine coagulation tests: Monitoring of prothrombin time, D-dimer, platelet count and fibrinogen can be helpful in determining prognosis in COVID-19 patients requiring hospital admission. • Management of bleeding: Bleeding is rare in the setting of COVID19 infection. If bleeding occurs, general ISTH guidance on transfusions may be followed. • Experimental therapy: Other treatments, such as antithrombin concentrate, recombinant thrombomodulin and hydroxychloroquine, can only be considered to be experimental at present. —G.S.

18 COVID-19 Pandemic

COVID-119 FEEDING continued from page 13

A 2015 Cochrane Review found probiotics to be better than placebo in reducing episodes of acute upper respiratory tract infections (URTI) by nearly 50% and the duration of an episode of acute URTI by nearly two days (Cochrane Database Syst Rev 2015;[2]:CD006895). “But these are not recommendations,” he said. “This is based on literature of other viruses and we need to study these to see if the same holds true for COVID-19. “The worst thing we can do is something that will harm this fragile group of patients, and any intervention needs to be based in evidence,” Dr. Martindale said.

COVID-19 Shortages Shortages of home PN drugs, such as amino acids, IV lipid emulsions, electrolytes, multivitamins and trace elements, have become routine in recent years. In 2017, for example, Hurricane Maria caused shortages of many components needed to compound PN. But it’s not only natural disasters that are a cause for concern. “I expect COVID-19 to result in shortages,” said Vanessa Kumpf, PharmD, a clinical pharmacist specialist at Vanderbilt Center for Human Nutrition, in Nashville, Tenn. “This includes supply shortages as well as medication shortages.” To that end, she advised health

COVID-19 CLOTTING continued from page 17

Dr. Sylvester also noted that angiotensinconverting enzyme 2, which is involved in COVID-19 viral entry, is expressed in cardiomyocytes, suggesting that some of the myocarditis seen in COVID-19 could be related to the virus inhabiting those cells and causing cell death. In a case series of 21 critically ill patients with COVID-19 in Washington state, 33% of these intensive care patients developed cardiomyopathy ((JAMA 2020 Mar 19. [Epub ahead of print]. doi: 10.1001/jama.2020.4326). “Also, since the disease’s primary target is the lungs, if a patient is not oxygenating their tissue well, we would see acute coronary syndromes due to lack of oxygen. This makes sense since we are primarily seeing myocarditis toward the end of the disease,” Dr. Sylvester said. “In addition, the cardiotoxicity seen at this stage of the disease may involve stress/cytokinemediated cardiomyopathy—perhaps a Takotsubo’s effect. It’s most likely these three factors acting in concert.” (Takotsubo cardiomyopathy is named after an octopus trap. Also known as broken heart syndrome, it often has the same symptoms as a myocardial infarction but is not caused by any underlying cardiovascular disease [bit.ly/2UTXsHj].)

Pharmacy Practice News • May 2020

care pro care rovi viide ders “nott to to use PN wh hen it is nott indi it ndicate t d and d work rk k to wean patients off PN whenever possible.” possible ” Reid A. Nishikawa, PharmD, the coordinator of clinical services and director of research for Nutrishare Inc., noted that the pandemic has already caused significant shortages of many items used in cleanrooms and supply items used by patients, such as masks, gloves (both sterile and nonsterile), sterile alcohol, alcohol pads and personal protective equipment. “It has not impacted the components used to compound PN,” he said. “That was already ongoing.” In fact, “in the last five to seven years, we’ve seen more drug shortages than we ever had in the last 30 years. These have caused many problems for PN compounding.” Dr. Nishikawa cited ongoing issues related to manufacturing, as well as sourcing of raw ingredients for pharmaceuticals and materials to manufacture medical products. Consolidation within the health care manufacturing industry also is a culprit, Dr. Nishikawa said. “It is a crisis [that] must be addressed immediately and resolved to prevent a repeat of what we are seeing now with [COVID-19].” —Lynne Peeples Dr. Boullata reported receiving honoraria as a speaker for several companies, including manufacturers of different IV lipid products. The other sources reported no relevant ﬁnancial relationships.

A Risky Constellation Any patient who has a significant underlying illness and, therefore, is at risk to be more severely affected by COVID-19 is also at higher risk for clotting and diffuse intravascular coagulopathy in the first place, Dr. Sylvester said. “We need to treat COVID-19 patients like other critically ill patients and use standardized risk assessment scores for prophylactic anticoagulation.” Patients with mild disease who are at home likely do not need VTE prophylaxis, she said, adding, “patients in the ICU, and even if on a step-down unit for multiple days, should have pharmacologic prophylaxis if there is not a contraindication. That’s my take from looking at the data that have been published to date.” Despite some lingering questions, clotting problems and antiplatelet therapy nevertheless should be included in the daily COVID-19 management process. Dr. Dager said. “Any symptoms consistent with a thromboembolic process such as a [pulmonary embolism] should be addressed and not be presumed to be from the infection.”

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20 COVID-19 Pandemic

Pharmacy Practice News • May 2020

Safety and efficacy raise persistent questions

Pharmacists Help Weigh Risks of Hydroxychloroquine T

here have been warnings again nst the indiscriminate use of hydroxyychloroquine in COVID-19 patients, givven the lack of peer-reviewed efficaccy data. But there’s another concern: th he cardiotoxities attributed to the med dication. Given that hydroxychloroquin ne often is prescribed in conjunction witth azithromycin, which carries its ow wn potential heart risks ((N Engl J Med 2012;366[20]:1881-1890), many providers are unsure how to proceed. That’s where pharmacists can help,, according to Marianne Pop, PharmD,, BCPS, a clinical assistant professor and d an emergency medicine clinical pharmacist at the University of Illinois College of Pharmacy in Rockford. Whether it’s managing potential side effects of hydroxychloroquine or reviewing the patient’s medication history for any other agents that might exacerbate cardiovascular problems, pharmacists can be valuable contributors, she noted.

Hype Versus Evidence President Donald Trump has been promoting hydroxychloroquine during press conferences, and the U.S. government has accepted millions of doses of the medication to the Strategic National Stockpile (bit.ly/2RAksZZ). But as noted, the drug’s efficacy data is a mixed bag, to say the least. In a French study of 20 patients who received 600 mg of hydroxychloroquine daily, the researchers concluded that the treatment was “significantly associated with viral load reduction/disappearance in COVID-19 patients,” particularly when combined with azithromycin ((Int J Antimicrob Agents 2020 Mar 20. [Epub ahead of print]. doi: 10.1016/j. ijantimicag.2020.105949). However, since the French study was published, it has been the subject of heavy scrutiny. As a result, the International Society of Antimicrobial Chemotherapy, which publishes the journal where the paper appeared, has flagged the paper, saying it did not meet its “expected standard” (bit.ly/2yY3xtY). “The take-home message is that it is not clear whether or not hydroxychloroquine with or without azithromycin reduces hospitalization duration, hastens [patients] becoming virus free, or prevents clinical deterioration,” said C. Michael White, PharmD, the department head and a professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs. It’s also not clear “how safe the use of hydroxychloroquine with or without azithromycin is in patients with COVID-19 infection,” Dr. White said. The potential side effect that worries him the most is QTc interval prolongation.

6 Steps for Safer Rx 1. Use no more than 600 mg per day of hydroxychloroquine in divided doses, and for no more than 10 days.

2. Review Mayo Clinic and ACC COVID-19 protocols for assessing QT prolongation and arrhythmia risk.

3. Consult physician and pharmacist ID specialists. 4. Avoid hydroxychloroquine in patients with a history of QTc interval prolongation. 5. Resolve hypokalemia and hypomagnesemia before use; use extra precautions in patients with renal dysfunction.

6. Have a therapy stop order for when QT prolongation exceeds 500 mseconds or rises more than 60 mseconds from baseline. ACC, American College of Cardiology

Researchers have reported cases of QTc prolongation among patients taking the drugs for other conditions, such as lupus ((J Clin Rheumatoll 2013;19[5]:286-288). Last year, the website Credible Meds added hydroxychloroquine to the list of medications known to increase the risk for torsades de pointes (bit.ly/3ceOXMP). Early warning signs for COVID-19 patients are already trickling in. One prepublication (sometimes called “preprints”) involving 84 patients reported

that 30% of those who received hydroxychloroquine and azithromycin saw their QTc value increase by greater than 40 mseconds. In 11% of treated patients, QTc increased by more than 500 mseconds, putting them at risk for arrhythmia, according to the researchers (bit.ly/ 2yZ0u4L). According to Bloomberg News, France has reported more than 40 heart incidents among COVID-19 patients who received hydroxychloroquine (bloom.bg/ 2ygV70b).

Can COVID-19 Hurt the Heart?

recent cohort study of COVID-19 patients from Wuhan, China, has given some experts pause: Nearly 20% showed signs of cardiac injury, and those who did were more likely to die (42/82 [51.2%] vs. 15/334 without cardiac injury [4.5%]; P<0.001) (JAMA Cardiol 2020 Mar 25. [Epub ahead of print]. doi: 10.1001/jamacardio.2020.0950). There are many potential mechanisms that might explain how the virus may damage the heart, according to C. Michael White, PharmD, the department head and a professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs. For example, COVID-19 enters cells via angiotensinconverting enzyme 2 (ACE2) receptors, which impedes their ability to convert ACE2 to angiotensin 1-7; too much ACE2 can lead to inflammation and heart problems. Alternatively, the virus may enter the blood cells and derange the hemoglobin so it doesn’t carry oxygen normally, causing systemic inflammation, he suggested. It’s too early to know whether the virus itself is to blame for patients’ cardiac injury, according to Marianne Pop, PharmD, BCPS, a clinical assistant professor and an emergency medicine clinical pharmacist at the University of Illinois College of Pharmacy in Rockford. For example, patients who experienced cardiac injury were more likely to have baseline cardiovascular comorbidities such as diabetes (24.4% vs. 12% without cardiac injury), hypertension (59.8% vs. 23.4% without cardiac injury), and heart failure (14.6% vs. 1.5% with no cardiac injury), according to the Wuhan investigators. And the researchers didn’t evaluate the treatments that patients received, “so we can’t know if they were given agents that might have induced the cardiomyopathy,” she said. “It is difficult to gain much from this study because there could be multiple reasons for cardiac injury (baseline morbidity, cardiac risk, hospital treatment, etc.). We won’t be able to identify a c clear correlation between COVID-19 and cardiac c injury until we are able to evaluate the outcomes of other patients worldwide.”

Cardiovascular side effects are more likely to occur with prolonged therapy at high doses, said Dr. White, so pharmacists should urge providers to stick with lower doses of hydroxychloroquine for no more than 10 days, and include a cardiologist in patient assessment and monitoring. “Therapy should not be used to prevent contracting COVID-19. This would result in long-term therapy, and there is no data on whether it would be effective,” he said. Pharmacists also should continue to do what they always do, Dr. Pop said: Take medication histories for any other medicines that might induce additional QTc prolongation, and make changes when warranted. Before hydroxychloroquine and azithromycin are prescribed, pharmacists can evaluate the patient’s baseline ECG for signs of QTc prolongation; once the treatment is over, pharmacists can help de-escalate therapy. Pharmacists also should keep an eye on the literature. On April 21, the National Institutes of Health issued treatment guidelines for COVID-19 that questioned whether data support the use of chloroquine or hydroxychloroquine, regardless of cardiac risk (bit.ly/2S2588K). “There are insufficient clinical data to recommend either for or against using” the drugs, the document stated.

Tech Can Help If a provider still is intent on prescribing anti-malarial–based regimens, Dr. Pop added a final suggestion: informatics pharmacists can help develop clinical decision tools, such as QTc prolongation risk scoring based on electronic health records, identifying patients considered to be low, moderate or high risk.

—A.M.

—Alison McCook The sources reported no relevant ﬁnancial relationships.

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INDICATIONS AND USAGE MORPHINE SULFATE INJECTION is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Morphine Sulfate Injection for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: have not been tolerated, are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia. IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS • Morphine Sulfate Injection exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2) • Prolonged use of Morphine Sulfate Injection during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4, 7)

MORPHINE SULFATE INJECTION is contraindicated in patients with: significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days, known or suspected gastrointestinal obstruction, including paralytic ileus, and hypersensitivity to morphine. Cardiovascular Instability: High doses are excitatory. Have Naloxone Injection and resuscitative equipment immediately available. Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Morphine Sulfate Injection in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Morphine Sulfate Injection in patients with impaired consciousness or coma. The most serious adverse reactions encountered are respiratory depression, apnea, circulatory depression, respiratory arrest, shock and cardiac arrest. Common frequently observed adverse reactions include: sedation, lightheadedness, dizziness, nausea, vomiting, constipation and diaphoresis. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, at 1-800-551-7176 option 5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Overdosage: Acute overdose with Morphine Sulfate Injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, snoring, and death. This important safety information does not include all the information needed to use MORPHINE SULFATE INJECTION safely and effectively. Please see full prescribing information, including Boxed Warning, for MORPHINE SULFATE INJECTION at www.simplist-us.com. Please see Brief Summary of Prescribing Information on the following page.

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BRIEF SUMMARY OF PRESCRIBING INFORMATION This brief summary does not include all the information needed to use MORPHINE SULFATE INJECTION safely and effectively. Please see full prescribing information for MORPHINE SULFATE INJECTION, including BOXED WARNING, is available at www.simplist-us.com. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Morphine Sulfate Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Morphine Sulfate Injection, and monitor all patients regularly for the development of these behaviors and conditions. Life-Threateningg Respiratory p y Depression p Serious, life-threatening, or fatal respiratory depression may occur with use of Morphine Sulfate Injection. Monitor for respiratory depression, especially during initiation of Morphine Sulfate Injection, or following a dose increase. Because of delay in maximum CNS effect with intravenously administered morphine (30 min), rapid IV administration may result in overdosing. Neonatal Opioid p Withdrawal Syndrome y Prolonged use of Morphine Sulfate Injection during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risks From Concomitant Use With Benzodiazepines p Or Other CNS Depressants p Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. • Reserve concomitant prescribing of Morphine Sulfate Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation. INDICATIONS AND USAGE Morphine Sulfate Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Morphine Sulfate Injection for use in patients for whom alternative treatment options [e.g., nonopioid analgesics or opioid combination products]: • Have not been tolerated, or are not expected to be tolerated, • Have not provided adequate analgesia, or are not expected to provide adequate analgesia

CONTRAINDICATIONS Morphine Sulfate Injection is contraindicated in patients with: • Significant respiratory depression. • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. • Known or suspected gastrointestinal obstruction, including paralytic ileus. • Hypersensitivity to morphine.

Other possible adverse reactions include: euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations and disorientation, constipation, biliary tract spasm, tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension, oliguria and urinary retention, pruritus, urticaria, skin rashes, opioid-induced histamine release (flushing of the face, diaphoresis, pruritus, and wheals and urticaria at the site of injection), androgen deficiency, anaphylaxis, serotonin syndrome, and adrenal insufficiency.

WARNINGS AND PRECAUTIONS (also see BOXED WARNING) • Cardiovascular Instability: High doses are excitatory. Have Naloxone Injection and resuscitative equipment immediately available. • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper. • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Morphine Sulfate Injection in patients with circulatory shock. • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Morphine Sulfate Injection in patients with impaired consciousness or coma. • Risks of Use in Patients with Gastrointestinal Conditions: Morphine Sulfate Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. • Increased Risk of Seizures in Patients with Seizure Disorders: Monitor patients with a history of seizure disorders for worsened seizure control. • Withdrawal: Use of mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. • Central Nervous System Toxicity: Dysphoric reactions may occur after any size dose and toxic psychoses have been reported. • Exposure, Hypothermia, Immersion and Shock: Caution must be used when injecting any opioid intramuscularly into chilled areas or in patients with hypotension or shock, since impaired perfusion may prevent complete absorption; if repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established. • Risks of Driving and Operating Machinery: Morphine Sulfate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Morphine Sulfate Injection and know how they will react to the medication.

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

ADVERSE REACTIONS Serious adverse reactions (see BOXED WARNING and WARNING AND PRECAUTIONS) associated with Morphine Sulfate Injection included, addiction, abuse, and misuse, life-threatening respiratory depression, neonatal opioid withdrawal syndrome, interactions with benzodiazepines or other CNS depressants, cardiac instability, adrenal insufficiency, severe hypotension, gastrointestinal adverse reactions, seizures, withdrawal, respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously. The most frequently observed adverse reactions included sedation, lightheadedness, dizziness, nausea, vomiting, constipation and diaphoresis.

USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm (see BOXED WARNING for neonatal opioid withdrawal syndrome). • Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Naloxone must be available for reversal for reversal of opioidinduced respiratory depression. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. • Lactation: Present in breast milk. Lactation studies have not been conducted and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Monitor infants for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of opioid analgesic is stopped, or when breast-feeding is stopped. • Females and Males of Reproductive Potential: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. • Pediatric Use: The safety and effectiveness of DILAUDID INJECTION in pediatric patients has not been established. • Geriatric Use: Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. Monitor for signs of central nervous system and respiratory depression. Start at the low end of the dosing range, titrate the dosage slowly and monitor for signs of CNS and respiratory depression. • Hepatic and Renal Impairment: Start these patients with a lower than normal dosage and monitor for signs of respiratory depression, sedation, and hypotension. DRUG INTERACTIONS Clinically significant drug interactions with Morphine Sulfate Injection: benzodiazepines and other central nervous system (CNS) depressants; serotonergic drugs; monoamine oxidase inhibitors (MAOIs); mixed agonist/antagonist and partial agonist opioid analgesics; muscle relaxants; cimetidine; diuretics; anticholinergic drugs; and Oral P2Y12 Inhibitors. OVERDOSAGE Acute overdose with Morphine Sulfate Injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose. In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Because the duration of opioid reversal is expected to be less than the duration of action of morphine in Morphine Sulfate Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished.

COVID-19 Pandemic 23

Pharmacy Practice News • May 2020

Pharmacists Respond to COVID -19:

An Army of Experts Needed Anthony T. Gerlach, PharmD, FCCM, FCCP

Debra Goff, PharmD, FIDSA, FCCP

Kerry Pickworth, PharmD, BCPS, AQ Cardiology

Mary Beth Shirk, PharmD, BCPS, FCCP

The Ohio State University Wexner Medical Center and College of Pharmacy Columbus, Ohio

nfectious diseases (ID) pharmacists and antibiotic stewardship programs (ASP) provide potent weapons for combating COVID-19 in hospitalized patients. However, an “army of experts” is needed to win the battle. We describe selected examples of how non-ID clinical pharmacists are stepping up to do whatever it takes to care for COVID-19 patients at The Ohio State University Wexner Medical Center, in Columbus.

Our ED pharmacists review discharge prescriptions, targeting high-risk medications and medications requiring follow-up coordination, such as colchicine or rabies vaccine. After hydroxychloroquine came front and center as a possible treatment and prophylactic regimen, we moved to add hydroxychloroquine to our list of discharge prescriptions to be reviewed.

Emergency Medicine

The ED pharmacists staffing model was adjusted to minimize our COVID-19 exposure, with a particular emphasis on promoting safe communications: • We limit face-to-face time with one another and all staff using a secure chat method within our electronic medical record as often as possible. • We use department-wide telephones and physical distancing when a discussion is necessary. • We switched to using hospital-owned iPads or the patient’s personal cellphone for patient–pharmacist counseling. This change not only limits staff exposure risk, but also minimizes use of personal protective equipment. • We engage as a full group on daily 30-minute calls.

Offset the Volume of Patients

The emergency department (ED) is the front door to our health system. Seven ED pharmacists and two ED residents work together to provide clinical pharmacy services for an 18-hour shift every day, from 7 a.m. to 2 a.m. Our health system’s first step in developing a COVID-19 preparedness plan involved working collaboratively with emergency medicine colleagues to establish a call center and drive-through COVID-19 testing stations. Not only do the call centers help answer COVID-19 questions from the public, they also divert patients from EDs to more appropriate locations for care. This enables the ED staff to better meet the growing demands of the COVID-19 pandemic. Similar to sandbags placed before a flood, these early initiatives will buy us time but won’t prevent the surge. Reevaluate the Medication Process

Whether a patient walks in or arrives via emergency medical services, very little is known about the patient. As such, a standardized approach to the initial triage is critical. All patients with COVID-19 symptoms and those with a respiratory complaint are placed in a designated section in our ED. We also assessed the need for changes to the automated dispensing cabinet inventory based on anticipated needs and location of COVID-19 patients to ensure critical medications are available near these patients.

Change ED Staffing And Communication

Emergency Response

Our pharmacists continue to provide 24/7 care for stroke, trauma, burn and cardiopulmonary arrest patients, many of whom may be infected with COVID-19. But we strive to provide that care with a buffer against exposure. For example, we now manage the crash cart from outside a patient room, when possible. However, sometimes exposure cannot be avoided. One such instance is when our staff has to assist with the transition of IV infusions from outside hospitals and infusion devices from transport teams to our own local devices. In these cases, pharmacists were refitted for N95 masks to ensure our protection.

Communicating COVID-19 Results to Patients

We worked with the ED medical director to ensure there is a process for notifying patients of both positive and negative COVID-19 test results. Because of the anticipated surge, we devised an alternative to the usual approach of having pharmacists handle the culture result callbacks. Instead, we requested standardized verbal scripting and written discharge instructions for patients on how to access their COVID-19 test results. This process change decreases calls from patients inquiring about their results coming to the ED pharmacist. Cross-Training Pharmacists

ED pharmacists will have frequent exposure to COVID-19 patients. These exposures may cause one or more of our team members to be “benched,” or quarantined at home. In response, we are cross-training pharmacists to provide emergency response pharmacy services. Our hospital canceled all elective surgeries to free up patient beds and free up pharmacists to cross-train.

Cardiology Cardiology pharmacists and PGY-2 cardiology residents worked with cardiologists to identify several cardiology issues, including risk factors for COVID-19. Managing STEMI Patients

We have shifted to thrombolytics as opposed to a trip to the catheterization lab for patients with ST segment elevation in myocardial infarction, or STEMI. The standard practice was to send patients directly to the coronary catheterization lab. After a recent statement from the American College of Cardiology, we shifted to thrombolytics for COVID-19 patients versus percutaneous coronary intervention to decrease exposure to the catheter laboratory staff, yet effectively treat STEMI patients. For the past 20 years, thrombolytics have had limited use in this setting due to the development of cardiac stents. So, our specialists worked to determine which thrombolytic to use, developed a checklist for use and provided education to staff for safe and effective treatment. Thrombolytics are preferred in the following order: tenecteplase, reteplase and alteplase, primarily due to ease of administration, which leads to decreased staff exposure to COVID-19 patients. Tenecteplase can be administered as a weight-based bolus over 5 minutes; reteplase is given

as a double-bolus 30 minutes apart; and alteplase can take as long as three hours to administer. Cardiovascular Risks Of COVID-19 Drug Therapy

Treatment of COVID-19 patients may include the administration of chloroquine or hydroxychloroquine. These older antimalarial drugs are associated with cardiovascular side effects, including QT prolongation, as noted in several published case reports ((J Clin Rheumatol 2013;19[5]:286-288; Clin Toxicol (Phila) 2006;44[2]:173-175), along with more recent online warnings (see article, page 20). So, one of our cardiac specialists worked with our cardiac electrophysiologists to develop monitoring criteria for COVID-19 patients receiving these drugs. Now, when the drugs are ordered, ECG monitoring is put in place to assist in protecting patients from potentially fatal arrhythmias. Code Blue for Inpatients

As part of the code team, pharmacists are responsible for obtaining and drawing up emergency medications from the code cart, as dictated by the code leader. To minimize exposure to members of the code team, our specialist assisted in designing an airborne-isolation code blue kit, which is attached to the backboard of the crash cart. This bag contains the first few advanced cardiac life support medications (epinephrine, atropine and others) that would be given during the initial minutes of an arrest. The medication bag can be taken into the room with the initial responders while the pharmacist remains outside with the crash cart. This strategy not only decreases the exposure of the pharmacist but also decreases the need for all code responding pharmacists to be fitted for N95 masks, leaving more protective personal equipment (PPE) for the medical staff who are in direct contact with the patient.

Critical Care Critical care pharmacists are on the front lines managing critically ill patients with COVID-19. As such, we have taken several steps to reduce their exposure as much as possible while still meeting the needs of patients. see ARMY OF EXPERTS, page 24

24 COVID-19 Pandemic

Pharmacy Practice News • May 2020

ARMY OF EXPERTS

Cod Co de Bllu de ue Re Resp ponse e in th the e IC CU

continued from page 23

Staffing Issues

Ten critical care pharmacists and two PGY-2 critical care residents provide clinical pharmacy services for patients in the surgical ICU, medical ICU and neuro-ICU. We followed the physician model to decrease the number of health care providers on rounds. We now have two pharmacists on site, and the others work remotely. We developed an on-call schedule for consults and questions.

We devel W elloped d a suppl pll plementa t l code d de blue kit to limit exposure of code blue carts in patient rooms. In addition, we developed a specific code blue pharmacist response for patients with suspected or confirmed COVID-19. Most notably, these pharmacists were fitted for and obtained N95 face masks. ICU Medication

The critical care pharmacy team has been working with our multidisciplinary critical care teams (physicians,

ad dva vanc nced d practtic ice pr prov ovid id der ers, s,, nur urse ses, se s,, diettit di itia i ns, respir ia iratory t th herapis i ts is t ) and d ID pharmacists to provide COVID-19 COVID 19 treatment algorithms. Specifically, we have provided guidance in sedation and analgesia. COVID-19 patients may require increased use of neuromuscular blockade, and sedatives are expected to be on shortage. We expanded our protocols to potentially increase the use of ketamine as well as use enteral agents when appropriate. In addition, we developed a guide for medication administration times to

asssi sist st wit ith h co cons nsollid dattion ion off med dic i at atio ion n ad dmini ini nisttrati tion i to pati tients i t wit ith it h suspectt ed or confirmed COVID-19, COVID 19 to reduce nurse exposure and the use of PPE. End-of-Life Care

The critical care pharmacy team has worked with the palliative care team to develop a COVID-19-specific end-of-life pathway. That process was based on existing pathways that our pharmacists worked to expand. One of the additions involved expanding the use of certain analgesics and sedatives due to potential drug shortages. A pathway for subcutaneous phenobarbital for proportional sedation also was developed.

Pharmacy Residents We have more than 30 pharmacy residents whose residency training has been disrupted. However, in this time of disruption, several other opportunities have emerged.

Choose the Amgen difference

HISTORY

Volunteer Opportunities

Testing for COVID-19 presented many challenges. Once hospitals were cleared to use a variety of methods, our microbiology supplies were dwindling. Under the guidance of the microbiology laboratory, pharmacy residents package individual viral testing kits. Specifically, they drew up an aliquot of viral media into individual test tubes and packaged with swab and other supplies to allow laboratory staff to spend more time on testing.

of reliable supply1

Screening of Visitors And Health Care Providers

Broad nationwide coverage:

100%

of Medicare Part B lives3 and

of commercially insured patients pay $0 OOP costs per dose of Neulasta® Onpro®2,*

93%

*Data based on quarterly SHS medical claims data of 20,862 commercial medical claims collected at the national level between January 2017 and December 2017. Physician service claims and hospital claims were included in this analysis. Neulasta® OOP is calculated using the sum of deductible, V «>Þ] > ` V ÃÕÀ> Vi >vÌiÀ Ì i w > «>ÞiÀ has paid their share of the cost. Each claim represents a single dose of Neulasta®.2

v V iÀV > Li iwÌ ÛiÃ V ÛiÀi`3

Learn more about Neulasta® Onpro® by visiting Ì i vwV > ÜiLÃ Ìi\ www.neulastahcp.com References: 1. Data on file, Amgen; [1]; 2018. 2. Data on file, Amgen; [1]; 2019. 3. Data on file, Amgen; [2]; 2019. OOP, out of pocket; SHS, Symphony Health Solutions.

Residents are assisting with screening of visitors and employees, checking temperature and symptoms of COVID-19 before these people enter the hospital. In addition, they assist at the COVID-19 call center, where they help answer questions from the public and health care providers. Communication Skills

One resident is responsible for writing a daily COVID-19 update email for the entire pharmacy department. This email covers multiple topics that change from day to day. Topics include drug shortages, staffing issues, managing stress, number of COVID-19 inpatients and COVID-19 policies. When drug shortages occur, a team of specialists meets to determine how to deal with the shortage. Input from purchasing, drug information and clinical specialists will identify alternative agents and help us to develop guidelines. While the COVID-19 global pandemic is unfolding, the challenges faced by pharmacists also are unfolding. The weeks ahead will take us to uncharted waters. Our pharmacy department has “all hands on deck,” ready to provide care to COVID-19 patients. ■

COVID-19 Pandemic 25

Pharmacy Practice News • May 2020

Innovative drug purchasing, clinical consults are key during crisis

Ochsner Draws on Its Preparedness Past

ew Orleans, which has faced devastating hurricanes and floods, has become one of the nation’s leading hot spots for COVID-19. The challenges faced in those earlier disasters may be one reason why Ochsner Health, Louisiana’s largest health system, was ready for the worst when the first COVID-19 patient was admitted on March 11, 2020. Then the worst became a reality. By early April, the number of COVID-19 hospitalizations had increased to nearly 900. It continued to rise but now is decreasing. The average ICU length of stay for COVID-19 patients was reported on April 2 to be 12 to 14 days, more than three times the typical ICU stay. An overwhelming amount of those intensive-care patients required mechanical ventilation for acute respiratory distress, according to the health system. Even with advanced preparations, Ochsner worked tirelessly to meet the rising demand for more ICU beds, ventilators, personal protective equipment, and clinical and support staffs. The health system reached out, often across state lines, to recruit additional nurses and respiratory therapists and to redeploy staff, and the pharmacy worked to provide remote pharmacy support. Licensing standards were relaxed to allow students who had completed their clinical education to begin working immediately. “We had our staff [contact] friends who had moved out of state,” said Deborah Simonson, PharmD, the vice president of pharmacy services at Ochsner Health. Retired pharmacists were contacted and asked to perform remote duty on an as-needed basis. A critical care pharmacist in California, who had worked at Ochsner, called to say she wanted to help and was immediately hired to do clinical consults remotely. “We have been impressed with the Louisiana Board of Pharmacy’s leadership and support to allow for novel models of care to ensure we could take care of patients,” Dr. Simonson said.

Multitasking a Must The remote pharmacy team that came together not only conducted clinical consults, but also handled order verifications, patient education and medication histories. They also fielded questions from nurses and physicians on the front lines. Their efforts took the burden off pharmacists who were struggling to keep up with the rising demand for critical care and ventilator-associated drug infusions. Some ventilator drugs were in short supply. “We used significant amounts of critical medications, including fentanyl,

in a very short amount of time and at a much faster rate than our normal rates of use, ” Dr. Simonson said, adding that she spent hours on the phone with numerous contacts before she was able to get the Drug Enforcement Administration’s cap on opioids lifted. Even with the cap eased, the call for ventilator-related sedation and analgesia drugs in other COVID-19

hot spots had begun to squeeze the national supply, as Vizient tracking studies have shown (see story, page 1). Adding to the pressure, Dr. Simonson said, was the need for daily calls to Ochsner’s wholesaler to address significant challenges with traditional allocation models. The usage of many drugs was exponentially higher than historical rates, so Ochsner worked

wiith w th h Ca C rdin rd din i all Wh Whol ollesal ale to add dre ress ss procurementt ch hallle l nges and d devellop solutions l ti for f medication di ti access for f COVID-19 hot spots. Being a member of CivicaRx, Dr. Simonson said, “made a huge difference” in filling supply gaps. One example was fentanyl, which she said remained “very difficult to get.” However, CivicaRx could only supply 2- and 5-mL vials of the opioid, not the 50-mL vials that were needed to make infusions for ventilated patients. “That see OCHSNER’S PLAN, page 47

Pharmacy Practice News • May 2020

CORPORATE SPOTLIGHT

American Regent Can Make a Difference Providing Rapid Response to Market Disruptions Manu Ma nufa nu fact fa ctur ct urrin ing g co comp mp mpli pli lica icati ca ati tion o s. Log on ogis isti is tica c l an and d re regu gula lato tory ry cha hall llen enge ges. s. Lac ack k of acc cces esss to raw ra w ma ate t ri rial alls. The a hese s are se e jus ustt so some me of th t e ca caus u es of th us the e dr drug ug sho hort rtag age e cr cris isis is tha hatt hass b ha be ee en n wo orrse seni ning ni ng ove verr th t e la ast dec ecad ade. ad e. At Am e. Amer eric er ican an Reg egen ent, t, we un unde ders rsta tand nd tha hatt pati pa tien ti ents en ts s canno an nno nott af affo ford fo rd d to wa wait it for the cri riti t ca ti c l me medi d ca di c ti tion onss th they ey nee eed. d. Amer Am erric ican an Re eg gen entt is a U.S..S S.-ba -ba base sed, se d, top 10 prrov de vi derr of hig ghh qu ual a it ity y st ster eril er i e in il inje ject je ctab ct able ab les, le s, as we w lll as the two lea adi ding ng bra ng and nded ed d IV ir iron o the on hera rapi ra pies pi es.. Fo es Forr over ov e 50 ye er year ear ars, s, we ha have ve e bee een n de d di dica cate ca ted te d to set etti t ng ti a hi high gher gh err sta e tand ndar ard ar d fo forr re resp spon sp on nsiive vene ness ne ss and rel e iabil ab ilit ity it y by qui uick ckly ck ly and con o si sist stten e tl tly y ma manu nufa nu fact fa ctur ct urin ur i g in h gh hi h-q -qua ua ali l ty pro rodu duct du cts. ct s. We wo w rk to co comb mbat mb at dru rug g shor sh orta or tage ta gess by ge by rem emai a ni ai ning ng com mmi mitt t ed tt e to tth he Fo Four ur Pill Pi llar ll arss of our org ar gan aniz iz zat ation: atio io on: n Spe p ed ed,, Fl F ex e ib bil i ity, ity, it y, Re elli-abil ab i it il ity y an nd Qu Q al alit ity. it y.

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erss ca er carr rryi ying ng our pro rodu duct c s na ct nati tion onwi wide de, Am A er eric ican an n Rege Re g nt is ab ge ble resspo p nd nd to sh shor orta or tage ta gess wi ge with th spe peed ed.. ed

Flexibility W en sup Wh uppl ply y di disr srup upti tion onss or or cha hang n es in ma ng mark rket rk et need ne ed cal alll fo forr im imme me edi diat ate, e, cor orre re esp spon ondi on d ng cha di hang ng ges in pro rodu d ct du ctio ion, n Ame n, meri r ca ri can n Re ege gent nt’s ’s man anuf uffac ctu turring in g pr prac acti ac t ce ti c s ma make ke us re read a y an ad and d ab able le to me meet et the th e ch hal a le leng ng ge he head ad-o ad -on. -o n Our n. u sho hort rt sup uppl ply pl y ch chai ain ai n and an d bu uil iltt-in tin man anuf ufac uf actu ac turi tu ring ri ng red edun unda anc cie iess al allo low lo w

us to in init itia it iate ia te or in incr crea cr ease ea se pro rodu duct du ctio ct ion io n on hig ighh-in hin inndema de mand ma nd inj njec ec cta tabl bles e . es We hav ave e bu buil iltt a gr il grea eatt de ea deal al of fl flex exib ex ibil ib ilit il ity it y in into to our manu ma nufa nu fact fa ctur ct urin ur in ng op oper erat er atio at ion io n an and d we hav ave e do done ne so by appr ap prop pr opri op riat ri atel at e y ma el mana nagi na ging gi ng the siz ize e of our bat atch ches ch es.. es We pro rodu duce du ce sma mall lll bat atch ches ch es tha hatt ar are e si size zed ze d to fil illl acro ac ross ro ss two filll sh shif iffts ts—w —we —w e ar are e ab able le to pr prep epar ep are ar e a prod pr oduc od uctt in one uc n day and n com omme menc me nce nc e ma manu nufa nu fact fa ctur ct ur-ur ing in g th the e fo f ll llow ow owin win ng da d y an and d we cou ould ld cha hang nge ng e at a mome mo ment me nt’s nt ’s not otic ic ce. Thi h s pr proc oced oc edur ed ure ur e ca can n al also so mit itiigate ga t sho te h rt rtag ages ag es tha hatt ma m y be cau ause s d by sit se itee-sp espesp ec fi ci fic c issu isssu sues es.. In ad es dd diittio on, our bui u ltt-i -in n re redu dund du ndan nd an nci c es en enab nab able le e us to o inc ncre ncr rease asse o ou utp tput u on ne ut ece cess ssar ss ary ar y dr drug ugss ug with wi hou out ut in nte terr rrup upti up ting ti ng pro ng odu d ct ctio io on or sup ppl ply y fo forr ou ourr othe ot herr ge he gene neri ne r c in nject je ect c ab ble es. s.

Reliability At Ame eri r ca can n Rege Re ege gent n , we und nder erst er stan st and an d th the e im mpo porrt nc ta nce e of of sup uppl ply pl y co cont n in nt inui uity ui ty.. To ens ty nsur ure ur e th that att we prov pr ovid ov id de th the e ma mark rket rk et witth a co cons nsis ns iste is tent te nt sup uppl ply pl y of ourr ge ou gene neri ne ric ri c in inje ject je ctab ct able ab les, le s, Ame s, meri rica ri can ca n Re Rege gent ge nt kee eps a rese re serv se r e st rv stoc ock oc k off pro oduct ducts du cts on han ct and d fo forr em emer erge er genc ge ncy nc y

situ situ uat atio io ons ns,, li like ke dru rug g sh shor orta or tage ta ges an ge ges nd wi will lll arr rran an nge g drop dr op p shi h pm pmen e ts as ne en ece cess ssar ss ary. ar y. Thi y. h s he elps lp ps us to re reli lli ably ab ly y res espo ond to pr prov ov ovid vider id der ers’ s nee s’ eeds d dur ds urin ing in g ma mark rket rk et d sr di srup upti up t on ti ons, s mak s, kin ng itt les esss liike kely ly tha hatt th they ey y willl ha have ve to o mak ake e su ubs bsti titu ti t tiion tu onss orr use sta tand n -i nd -in n th t er e ap apie ies. ie s. Curr Curr Cu rren en ntl tly, y, Ame meri rica ri can ca n Re Regent Rege gent has the cap ge a ac a itty to o prod pr oduc od uce uc e ap appr prox pr o im ox mat atel e y 70 el 0 mil illi lion li ion uniitss per ye ea ar— ar— ourr $2 ou $200 00 mil illi lion li on inv nves estm es tmen tm entt in en into to mod o er erni erni nizi ziing and z ex xpa p nd din ing g ou ourr U. U.S. S -b S. -bas ased man as anuf ufac uf actu ac turi tu rriing fac a il ilit itie it ie es will wi ll dou oubl ble bl e ou o r ca c pa p ciity ty.. Th This is exp xpan an ansi nsi s on wil illl a allso allo al lo ow us to bu b il ild d mo ore e red edun unda un danc da nc cie es an and d co cont ntin nt in-in genc ge ncie nc iess in ie into to o our u sys yste tems te mss hel elpi ping pi ng g to en ensu su ure tha hatt we alw lway ayss ha ay h ve a ste tead ady su ad upp p ly of th the e pr p od oduc ucts uc ts ourr cu ou ust stom om omer mers ers need ne eed d.

Quality A co Ac cord rdin rd ing in g to o th he e FDA DA,, Am Amer eric er ican ic an man anuf ufa uf actu ac turi ring ng s tte si es sc scor ored or ed sta ed tati tist ti stic st ical ic ally al ly y hig ighe herr in terrms he ms of qu q al alit itty than th an n did d glo loba ball si ba site tes. te s.3 Ame meri rica ri can ca n Re Rege gent ope ge p ra ate tess seve se vera ve r l ma ra m nu nufa fa act ctur urin ur ing in g fa faci cili ci liti li ties ti es,, al es alll of o whi hich c are ch loca lo cate ca ted te d in the Uni nite tte ed St Stat ates at es.. Wi es W th the wid de ma majo jorjo ritty of o our man anuf ufac uf actu ac turi tu ring ri ng occ ccur urri ur ring ri ng in th the e Un U itted Stat St ates at es and the e bul ulk k of our act ctiv iiv ve ph phar arma ar mace ma c ut ce utic ical ic all ingr in grred gred e ie ient ntss sso nt ou urrce ced d in i the Uni nite ted te ed Stat Stat St ates ess, Am es, Amer e ic er ican an Rege Re gent ge ntt und nder e sttan a ds d the e imp m or orta tanc ta nce e of qua uali lity li t . Ourr pr Ou prod od du uc cts are e sub bje ject c to rigo ct riigo goro ro ous us tes esti ting ti n , and an d ou ourr ex xte tens nsiv ns ve or orga ga ani n za z ti tion o al and qu on ua alliity ty cont co ntro nt roll sy ro yssttem emss en ensu sure su re tha hatt we are e mee eeti ting ti ng the he high hi igh ghes estt qu es qual a itty st al s an a da d rd rds. s Our sta s. t te te-o -o off-th theth e ar eartt tech te chno ch nolo no logi lo gies gi es hel elp p to o sig gn niifi fica cant ca nttly y limit im mit i the amo moun untt un of hum uman an int nter erac er ac cti tion on inv nvol ollve ved ed wi w th h man anuf ufac uf actu ac turi tu ring ri ng comp co mple mp lex le x st s er eril ile il e in inje ject je ctab ct ab able ble es. s. At Ame merri rica rica can n Re Rege g nt ge nt, t, we we und der e st stan and an d th that at pro r vide vi ders de rs hav ave e en enou o gh ou h to wo worr rry rr y ab bou outt wh when e it co en come mess me to o mee eeti ting ti ng pat a ie ient n nee nt eds d . Th Ther e e ar er are e do osa s ge g s to conf co nfig nf igur ig ure, ur e tim e, me li line ness to fac ne acto tor, to r and r, n costs ossts ts to ca callcula cu late la te e. Sh Shou Shou ould ld d the ava vail ilab il abil ab ilit il ity it y an and d qu qual alit al itty of the nece ne c sssar ce a y, lif ifes fes e av avin ng drrug ugss th they e nee ey eed d re eal ally ly be an add dit i io onal na al co conc n er nc ern? n? Rem mov ve do doub ubt ub bt fr from o the om h equa eq ua ati tion on.. Ch on Choo oose oo se Ame meri rica ri can ca n Re ege gent ntt. Wi n W th our stat st ateat e-of eof-t of -the -t he-a he -art -a rt fac acil ilit il itie it ies, ie s, man anuf u ac uf a tu turi r ng red edun un u ndanc da ncie nc ie es, sho hort rt sup uppl ply pl y ch chai ain ai n an and d sa same me e-d -day ay del ay eliv iver iv ery er y capa ca pabi pa bili bi liti li ties ti es,, ou es ourr wo work rk add ddss up p to hi high g -q gh -qua uali ua liity t , gene ge nerri ne ric in ric nje ject ctab ct able ab le pro rodu duct du ctss an ct and d IV iro ron n th ther errap pie es, supp su ppor pp orte or ted te d by the Fou ourr Pi Pill llla arrs of o our org rgan gan niz izat zat atio ion: io n: Sp pee eed, d, Fle lexi xibi xi bili bi lity li ty,, Re ty Reli liab li abil ab illit ilit ity y an and d Qu Qual alit al iitty. y.

References 1 1.

More tha than n 99% 99% of uni un ts manuf manuf anufactu actured actu red in 2018 2018 8 were man m ufac uff cufa tured ture d in Ame m rica me ica wit with h remain remain a ing in ng unit un vol vo o ume u com comi om ng g from m Canada and Fran France. ce ce.

2 2.

Data on File File.. S Shirle Shirle rley, y, NY: NY:: Ameri Ameri merican can Rege Reg eg nt, n Inc. nt nc

3. 3.

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28 Clinical

Pharmacy Practice News • May 2020

ASHP Clinical Pearls

Pharmacists shine in managing hypoglycemia, cardiovascular disease and AML

Making Glucagon Less Scary, and Other Practical Tips Medicine changes rapidly. Pharmacists have to stay current to keep up with emerging medications and new side effects their patients may experience. At the ASHP 2019 Midyear Clinical Meeting, pharmacists presented the latest data on several clinical advances, including new forms of glucagon that make it easier for caregivers to save someone with life-threatening hypoglycemia; a new tool to curb exacerbations in chronic obstructive pulmonary disease (COPD); and the warning signs of a new adverse effect associated with a type of treatment for leukemia. Treating Hypoglycemia Just Got a Whole Lot Easier Recently, Diana Isaacs, PharmD, a clinical pharmacist and diabetes care and education specialist at Cleveland Clinic in Cleveland, counseled a man who developed diabetes secondary to pancreatitis. After Dr. Isaacs learned the man was experiencing unpredictable hypoglycemia, she recommended that he obtain a prescription for glucagon. That way, if his blood sugar got so low that he couldn’t eat anything—putting him at risk for seizure or passing out— his wife could administer the lifesaving medication. But she refused. “No way,” the patient’s wife told Dr. Isaacs at the appointment. “I can’t do that in that situation. I’m just going to call 911.” Dr. Isaacs couldn’t blame her. To administer glucagon, the patient’s wife would have to get the glucagon powder, mix it into a liquid, shake the formulation, draw it up in a syringe, and inject it right away—all while her husband is fighting for his life and every lost second could result in brain damage, coma or death. “That’s really asking a lot,” Dr. Isaacs told meeting attendees. But, the treatment landscape for hypoglycemia has changed with two new formulations of glucagon now available that are much easier to administer. One product, Baqsimi (Lilly), a nasal powder that is stable at room temperature, comes ready to use. It can be sprayed into a patient’s nose and doesn’t require inhalation, so it works even if the patient is unconscious (www.baqsimi.com/). “It’s simple and easy to use,” Dr. Isaacs said. A 2017 study of patients who experienced severe hypoglycemic episodes showed that when caregivers and acquaintances had access to nasal glucagon, more than 90% administered it correctly, something managed by only 13% of caregivers using the traditional injectable formulation of glucagon ((Diabetes Technol Ther 2017;19[7]:423-432). The second new formulation of glucagon is Gvoke (Xeris), a prefilled syringe or pen that’s also stable at room temperature. “Think of it like an Epipen [epinephrine, Mylan],” Dr. Isaacs said.

“Easy to use, works very quick kly, and a person is safe.” Phase 3 trials have shown that the new auto-injector was as effective as traditional glucagon, according to oral and poster sessions at the American Diabetes Association’s 78th Scientific Sessions,, June 22-26, 2018. These two new products are potential game changers in th he field, agreed Bruce Canaday, PharmD, mD, the dean emeritus and a professor at the St. Louis College of Pharmacy, who moderated the clinical pearls session. For one, he said, it may change how patients and providers think about glucagon, which has largely been used only in health care settings because it’s so difficult to administer. “If we could make this available and you couldn’t screw it up, would we use it more? I think the answer is yes,” he told Pharmacy Practice News. As a consequence, the community will have to define under what circumstances patients should use glucagon. Noting that more than 10% of people in the United States have diabetes, Dr. Isaacs said that nearly every pharmacist can benefit from this new hypoglycemia treatment. “Regardless of any area you’re practicing in,” she said, “you’re going to see diabetes.”

A New Tool to Guide COPD Treatment Decisions For patients with COPD, controlling exacerbations is a main priority. Providers now have a new way to help predict which patients will respond to more aggressive therapy with inhaled corticosteroids: eosinophil count. “We see by and large, increasing eosinophil counts indicates responsiveness to inhaled corticosteroids,” Nathan Pinner, PharmD, an associate clinical professor in the Department Pharmacy Practice at Auburn University Harrison School of Pharmacy, in Alabama, told meeting attendees. Last year, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) released an update to its guidelines that introduced providers to the

concept of using blood eosinophil count as a biomarker to predict how well inhaled corticosteroids will work to prevent exacerbations. In short, the higher a patient’s eosinophil count, the less likely monotherapy will work. According to the GOLD guidelines, patients with blood eosinophil levels below 100 cells/mcL probably won’t benefit from inhaled corticosteroid

Center, in Birmingham, Ala. This concept may be relatively new to more seasoned pharmacists, who were taught that eosinophils were linked to allergic-type diseases, Dr. Canaday said. Hearing that this metric can guide practice with COPD and is included in the GOLD guidelines may news to some, he said. Data about patients’ eosinophil counts can be useful to pharmacists working in a

therapy, but once eosinophils rise to higher than 300 cells/mcL, that additional therapy is most likely to have an impact. There is not enough evidence to predict whether eosinophil counts, on their own, predict the risk for exacerbations (goldcopd.org/wp-content/ uploads/2018/11/GOLD -2019-v1.7FINAL-14Nov2018-WMS.pdf ). When deciding whether patients can be weaned off inhaled corticosteroids, that’s slightly more complicated, Dr. Pinner noted. If patients have eosinophil counts above a certain level (300 cells/mcL at baseline, according to GOLD guidelines), withdrawing their inhaled corticosteroids could increase the risk for exacerbations, he noted. Alternatively, if a patient has relatively few exacerbations and the blood eosinophil count is low, “the inhaled corticosteroid probably is not benefiting that patient and can be safely withdrawn,” said Dr. Pinner, who also is a clinical specialist at Princeton Baptist Medical

hospital setting and help guide their conversations with prescribers about when to escalate therapy, Dr. Canaday noted.

Icosapent Ethyl To Protect the Heart Despite major advances in the field, cardiovascular disease remains a killer nationwide. It has been particularly challenging to protect patients with elevated triglycerides from cardiovascular events and death. This has led to several trials evaluating compounds, such as components of fish oil, as add-ons to statin therapy to help patients with elevated triglycerides. In January 2019, results from one of those trials, REDUCE-IT, showed that patients with elevated triglycerides who took the omega-3 fatty acid icosapent ethyl (Vascepa, Amarin) along with their statins had a lower risk for ischemic events—including death from cardiovascular causes—relative to patients on placebo. Specifically, during the

Clinical

Pharmacy Practice News • May 2020

ASHP Clinical Pearls Amarin-sponsored trial, 17.2% of the treatment group experienced the composite primary end point event of cardiovascular death, stroke, myocardial infarction, coronary revascularization or unstable angina, compared with 22.0% in the placebo group (hazard ratio, 0.75; 95% CI, 0.68-0.83; P<0.001) ((N Engl J Med d 2019;380[1]:11-22). “This is the first add-on therapy showing we can reduce the risk for death from cardiovascular causes with another treatment for dyslipidemia, specifically [high] triglycerides,” said Matthew P. Lillyblad, PharmD, a clinical

pharmacy coordinator in cardiology and critical care at Allina Health’s Abbott Northwestern Hospital, in Minneapolis. “So, this is an exciting advancement when we talk about mitigating the risk of cardiovascular disease.” Icosapent ethyl has a “pretty reasonable adverse effect profile,” Dr. Lillyblad told meeting attendees. The compound is pure eicosapentaenoic acid. However, patients treated with icosapent ethyl had a higher chance of being hospitalized for atrial fibrillation or flutter compared with those given placebo (3.1% vs. 2.1%; P=0.004), “which came as a surprise,” he said. Icosapent ethyl also was associated with a higher risk for serious bleeding events (2.7% vs. 2.1%; P=0.06). “It’s early on, so we still have a lot to learn about the drug.” The idea of icosapent ethyl and its derivatives as a potential treatment for heart disease has been around for a while, with mixed opinions, Dr. Canaday told

Pharmacy Practice News. “People said this is very expensive fish oil,” he said. But the REDUCE-IT trial may change some of those opinions. “These data begin to suggest that there may be more benefit from this than taking a couple of fish oil capsules per day,” Dr. Canaday said. “And this is exciting and intriguing news, because it’s pretty low risk.”

Psst: Don’t Forget About Propylene Glycol There is a hidden danger lurking in many medications that is easy to overlook: propylene glycol. Used to solubilize

many common medications, propylene glycol has been classified as “generally regarded as safe (GRAS)” by the FDA, but the World Health Organization has suggested a daily limit of 25 mg per kilogram of body weight (bit.ly/3cFb3Ze). For many patients, that limit is all too easy to reach, according to Martha J. Roberts, PharmD, a clinical pharmacist at Kent Hospital, in Warwick, R.I. In the ICU at Kent Hospital, as in most ICUs, patients can receive many IV medications that contain propylene glycol, such as diazepam, digoxin, etomidate, lorazepam and phenytoin. It’s not only injectables that pose risks, she added. Propylene glycol is present in lorazepam intensol, diazepam intensol and amprenavir, and is a component of some dosage forms of oral rifaximin and silver sulfadiazine cream, used for burn patients ((JAMA 1985;253[11]:1606-1609). “An increasing number of ICU patients are dealing with drug and alcohol detox and are often given multiple

doses of lorazepam,” Dr. Roberts said. “Pharmacists and other providers need to be alert to signs of potential toxicity from propylene glycol, such as hyperosmolar metabolic acidosis, renal dysfunction, seizures and central nervous system depression.” Dr. Roberts often reviews patients’ medication lists for all potential sources of propylene glycol and estimates each patient’s total daily intake based on the amount of propylene glycol listed on labels. “There are reports of lorazepam doses as low as 1 mg per kilo per day precipitating toxicity,” she said. “We’ve known that propylene glycol is in things, and known it’s a problem,” Dr. Canaday told Pharmacy Practice News. “I think it’s a good idea to call it back to people’s attention.” Part of the reason propylene glycol may have fallen off of pharmacists’ radars, he said, is that the symptoms of overexposure are so general; it’s pretty common for an ICU patient to develop metabolic acidosis, renal dysfunction or seizures, and providers may not trace these back to pr propylene glycol. But pharmaciists who trained decades ago will definittely be familiar with the risks associated d with propylene glycol, he noted. For in nstance, when Dr. Canaday worked as a hospital ph harmacist, he and his ccolleagues would swap th he diluent that came wiith chlordiazepoxide with saline when administerring it intravenously to reduce patientss’ exposure to propylene glycol. For patients you suspect have propylene glycol to oxicity, Dr. Roberts recommended obttaining serum osmolality, arterial it t i l blood bl gases and lactate, and changing therapy as needed to remove or replace drugs that contain propylene glycol. “With some patients, it may be as easy as transitioning from IV to oral lorazepam,” she said. The best advice, said Dr. Canaday: Keep the risks for propylene glycol toxicity on your radar. “I think it’s something that people don’t think enough about.”

New Drugs, New Side Effects The many new oncology medications available means patients have more options than ever before—and pharmacists have to anticipate more potential adverse effects. A new class of drug treats a form of acute myeloid leukemia (AML) by promoting healthy differentiation of blood cells. As a result, explained Donald Moore, PharmD, a pharmacist clinical coordinator in hematology/oncology at Levine Cancer Institute in Concord, N.C., these agents also can put patients at risk for differentiation syndrome (DS), with potentially life-threatening results.

DS typically was associated with other differentiating agents used to treat acute promyelocytic leukemia (APL), but providers now are seeing cases in patients with AML. Approximately onefifth of patients with AML have somatic mutations in the IDH 1 and 2 genes coding for isocitrate dehydrogenase ((Future Oncoll 2018;14[10]:979-993) and, therefore, can be treated with the new IDH inhibitors ivosidenib (Tibsovo, Agios) and enasidenib (Idhifa, Celgene). These oral agents, taken in the ambulatory setting, put patients at risk for DS by sparking a rapid maturation of white blood cells, potentially causing a cytokine storm, Dr. Moore explained. “Their mechanism of action in how they treat leukemia can really explain how they can cause this side effect.” As the effect of the cytokine storm reaches organ systems, patients develop the symptoms of DS, including fever, peripheral edema, dyspnea and acute renal failure, he noted. Studies have estimated that 3.9% of patients taking ivosidenib and 11.7% of those taking enasidenib develop DS ((N Engl J Med d 2018;378[25]:23862398; JAMA Oncoll 2018;4[8]:1106-1110). Although the risk for DS with differentiating agents for APL, such as all-trans retinoic acid and arsenic, is highest within the first two weeks of therapy, DS can occur weeks or even months from the start of therapy with the IDH inhibitors, Dr. Moore said ((JAMA Oncol 2018;4[8]:1106-1110). It can be challenging to identify DS because it produces “relatively nonspecific signs and symptoms,” Dr. Moore noted. So, any pharmacist with a patient on an IDH inhibitor presenting with potential symptoms of DS should “keep DS high on their differential.” Once you suspect DS, consider dexamethasone and hemodynamic monitoring, and watch for other conditions that may mimic DS, such as pneumonia, Dr. Moore said. “It’s really a diagnosis of exclusion, and/or based on a constellation of clinical findings,” he said. “This is potentially fatal if left untreated. So, patients do need to be thoroughly educated to immediately report any signs of symptoms.” Oncology pharmacists will play a key role in helping patients understand DS, Dr. Canaday said. They are the ones most likely to educate patients about specific signs and symptoms when patients pick up their medications, and they may be the first to notice that something is wrong. “A patient might just report feeling bad,” he added, “so oncology pharmacists will have to ask some really good, well-directed questions to diagnose DS.” —Alison McCook None of the presenters reported any relevant ﬁnancial relationships.

30 Clinical

Pharmacy Practice News • May 2020

ASHP Medication Safety Pearls

Strategies to Mitigate Errors and Improve Safety Medication safety remains a major pain point in health care, and pharmacists are uniquely positioned to help reduce and prevent medication errors. In a session at the ASHP 2019 Midyear Clinical Meeting, pharmacists shared tips on optimizing IV workflow solutions, improving pediatric transitions of care, applying pharmacogenomics, implementing biosimilars, and more to help reduce medication errors within health systems.

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macy workflow in the inpatient setting. “When it comes to technology, we do a good job with barcode scanning, [BD] Pyxis machines, and incorporating [computerized prescriber order entry (CPOE)] prescribing for physicians, but IV workflow technology is not well utilized or implemented across the United States,” said Michael C. Dejos, PharmD, RPh, a system medication safety officer at Methodist Le Bonheur Healthcare, in Memphis, Tenn., and an immediate past chair of ASHP’s medication safety advisory group. Successfully integrating workflow solutions requires technology that can interface with existing technologies, such as electronic health records (EHRs). Integrating software into existing EHRs requires time, testing for failure, and staff training, according to Natalie Kuchik, PharmD, a clinical assistant professor of pharmacy practice at Northeast Ohio Medical

University, in Rootstown, who discussed IV workflow strategies at her institution. Additional checks to help verify that special populations such as pediatric and neonatal populations receive the correct medications are important. For example, high-alert medications undergo dual pharmacist verification. Dr. Kuchik noted that the software her organization uses offers guidance on every step and has the added benefit of ensuring that special products are prepared correctly. Arpit Mehta, PharmD, MPH, the director of pharmacy at Allegheny General Hospital, in Pittsburgh, explained that technologies employed for IV workflow must work together to ensure that standardized procedures prevent end users from having the ability to bypass the technology. Equally important is engaging the information technology, data security and EHR teams in the early phases to build the interfaces, etc. “IV workflow [solutions are] the future of compounding,” Dr. Mehta predicted. “It is an absolute necessity, and IV accuracy must be equally important as the sterility of compounding.”

Considerations for Ordering IV And Oral Solutions For Pediatric Patients The pediatric population faces a unique set of circumstances that make them more susceptible to medication errors than other patient populations. Medication dosing in this population is more complex, according to Calvin Daniels, PharmD, a clinical pharmacist in medical safety and informatics at St. Jude Children’s Research Hospital, in Memphis. Many medication errors within the pediatric population that have lifethreatening or fatal consequences go unreported ((J Med Life 2015;8[3]:612). “Many errors—especially with oral solutions in the pediatric population— are unreported because the instructions can be misleading for parents looking at the syringe,” and they don’t realize they are making a mistake, Dr. Dejos said. “Parents will think, ‘Oh, I can draw up 10 mL, when the dose is really 10 g.” Many oral drugs for pediatric patients use dosing devices that have different units for measuring volume, such as milliliters, fluid ounces, teaspoon/tablespoon, etc., and “some measuring devices can have multiple units of measure on the same syringe or cup,” Dr. Daniels cautioned (Figure). This variability further increases error risk, Dr. Daniels explained. In addition, pediatric dosing often

Clinical

Pharmacy Practice News â&#x20AC;˘ May 2020

ASHP Medication Safety Pearls requires clinicians to calculate the dose, therefore increasing the risk for errorbased dosing. Calculations that require multiple steps carry greater error potential. Erroneously placed decimal points can result in either significant supra- or subtherapeutic dosing. To reduce these errors, Drs. Dejos and Daniels recommended establishing standardized practices. These include employing clinical decision support to facilitate orders that consider patientspecific factors. Health systems can enact several strategies to improve calculationbased dosing by using CPOE and standardized dosing for IV and oral medications and referring to dosing charts. â&#x20AC;&#x153;The concerns are visible,â&#x20AC;? Dr. Dejos told Pharmacy Practice News, â&#x20AC;&#x153;but the impetus lies on medication safety officers, pharmacists and nonpharmacists to carry out the actions truly needed.â&#x20AC;?

should occur with every patient encounter within the health care system and at the time of discharge.â&#x20AC;?

Maintaining Safety Through Biosimilar Implementation Health care systems continue to struggle with implementing biosimilars into existing operations, according to Margaret Kronz, PharmD, a pharmacy resident at Allegheny General Hospital, and Indrani Kar, PharmD, a drug policy and formulary specialist at University Hospitals Health System, in Cleveland.

As additional biosimilars enter the market, it is imperative for health systems to develop safe implementation processes at the point of order entry, pharmacist verification, dispensing and administration. Among the challenges are the nomenclature used for biosimilars, which creates the potential for error during order entry, Dr. Dejos explained. The FDA requires that biosimilars bear the drugâ&#x20AC;&#x2122;s brand name along with a fourletter suffix. However, in March 2019, the FDA released an update stating

that it may reverse this decision and no longer require suffixes on biosimilar products approved in the future (bit.ly/ 39PAAx4). While final guidance is pending, omission of the suffix may increase errors. â&#x20AC;&#x153;A pharmacy technician may pull the wrong biosimilar product by mistake, and thatâ&#x20AC;&#x2122;s important because not all payors are paying for biosimilars,â&#x20AC;? he said. This may become more of a challenge as additional biosimilars enter the market.

Minimizing Errors in Pediatric Patients During Transitions The absence of an industry standard and poor compliance with guidelines set by the American Society for Parenteral and Enteral Nutrition have contributed to industry-wide variations in compounding and labeling practices for home parenteral nutrition (HPN). Pediatric patients transitioning to home are at higher risk for medication errors at these transitions of care ((Front Pediatr 2017;5:149). â&#x20AC;&#x153;Due to lack of standard concentrations and standard ingredients, we have a way to go with establishing an industry standard for HPNs,â&#x20AC;? Dr. Dejos said. â&#x20AC;&#x153;Not every facility has a standard HPN process.â&#x20AC;? Each setting the patient encounters or medical service the patient receives creates a new opportunity for an error to occur. Examples of potential risks include when the clinical pharmacist reconciles the patientâ&#x20AC;&#x2122;s PN and compounding record, a provider modifies the childâ&#x20AC;&#x2122;s PN prescription for home care, or the PN prescription is faxed to an infusion company that compounds PN weekly. The most important way to minimize errors in pediatric HPN transitions of care is to develop a system in which the referring health system and accepting home care company communicate at every point of transition of care, said Kathleen M. Gura, PharmD, the manager of clinical research in the Department of Pharmacy at Boston Childrenâ&#x20AC;&#x2122;s Hospital. Doing so requires clinicians to be willing to share orders and compounding records, communicate, and maintain an open and transparent environment. Dr. Gura also recommended that pharmacists and other health care providers caring for patients receiving PN be familiar with the ASPEN guidelines for PN ordering, order review, compounding, labeling and dispensing. And she stressed that â&#x20AC;&#x153;PN order reconciliation

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32 Clinical

Pharmacy Practice News • May 2020

ASHP Medication Safety Pearls

REDUCING ERRORS continued from page 31

To curb potential barriers when using biosimilars, Dr. Kar noted that University Hospitals follows the following process: • The health system selects one preferred agent when applicable. • Order sets contain one generic order that defaults to the preferred agent. • If a prior authorization is required, a communication plan exists for insurance denials.

• Drug orders for biologics with available biosimilars automatically default to the preferred biologic, which requires pharmacist verification. • The product label and EHR bear the full name of the biosimilar or biologic along with its suffix.

Oral Chemotherapy Safety Practices The increased prescribing of oral chemotherapy along with the patient’s selfadministration of these anticancer agents increase concerns about medication

safety, Oxana Megherea, PharmD, a PGY2 oncology pharmacy resident at the Johns Hopkins Hospital, in Baltimore, told Pharmacy Practice News. “The patient administers the medications at home, thus taking responsibility for the adherence with these agents,” Dr. Megherea said. In addition, patients need to “take a more active role in recognizing toxicity with these agents as well as proper handling, storage and disposal." Drug–drug and drug–food interactions present additional potential

challenges for patients. Education plays a critical role in ensuring the safe use of oral chemotherapy agents, Dr. Dejos noted. “I’ve seen patients cut chemotherapy tablets on the same cutting boards they use to cut vegetables and meat, so then you’ve got noncancer patients eating a meal contaminated with traces of cancer drugs.” In addition to creating standardized educational materials, using the teach-back method helps reinforce and confirm the patient's knowledge of proper medication use, Dr. Dejos said, stressing the importance of “setting up patients for success.” —Frieda Wiley, PharmD

O UR TEST, Y O U R C U R E . . .

Dr. Gura reported financial relationships with Alcresta, Baxter, B. Braun, Fresenius Kabi, Northsea Therapeutics, Omegaven, Otsuka, Pfizer and Xellia. The other sources reported no relevant financial relationships.

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Clinical

Pharmacy Practice News • May 2020

Critical Care

ERAS surprise:

Protocol Falls Short on Outcomes, Cost for Colon Resection New Orleans—Although enhanced recovery after surgery (ERAS) protocols are associated with reduced hospital length of stay (HLOS), fewer complications and lower costs, a new study by the University of Tennessee (UT) Medical Center, in Knoxville, found no improvement in outcomes and higher costs after implementing an ERAS protocol. Although the ERAS data were a mixed

bag, other studies have shown that the protocols work—including those implemented, at least in part, by pharmacists. Also known as enhanced recovery pathways, one such program targeted at colorectal surgery patients at Sparrow Hospital in Lansing, Mich., a 733-bed teaching hospital and level 1 trauma center, led to notable reductions in HLOS, oral morphine equivalent usage and

readmission rates, as reported in Pharmacy Practice News (bit.ly/2V90S82). The concept for these pathways— which involve standardized activities such as hydrating patients before surgery, decreasing the use of opioids, and getting patients out of bed and walking the hallways within hours after procedures—originated in Europe in the 1990s, said Peggy Malovrh, PharmD, BCPS, a

pharmacy clinical supervisor at Sparrow Hospital. “The general purpose is to return normal physiological function and stop artificial introduction of fluids and drugs as soon as possible after surgery. It’s been shown this will decrease catecholamine-induced stressors on the body and organ dysfunction, and improve recovery.” see ERAS PROTOCOLS, page 34

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34 Clinical

Pharmacy Practice News • May 2020

Critical Care

ERAS PROTOCOLS continued from page 33

Still, the strategy isn’t fool-proof, as shown in the UT Medical Center study. The reseachers analyzed data from 598 patients undergoing elective colon resection: 100 before the implementation of an ERAS protocol in 2014, and 498 between implementation and 2017. Before implementation, the most frequently performed surgery was right colectomy; after implementation, sigmoidectomy was most commonly performed. As for

the specific ERAS protocol used, “our approach parallels the cleveland clinic’s [box, page 33],” said co-investigator Miles Landry, MBBS, the academic chief resident at UT Medical Center. He cited the following key steps: • Minimize preoperative dehydration and nutritional depletion (usually low-volume prep, NPO for 4 hours prior to surgery, plus carbohydrate supplement on the day of surgery. • Minimize fluids intraoperatively and avoid perioperative hypothermia with strictly maintained temperature

within the normal range. • Use standard antibiotic prophylaxis and preoperative alvimopan for patients who are opioid naive. • Encourage postoperative early ambulation, enteral nutrition and minimize opioids via multimodal analgesia. • Maintain an oxygen tension optimization period for six hours postoperatively with a non-rebreather mask. The UT Medical Center researchers found a general cost increase that was statistically significant for every site of resection except transverse

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Early mobility after surgery is a core component of ERAS protocols.

colectomy. The latter procedure “had a more than $2,000 increase, but with the low number of procedures, it failed to reach statistical significance,” said Dr. Landry, who presented the study at the 2020 Southeastern Surgical Congress (abstract 67) in New Orleans. There was a smaller difference in the cost increase with the frequently performed right colectomy and sigmoidectomy procedures, “which suggests we’re gaining some level of efficiency from doing those more regularly,” he explained. Moreover, HLOS, averaging 4.5 days for open procedures and 3.5 days for minimally invasive procedures prior to the protocol, improved initially in the laparoscopic surgery cohort, but then returned to average. “Is this a worthwhile thing to do? I think if we can truly establish the preoperative and perioperative factors that identify patients who would be in the hospital for five to seven days rather than two to three, we’ll be able to see the real benefit of the ERAS protocol,” Dr. Landry said. Russell Farmer, MD, an assistant professor of colon and rectal surgery at the University of Louisville, in Kentucky, congratulated the authors for examining a topic that is becoming a standard of care in minimally invasive colectomy. “Many accrediting bodies outside the [United States] include ERAS protocol components as a mandatory part of their board examination,” he said. Dr. Farmer asked if the shift from right colectomy to sigmoidectomy might have affected the researchers’ findings. “I do think that hints at the idea that the expected outcomes for patients would have been different as we included more difficult patients, but we didn’t design the database that way,” Dr. Landry said. “That’s a key component that we’ll include in future evaluations.” —Monica J. Smith, Karen Blum The sources reported no relevant ﬁnancial relationships.

Clinical

Pharmacy Practice News • May 2020

Blood Management

Anticoag Teams Help Optimize DOAC Monitoring Las Vegas—A major marketing pitch for direct oral anticoagulants (DOACs) is that DOAC patients don’t require routine monitoring—one of the chief downsides of warfarin therapy. But do they? According to one pharmacist-run anticoagulation program, the answer is a definite yes. Because of that, since June 2018, the outpatient anticoagulation management service (AMS) at MelroseWakefield Healthcare, in Massachusetts, has treated an increasing number of DOAC patients, supporting and monitoring them with regular encounters with qualified anticoagulation pharmacists. The approach seems to be working. Only two of 117 patients (1.7%) enrolled in the AMS from June 1, 2018, to Feb. 1, 2019, were hospitalized for a bleeding or thromboembolic event, according to a retrospective case review described at the ASHP 2019 Midyear Clinical Meeting. Antonia DeQuevedo, PharmD, the health system’s pharmacy clinical coordinator of anticoagulation, who reported the results, offered other findings from the study showing what can happen when DOAC patients aren’t routinely monitored. During the same eight-month study period, she said, 18 (29%) of the 62 DOAC patients who were admitted to the hospital for a bleeding or clotting event had a DOAC medication error. The errors included incorrect dosages or frequency of administration, contraindications to DOAC usage, or inappropriate use of DOACs based on renal or liver function. “These are high-risk medications,” Dr. DeQuevedo told Pharmacy Practice News. “Just putting patients on them and not routinely following up was not an appropriate way to manage them, especially in light of the trends we were seeing with patients admitted to our hospital,” including “a lot of inappropriate

dosing and adversee events.” Today, approxim mately 150 out of the nearlyy 1,000 patients enrolled in n MelroseWakefield Heaalthcare’s 8-year-old an nticoagulation servicce are taking DOACS S. They receive an n array of clinical, educational and financial services from a threemember pharmacist team that operates the clinic on-site approximately nine hourss per day and then n provides on-caall coverage on the evevenings and weekends to deliver 24/7 attention. DOAC patients often are older and take multiple drugs. Dr. DeQuevedo described a typical case involving an 80-year-old woman with atrial fibrillation who was discharged home on 150 mg of dabigatran (Pradaxa, Boehringer Ingelheim) twice daily. To aid compliance, the patient’s pharmacy had been packaging her other medications in blister packs, but dabigatran’s special storage requirements prevented it from being added to her other medications. So, an AMS pharmacist had the prescription switched to rivaroxaban (Xarelto, Janssen), which could be packaged with her other medications. In another case, a 64-year-old patient was started on 5 mg of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) twice daily for a pulmonary embolism, but after a month of treatment she called the AMS and asked how she could “wean herself off” the medication. It turned out she was struggling to meet the medication’s copayment. The service was able to arrange for a copay card that made the

medication affordable. The AMS pharmacists work largely by telephone, reaching out to patients at regular intervals based on their assessment of need. “If DOAC patients are new to the medication or if they’ve had a recent procedure, we schedule them for a one-month follow-up,” Dr. DeQuevedo said. “But if the patient is stable and nothing else is going on, we usually check with them every three months or so.” In addition to making sure patients are adherent and not experiencing any adverse events, the pharmacists are proficient at overcoming obstacles that can interfere with compliance. For example, they’ve helped to have medication timers installed on telephones, created pillboxes for multi-medication use, and arranged deliveries from local pharmacies that can prepackage medications. “We also call local pharmacies to make sure patients are being timely with refills,” Dr. DeQuevedo said. Checking patients’ medications, including overthe-counter drugs and herbal remedies

Even Limited Monitoring Services Can Be Beneficial

hen resources are tight, it can be hard to add services. Yet, health systems can implement direct oral anticoagulant (DOAC) monitoring programs that are narrower in scope but still worthwhile. The University of Maryland Medical Center (UMC), for example, has an inpatient program where DOAC patients are monitored and “teed up for discharge,” said Zachary Noel, PharmD, an assistant professor of pharmacy practice and science at the University of Maryland School of Pharmacy, in Baltimore. Also, the UMC outpatient antico-agulation service has started to take on more complex DOAC patients, such as those having ga surgical procedure who require perioperative anticoagulation management. At the University of Utah Health in Salt Lake City, Ryan Fleming, PharmD, the Thrombosis Center manager, described a different approach. “Most of our monitoring is done at the

time of refill request,” Dr. Fleming explained. “We approve refills for the amount of time we think it is safe for patients to go without contacting them or reviewing their chart, whether it be three, six or 12 months, for example.” When another a refill is requested,” he said, “we review th he DOAC regimen again for indication, efficacy,, safety and adherence,” which may or may no ot include contacting the patient. “We have fo ound many advantages to the refillbased approach, instead of so much cold-calling patients between refill encounters. Our intervention rate also has gone up O because authorizing a refill is an intervention. So essentially, while we are making an intervention, whether for m authorizing a refill or temporarily stopping medication for an upcoming procedure, we also are performing a complete review of that patient’s DOAC regimen.” —B.B.

for potential interactions, also is a routine part of every encounter. “We also provide perioperative management,” Dr. DeQuevedo said. “So, when patients are having procedures, we advise when they need to stop their DOAC and when it’s safe to restart. And we communicate both plans to the patient’s surgeon or person doing the procedure to make sure they’re comfortable with the plan.” Dr. DeQuevedo is optimistic about the future of DOAC monitoring programs. “There are a lot more patients being placed on these medications. The Joint Commission supports the need for this type of surveillance program, and physicians are starting to realize the value. So, yes, I think we’re going to continue to see more patients being enrolled.” Zachary Noel, PharmD, an assistant professor of pharmacy practice and science at the University of Maryland School of Pharmacy, in Baltimore, said, “The notion that DOACs don’t need monitoring is really a misconception. They don’t require frequent monitoring, as warfarin does, but routine monitoring is still necessary.” However, he added, “that doesn’t just mean lab monitoring—certainly we’re going to monitor renal function periodically with the DOACs. But it also means monitoring for drug interactions, reevaluating the risk-to-benefit ratio, and things like that,” he said. “What they have done at MelroseWakefield is terrific,” he added. “More institutions should implement some sort of DOAC monitoring service. These are high-risk medications, and so continuous evaluation is certainly appropriate.” —Bruce Buckley None of the sources reported any relevant ﬁnancial relationships.

36 Clinical

Pharmacy Practice News • May 2020

Blood Management

TEG Talk: Sometimes the Entire Picture Matters T

he liver transplant patient was bleeding, and no one knew why. The attending physician at the Medical University of South Carolina (MUSC), in Charleston, suspected the patient was breaking down clots too quickly and wanted to give him an antifibrinolytic agent. But if a rapid breakdown was not the culprit, an antifibrinolytic could render him prothrombotic, putting him at risk for stroke, embolism or deep vein thrombosis, cautioned Melanie Smith, PharmD, a surgery/trauma ICU clinical pharmacy specialist at MUSC. The treatment team needed answers, but acute coagulopathy events such as liver failure can affect the accuracy of some traditional lab tests, including the international normalized ratio. Dr. Smith suggested the team get a better look at the patient’s coagulopathic picture. So the doctor ordered a viscoelastic hemostatic assay—in this case performed by rotational thromboelastometry (ROTEM)—which shows how quickly the body is forming clots, how strong the clots are, and how long they last. Within minutes, the team realized it wasn’t that the patient was not breaking down clots too quickly; he wasn’t forming them quickly enough. He didn’t need an antifibrinolytic; he needed frozen plasma, with the clotting factors that would reverse his condition. Using ROTEM “completely changed the treatment plan for this patient,” Dr. Smith told Pharmacy Practice News. An increasing number of ORs and emergency departments are adding viscoelastic hemostatic assays—ROTEM and thromboelastography (TEG)—in patients for whom traditional lab tests won’t suffice. This year, the Society of Critical Care Medicine recommended the use of viscoelastic assays in critically ill patients with acute liver failure and acute-on-chronic liver failure who are undergoing procedures (Crit Care Med d 2020;48[3]:415-419). By targeting the nature of the patient’s hematopathology, doctors avoid wrong or unnecessary treatments, potentially saving costs and lives. “The TEG is a more dynamic measure and can give you a better picture of what the actual coagulopathic picture looks like,” Nicole M. Acquisto, PharmD, an emergency medicine clinical pharmacy specialist at the University of Rochester Medical Center, in New York, told Pharmacy Practice News. “This is a more global and functional assessment of coagulation than just our conventional concentrations.”

How It Works Using the newest version of the TEG machine (6s), users simply add a patient’s blood sample to a cartridge, and

‘The TEG is a more dynamic measure and can give you a better picture of what the actual coagulopathic picture looks like.’ —Nicole M. Acquisto, PharmD

Å Coagulation

Æ|Å

Fibrinolysis

α-angle: speed of fibrin accumulation Angle LY30 R

Reaction time: time to first significant clot formation

Lysis at 30 min: percent of clot strength amplitude lost 30 min after reaching MA

MA: maximum strength of clot

How Fast?

How Strong?

For How Long?

Figure. Thromboelastography (TEG) assay. MA, maximum amplitude

within minutes the machine prod duces the coagulopathic picture. The image appears like a sid deways spade (Figure); the left sside shows how well the body is fo orming clots, and the right side illustratees how well the clots are broken down. The h lleft f side of the image includes metrics such as the “r” time or reaction time, which describes the time to the formation of the first significant clot, and the alpha-angle, which depicts the speed with which the body accumulates fibrin. The height of the image is the maximum amplitude, or MA, showing the maximum strength of the clot. On the right is LY30, the percentage of clot strength amplitude that has disintegrated (undergone lysis) 30 minutes after MA. Although the entire analysis requires up to one hour, within several minutes users can see the “r” time value, Dr. Acquisto said.

not just the static count” that comes from conventional blood tests, she said.

When It Works Having this information may help in decision making outside of hemorrhagic situations, Dr. Acquisto said. For instance, if a patient receives heparin after a myocardial infarction and then experiences an embolic stroke, TEG may give providers additional information to determine whether there are contraindications to recombinant tissue plasminogen activator (tPA) if the “r” time is prolonged. Conversely, if someone has a bleeding event after tPA administration, TEG may help determine whether platelets or cryoprecipitate are needed based on the MA or LY30, respectively. Providers also can use the LY30 on the TEG curve to determine whether trauma patients are hyperfibrinolytic and would benefit from tranexamic acid, which may reduce blood transfusion requirements and potentially reduce mortality, Dr. Acquisito said. Knowing the specific nature of a patient’s coagulopathy enables providers to give the patient-specific products, rather than just whole blood, added Dr. Smith, which saves money and reduces the volume given to patients.

Digging Deeper To Reduce Transfusions

During i the h ASHP 2019 Midyear id Clinical Meeting, Dr. Acquisto explained how the shape of that sideways spade tells providers what’s happening in real time in the patient’s blood: A long “r” time and low MA is common in the setting of hemorrhage, when coagulation factors and platelets are consumed, whereas a short “r” time and high, longlasting MA is a sign the patient is thrombotic. Studying the specific configuration produces a more specific diagnosis, such as low clotting factors, low platelet function or platelet hypercoagulability. “You’re getting the functionality of what’s happening in the patient’s blood,

Research is supporting the use of these mac machines in certain patients. A 2015 revieew showed that patients who underwen nt cardiac surgery or had traumaindu uced coagulopathy or postpartum hem morrhage and whose care included visscoelastic devices were less likely to neeed transfusions of red blood cells (relative risk [RR], 0.88; 95% CI, 0.800.96), platelets (RR, 0.72; 95% CI, 0.58-0.89), and fresh frozen plasma (RR, 0.47; 95% CI, 0.35-0.65) relative to control patients. Also, using th he devices can save money ((Health Tech hnol Assess 2015;19[58]:1-228). Other evid dence suggests that severely injured patieents whose transfusion protocols are iinformed by the use of TEG require lless plasma and platelet transfusions during the beginning phase of resuscitation ((Ann Surgg 2016;263[6]:1051-1059). Although TEG is used more commonly at large academic centers and teaching hospitals, the average community pharmacist likely won’t come across one anytime soon, Dr. Smith said. But, in the ER, OR and ICU, she is quick to recommend the device to doctors. “I find myself bringing it up a lot, saying, ‘Hey, we should look at this.’ It often helps add to the picture.” —Alison McCook None of the sources reported any relevant ﬁnancial relationships.

38 Clinical

Pharmacy Practice News • May 2020

Blood Management

Novel Agent Shows Beneﬁt in Anemia Disorder Orlando, Fla.—An investigational monoclonal antibody called sutimlimab was found to be effective in controlling cold agglutinin disease (CAD) in a pivotal phase 3 trial. The novel treatment binds to complement component 1 (C1), preventing the hemolytic anemia that characterizes CAD, an autoimmune disorder. “Based on these results, we believe sutimlimab could become the first

approved treatment for this challenging disease,” reported Alexander Röth, MD, from the Department of Hematology at the University of DuisburgEssen, in Essen, Germany. In this trial, called CARDINAL, 24 patients with relatively severe CAD were enrolled and 22 completed the 26-week study. The two dropouts were for reasons unrelated to treatment. Entry criteria were a hemoglobin level

of 10 g/dL or less and an elevated bilirubin. In the six months before trial enrollment, participants had received a median number of two transfusions, with a range of up to 19. Patients received infusions of sutimlimab on days 0 and 7, and then biweekly over 26 weeks, Dr. Röth explained in a late-breaker presentation at the 2019 annual meeting of the American Society of Hematology (abstract LBA-2).

Rapid Response to Therapy The effect of treatment was rapid. By week 3, median hemoglobin climbed from approximately 8.5 to nearly 11 g/dL. It climbed further to 11.5 g/dL by week 7, and remained between 11 and 11.5 g/dL for the rest of the study. Median bilirubin level fell from more than 50 to less than 20 mcmol/L (the upper limit of normal) by week 3, and it remained at that level over the course of the trial.

Clinical

Pharmacy Practice News • May 2020

Blood Management

From week 5 to the end of the study, 17 patients, or more than two-thirds of those enrolled, remained transfusionfree. Median scores on the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scale climbed from 20 (significant impairment) to 40 within one week. FACIT-F scores hovered at 50 from week 7 to the end of the trial. “Patients responded very quickly, not just in regard to laboratory measures

of disease but on the basis of change in quality of life,” Dr. Röth reported. The therapy was well tolerated, with no serious unexpected treatmentrelated adverse events. Serious infections did occur but were reported to be manageable. There were no thromboembolic events. A death from hepatic cancer was considered to be unrelated to treatment. All 22 patients who completed the

26-week trial have been enrolled in an ongoing extension study. Cold agglutinin disease develops when circulating antibodies bind to red blood cells, activating the classic pathway of the complement system to induce hemolysis. The primary form of the disease typically occurs in adults over 50 years of age. Secondary CAD can be induced by other events, such as infection. Exposure to cold temperatures triggers the

disease, but cold avoidance is not sufficient to avert symptoms in patients with moderate to severe involvement. Although there are no approved therapies for CAD, a disorder with an estimated prevalence of 16 per 1 million people, several therapies provide benefit for limited periods. Steroids, for example, reduce symptoms but at doses that are not tolerated over the long term. Rituximab has been associated with efficacy, but responses have been transient. “Not all patients respond to rituximab, and the benefit usually lasts only about six months,” said Robert Brodsky, MD, the director of the Division of Hematology at Johns Hopkins University School of Medicine, in Baltimore. At the ASH meeting, Dr. Brodsky called these data “very exciting” because of the limited options for this disorder.

‘An Exciting New Approach’ By targeting only the C1 complex of complement and leaving the alternative and lectin complement pathways intact, sutimlimab appears to preserve most complement functions, which are critical for fighting pathogens. Dr. Röth suggested this therapy could be transformative for people with CAD if longer follow-up confirms sutimlimab has sustained effectiveness. He noted that the same mechanism of action used to inhibit complement in this disease could be relevant to other complement disorders. “This treatment methodology is novel and an exciting new approach of targeted therapy for patients with CAD,” observed Jerry Siegel, PharmD, a clinical associate professor at Ohio State University, in Columbus. The sustained increases in hemoglobin and quality of life achieved in the majority of patients by this strategy of blocking the C1 complex of complement is encouraging for a disease with limited treatment options, he noted. “Both plasmapheresis and polyvalent IVIG have been used in the past, but the current therapy is rituximab alone or in combination with bendamustine or fludarabine,” Dr. Siegel told Pharmacy Practice News. Many other therapies have failed. “Historically, splenectomy and high-dose corticosteroid therapy have been ineffective for CAD,” he noted, indicating there is a need for alternative strategies with long-term benefit. —Ted Bosworth Dr. Röth reported financial relationships with Alexion, Novartis and Roche. Dr. Brodsky reported no relevant financial relationships. Dr. Siegel reported financial relationships with Coherus, Kedrion and Takeda.

40 Policy

Pharmacy Practice News • May 2020

Safe Handling

A ‘starship’ enterprise

Lessons Learned From a Once Not-So-Sterile CR Las Vegas—An ongoing pattern of contamination over nearly three years in a sterile compounding suite illustrates the challenges in building and maintaining a safe and efficient cleanroom. But the systematic and ultimately successful approach used to combat the problem may offer valuable lessons for other compounding pharmacies, according to a poster presented at the ASHP 2019 Midyear Clinical Meeting. The consistent sampling excursions began shortly after the Augusta Health cleanroom in Fishersville, Va., was remodeled in late 2015. "We were frequently having to reclean, investigate causes and resample," said John Lubkowski, BSPharm, MBA, the pharmacy director at Cardinal Health and author of the poster (abstract 8-166). “I think that some people may believe that it’s better to quickly and covertly address issues, but we engaged everyone possible and didn’t cut corners,” Mr. Lubkowski said. “Our mission is always, first and foremost, patient safety.” Mr. Lubkowski developed a system to track environmental monitoring results over time by location, created an escalating action plan to address issues identified during investigations, and then engaged both internal and external subject matter experts to implement higher-level action plans. One of the investigations, for

example, revealed that the epoxy paint used on the walls had degraded over time. “So we actually shut down the IV room and utilized another IV room in the facility,” Mr. Lubkowski said. “We then repainted, reepoxied and allowed cure time—approximately two weeks— before we recleaned, recertified and resampled the room.” Continuing incidents of contamination eventually resulted in the cleanroom shutting down for a couple of months for a complete remodeling. A particular focus was relocating the air returns from the ceilings, where they were originally right next to the facility’s incoming HEPA-filtered air, to a position lower on the walls that ensured more optimal airflow. “I see the improper placement of air returns a lot," said Patricia Kienle, BSPharm, the director of accreditation and medication safety at Cardinal Health, who was not involved in the poster. Mr. Lubkowski “recognized that was an issue and had it corrected. It’s part of looking for the patterns.” The remodeling also included the addition of fan-assisted HEPA filters, upgraded lighting, new solid surface walls and the replacement of hinged wooden doors that opened into the clean spaces with automatic glass sliding doors. “Previously, we had signage about not opening the two doors simultaneously.

‘We’ve already implemented much of the new USP <797> protocols, including monthly surface sampling and our own internal air sampling. Our IV room now looks like a starship.’ —John Lubkowski, BSPharm, MBA

The Augusta Health cleanroom remodeling included the replacement of hinged wooden doors that opened into the clean spaces with automatic glass sliding doors.

Now, it’s physically impossible, unless it’s an emergency,” Mr. Lubkowski said. They also eliminated anything that could be considered clutter, including compounding supplies and drug stock kept in the anteroom, as well as redesigned workflows and reeducated team members on the reasons for the new changes and processes. Involving infection control practitioners and risk managers may pay dividends when asking for the necessary funds to solve cleanroom contamination issues. “In our case, we needed to remodel a newly remodeled IV room,” Mr. Lubkowski added, noting that can be a particularly tough sell. Ms. Kienle agreed. “Dollars can be a real stumbling block. Even minor changes can require significant capital expenses, and it often ends up low on the priority list because the hospital doesn’t realize the implications. You need to present the case that this is best for patient care.”

Remediation Speed an Issue

Relocating the air returns from the ceilings to a position lower on the walls helped to ensure more optimal airflow.

Jerry Siegel, PharmD, the vice president of Safe Medication Management Associates Inc., applauded the systematic approach but was surprised by the length of time it took the team to resolve the repeated contamination situation. “These are things that need to be remediated in a month,” he said. “We’ve got to keep rooms clean and techniques good, while still reducing the length of time between when we start compounding and when we give it to the patient,” Dr. Siegel added, “because

bacteria will multiply more rapidly than rabbits will have babies.” Dr. Siegel underscored the importance of having a multidisciplinary quality control committee within an organization to determine what to do with test results, and what to do about patients who have received medications made under contaminated conditions. The revised USP Chapter <797>, which was scheduled to go into effect last December but remains indefinitely delayed, could help compounding pharmacies maintain a state of control. “It will help you reduce the microbial contamination that is very easy to introduce into cleanrooms by having standards on positive pressure, having better standards on PPEs [personal protective equipment], and by better training of technicians,” Dr. Siegel added. Since construction finished last April, Mr. Lubkowski noted that his compounding pharmacy has had only one action-level excursion in an air sample, just inside the anteroom entrance. His team also implemented monthly internal air sampling and since last July, there have not been any further actionlevel findings. “We’ve already implemented much of the new USP <797> protocols, including monthly surface sampling and our own internal air sampling,” Mr. Lubkowski said. “Our IV room now looks like a starship.” —Lynne Peeples Mr. Lubkowski and Ms. Kienle are employed by Cardinal Health. Dr. Siegel reported a ﬁnancial relationship with BD.

Policy

Pharmacy Practice News • May 2020

FDA Watch

Breakthrough Therapy for Advanced Cholangiocarcinoma Approved

he FDA granted accelerated approval to pemigatinib (Pemazyre, Incyte Corp.), the first treatment approved for adults with cholangiocarcinoma that is locally advanced or metastatic and who have tumors that have a fusion or other rearrangement in fibroblast growth factor receptor 2 ((FGFR2). “This approval demonstrates that while we continue to focus our efforts on addressing the COVID-19 pandemic, the FDA remains committed to the important work of reviewing treatments for patients with cancer and other serious conditions,” said Richard Pazdur, MD, the acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “With Pemazyre, we considered the observed efficacy results to be clinically meaningful and the overall risk-to-benefit assessment for patients with tumors harboring FGFR2 gene fusions and other rearrangements to be favorable, particularly when we considered that these patients have no other good options following first-line treatment with chemotherapy.”

Of the 38 patients who had a response, 24 (63%) had a response lasting six months or longer and seven (18%) had a response lasting 12 months or longer. The most common adverse reactions occurring in 20% or more of patients who received pemigatinib were hyperphosphatemia and hypophosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation,

stomatitis, dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin. Ocular

toxicity also was a risk of pemigatinib. “Although cholangiocarcinoma is considered a rare disease, it has been on the rise over the past three decades,” Ghassan Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York City, said in the Incyte press release. “It is encouraging to have a new targeted treatment option for patients who historically have had limited options after first-line chemotherapy or surgery, in which relapse rates remain high.” —PPN News Staff

A Rare Cancer Cholangiocarcinoma is a rare form of cancer that forms in the bile ducts. At diagnosis, most patients with the malignancy have advanced disease that is no longer treatable with surgery. For these patients, there have been no FDA-approved therapies; a combination of chemotherapy drugs has been the standard initial treatment, the FDA noted in a statement announcing the drug’s approval. FGFR2 fusions have been found in the tumors of approximately 9% to 14% of patients with cholangiocarcinoma. Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading. The drug’s approval was based on the results of a clinical trial that enrolled 107 patients with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement, who had received previous treatment. During the clinical trial, patients received pemigatinib once daily for 14 consecutive days, followed by seven days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects. Patients were monitored by scans every eight weeks. The trial used overall response rate (ORR) to measure the number of patients who experienced a complete or partial shrinkage of their tumors during treatment. The ORR was 36%, with 2.8% of patients having a complete response and 33% having a partial response.

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Medium-chain triglycerides are a source of rapidly available energy 1

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SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. Contraindications: Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL.

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

42 Policy

Pharmacy Practice News • May 2020

FDA Watch

FDA Approves Reblozyl to Treat MDS Anemia

he FDA approved luspaterceptaamt (Reblozyl, Celgene) for the treatment of anemia in adults with very low- to intermediate-risk myelodysplastic syndromes (MDS). The approval includes MDS patients with ring sideroblasts or a myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis who

failed an erythropoiesis-stimulating agent (ESA) and required two or more red blood cell (RBC) units over eight weeks. The approval was based on results from the phase 3 MEDALIST trial (ClinicalTrials.gov Identifier: NCT02631070). Of the 153 patients who received luspatercept, 58 (37.9%; 95% CI, 30.2%-46.1%) were RBC-transfusion independent for at least eight weeks, compared with 10 patients (13.2%; 95% CI, 6.5%-22.9%) who received placebo (difference, 24.6% [95% CI, 14.5%-34.6%; P<0.0001]). The most common all-grade adverse

reactions (occurring in ≥10% of patients) included fatigue, musculoskeletal pain, dizziness, diarrhea, dyspnea, nausea, hypersensitivity reactions, headache and upper respiratory tract infection. Most patients with MDS require regular RBC transfusions, “which can lead to additional complications,” said investigator Guillermo Garcia-Manero, MD, the chief of the Section of Myelodysplastic Syndromes in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston. "In our current environment, we

are reminded of the significant burden frequent blood transfusions can have on individuals and the health care system.” Access prescribing information for luspatercept at bit.ly/2yZGGxY.

Koselugo Approved For Pediatric NF1

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

>(9505.! +,(;/ 05 79,;,94 05-(5;: +LH[OZ PU WYL[LYT PUMHU[Z HM[LY PUM\ZPVU VM PU[YH]LUV\Z SPWPK LT\SZPVUZ OH]L ILLU YLWVY[LK PU [OL TLKPJHS SP[LYH[\YL (\[VWZ` ÄUKPUNZ PUJS\KLK PU[YH]HZJ\SHY MH[ HJJ\T\SH[PVU PU [OL S\UNZ 7YL[LYT PUMHU[Z HUK SV^ IPY[O ^LPNO[ PUMHU[Z OH]L WVVY JSLHYHUJL VM PU[YH]LUV\Z SPWPK LT\SZPVU HUK PUJYLHZLK MYLL MH[[` HJPK WSHZTH SL]LSZ MVSSV^PUN SPWPK LT\SZPVU PUM\ZPVU INDICATIONS AND USAGE Smoflipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in Smoflipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. DOSAGE AND ADMINISTRATION The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. Smoflipid 1000 mL is supplied as a Pharmacy Bulk Package for admixing only and is not for direct infusion. Prior to administration, transfer to a separate PN container. CONTRAINDICATIONS Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL. WARNINGS AND PRECAUTIONS • Death in Preterm Infants: (see BLACK BOX WARNING) • Hypersensitivity Reactions: Smoflipid contains soybean oil, fish oil, and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut oil. Signs or symptoms of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of Smoflipid immediately and undertake appropriate treatment and supportive measures. • Risk of Catheter-Related Infections: Lipid emulsions, such as Smoflipid, can support microbial growth and is an independent risk factor for the development of catheter-related bloodstream infections. The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions or drugs. • Fat Overload Syndrome: This is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, fatty liver infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). • Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop.

• Aluminum Toxicity: Smoflipid contains no more than 25 mcg/L of aluminum. During prolonged PN administration in patients with renal impairment, the aluminum levels in the patient may reach toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, including preterm infants, who receive parenteral intakes of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products. • Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If Smoflipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction. • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. • Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. • Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. ADVERSE REACTIONS Most common adverse drug reactions >1% of patients who received Smoflipid from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device-related infection. Less common adverse reactions in ) 1% of patients who received Smoflipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis. The following adverse reactions have been identified during post-approval use of Smoflipid in countries where it is registered. Infections and Infestations: infection. Respiratory, Thoracic and Mediastinal Disorders: dyspnea. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters. USE IN SPECIFIC POPULATIONS • Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women. • Pediatric Use: The safety and effectiveness of Smoflipid have not been established in pediatric patients. • Hepatic Impairment: Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure. OVERDOSE In the event of an overdose, fat overload syndrome may occur. Stop the Smoflipid infusion until triglyceride levels have normalized. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum.

9,-,9,5*,:! Deckelbaum RJ, et al. Medium-chain versus long-chain triacylglycerol emulsion hydrolysis by lipoprotein lipase and hepatic lipase: implications for the mechanisms of lipase action. Biochemistry (Mosc). 1990;29(5):1136-1142. Kalish BT, Fallon EM, Puder M. JPEN J Parenter Enteral Nutr. 2012;36:380-8. Fresenius Kabi USA, LLC Three Corporate Drive, Lake Zurich, IL 60047 Phone: 1.888.386.1300 www.fresenius-kabi.com/us

he FDA approved selumetinib (Koselugo, AstraZeneca) for children aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PNs). NF1 is a debilitating genetic condition caused by a spontaneous or inherited mutation in the NF1 gene and is associated with many symptoms, including cutaneous neurofibromas and skin pigmentation and, in 30% to 50% of patients, PNs. These tumors on the sheath of the nerves can cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder/bowel dysfunction. The efficacy of selumetinib, a kinase inhibitor, was investigated in SPRINT, a National Cancer Institute–sponsored, open-label, multicenter, singlearm trial in children with NF1 and a measurable target PN that could not be surgically removed without risk for substantial morbidity. Patients received 25 mg/m2 of selumetinib orally twice a day until disease progression or unacceptable toxicity. The primary efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients who experienced at least a 20% reduction in tumor volume on MRI confirmed with subsequent MRI within three to six months. The ORR was 66% (n=33; 95% CI, 51%-79%). All patients had a partial response, and 82% of responders had sustained responses lasting at least 12 months. An independent central review of ORR was performed using the same response criteria and demonstrated an ORR of 44% (95% CI, 30%-59%) ((N Engl J Med 2020;382[15]:1430-1442). The most common adverse reactions (≥40% of patients) were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acne, stomatitis, headache, paronychia and pruritus. Selumetinib also can cause cardiomyopathy; ocular toxicity, including retinal vein occlusion, retinal pigment epithelial detachment and impaired vision; and increased creatinine phosphokinase. Access the prescribing information at bit.ly/2RIoTSm.

Policy

Pharmacy Practice News • May 2020

Reimbursement Matters

One goal: getting your 20% Medicare add-on payment for COVID-19

Be Prepared, Be Innovative and Be Safe! I

n unprecedented crisis of COVID-19, the first instinct is to triage our activities, often weeding out the ones that seem to be the least important. Some of those will never surface again and just become part of the detritus left behind. However, documentation mustn’t be one of them. From a clinical standpoint, documentation is critical to caring for patients with COVID-19; it’s essential to tell the patient’s story accurately and completely. When this is done in a codable manner, it’s the key to bringing in desperately needed income and decreasing financial toxicity for the patient who’s often eligible for expanded resources. Such efforts also will help avoid medical billing and payment issues in the months and years following this pandemic. Tucked into the recent CARES Act, the Coronavirus Preparedness and Response Supplemental Appropriations Act (also known as the stimulus package), is a provision that temporarily removes the Medicare sequester from May 1 through Dec. 31, 2020, and extends it an additional year past its original end date. This provides you with a guaranteed 2% increase on all Medicare payments. The caveat: The claim needs to be clean and complete with no inaccuracies, errors or missing information to be processed quickly and paid completely. I’m urging you to find someone within your department who can shoulder the responsibility of making this happen. Perhaps it’s someone, even working from a remote location, who will be the steady driving force for financial solvency. The stimulus package is providing the funding, but it’s up to each one of you to ask for it and use it wisely to help cover COVID-19-related expenses and lost revenue. The supplement also provides a 20% add-on payment to the DRG rate for COVID-19. This Medicare add-on payment applies to patients treated at hospitals that are reimbursed through IPPS with a new ICD-10-CM diagnosis code, U07.1. An enhanced grouper assignment effective for discharges on or after April 1, 2020, corrects the underpayments possible from the original grouper assignment. Other key features include: • eliminating $8 billion in Medicaid disproportionate share hospital payment cuts in FY2020, FY2021 (a $4 billion reduction with implementation of cuts is delayed until Dec. 1, 2020); • extending Medicare and Medicaid programs set to expire on May 22 until Nov. 30, setting up a potential vehicle for legislation to ban surprise medical bills and address prescription drug prices after the 2020 election; • mandating more reporting require-

ments about where drug companies source their materials and allowing the FDA to prioritize drug applications that could help address a shortage; and • covering vaccines that meet certain effectiveness standards with no cost sharing.

Telehealth Shines! In addition to several initiatives, HHS will waive federal licensing regulations so that out-of-state physicians can treat COVID-19 patients through telehealth in states that have large outbreaks. The agency also is helping on the payment front by developing and implementing a new payment rule for federally qualified health centers and rural health clinics that provide telehealth services to eligible patients. Payment rates would be based on the payment that currently applies to comparable telehealth services under the PFS. In addition, HHS is to issue guidance on using telehealth for home health services. This allows Medicare beneficiaries to use telehealth services regardless of whether they had seen the provider in person in the preceding three years.

CMS issued a MLN Special Edition with more guidelines (go.cms.gov/2VmrjZe) and the subsequent edit to it is published in the MLN Special Edition – Friday, April 3, 2020 (go.cms.gov/2VEZ3jw). Medicaid also has telehealth provisions related to COVID-19 (bit.ly/3eur85J). On April 23, the Trump administration issued its own telehealth toolkit to accelerate states’ use of the technology (bit.ly/ 34ZRTdS). For more information on COVID-19 and telehealth, see page 51.

HIPAA Comments The HHS Office for Civil Rights (OCR) announced it will waive potential penalties for HIPAA violations against health care providers who serve patients through widely available communication apps such as FaceTime or Skype. Officials at the OCR said the agency will exercise its enforcement discretion when providers use apps “in good faith” for any telehealth treatment or diagnostic purpose, regardless of whether the telehealth service is directly related to COVID-19. “In support of this action,

“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

A Reimbursement Lexicon AMA, American Medical Association; CMS, Centers for Medicare & Medicaid Services; DRG, diagnosis-related group; FY, fiscal year; HHS, Department of Health and Human Services; ICD-10-CM, International Classification of Diseases, 10th Revision, Clinical Modification; IPPS, Inpatient Prospective Payment System; PFS, physician fee schedule

OCR will be providing further guidance explaining how covered health care providers can use remote video communication products and offer telehealth to patients responsibly,” OCR said. Providers are encouraged to enable all available encryption and privacy modes when using such applications. Officials noted that Facebook Live, Twitch, TikTok and similar video communication applications are public facing and should not be used to provide telehealth services, as reported in Fierce Healthcare (bit.ly/3ewIeQz). ■

Put These Into Your e-Library! On March 20, CMS released two digital telehealth tool kits, one specific to general practitioners (go.cms.gov/2XVuR6p) and the other for providers treating patients with end-stage renal disease. “Each toolkit comprises electronic links to telehealth resources to reduce the amount of time providers spend looking for answers on new regulations,” the agency stated. “The toolkits is structured to help you learn more about the general concept of virtual care, choose telehealth vendors, initiate a program and develop documentation tools,” and also outline temporary telehealth services that could be implemented during the COVID-19 pandemic. According to CMS's March 17 fact sheet (go.cms.gov/34KhxmN), clinicians could bill immediately for dates of service starting March 6, 2020. Telehealth services are paid under the PFS at the same amount as in-person services. HHS also is waiving certain Medicare telehealth payment requirements to enable telehealth services to be provided in all settings, including a patient's home, and enables Medicare beneficiaries to use telehealth services even if they aren’t in a rural community. A range of health care providers will be able to offer telehealth to Medicare beneficiaries with services including common office visits, mental health counseling and preventive health screenings. For a list of frequently asked questions regarding the telehealth initiative, visit bit.ly/3bu0JmR. Additionally,

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44 Operations & Management

Pharmacy Practice News • May 2020

Medication Safety

Flashpoint for Improving

Table. Survey Results on Error Prevention Efforts At Small Hospitals

continued from page 1

barcode that associated one drug with one patient. The incident became a process improvement flash point and a teachable moment for positive proactive change for patient safety. According to Christina Michalek, BS, RPh, a medication safety specialist at the Institute for Safe Medication Practices (ISMP), in Horsham, Pa., small and rural facilities face unique challenges when trying to prevent errors involving high-alert medications. Often, she said, smaller facilities don’t have the same resources as larger hospitals, such as a staff member dedicated to medication safety. Instead, employees often wear multiple hats,

with pharmacists serving the roles of directors, clinicians, technicians and medication safety experts. Smaller facilities also may not have access to more sophisticated EHRs or other technologies that can help identify and prevent errors, Ms. Michalek said. In 2018, hundreds of facilities completed an ISMP survey asking how they try to prevent errors involving 11 high-alert medications. Approximately one-third of respondents had less than 100 beds. The results, released last year, showed that smaller facilities performed slightly worse than average. At the ASHP 2019 Midyear Clinical Meeting, Ms. Michalek and Deborah

Source of Error

Error Prevention Strategy Result

Methotrexate

3.1% above average

Opioids

2.2% above average

Lipid-based medications

0.9% above average

Insulin

2.4% below average

Neuromuscular blocking agents

2.2% below average

Magnesium

2.1% below average

General medication safety strategies applicable to all classes/categories of high-alert medications

2.6% below average

Source: ISMP Medication Safety Self Assessment for High-Alert High Alert Medications.

Sadowski, BS, RPh, MHA, the director of pharmacy services at Deborah Heart

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and Lung Center, shared tips for small and rural facilities to avoid potentially deadly medication errors. “It’s a worry for everybody. Nobody wants to hurt a patient,” Ms. Michalek said. “Smaller facilities have to be more creative in how they address the same risks that are present for all organizations.”

Clear and Present Danger For the survey, which was funded by the FDA, 867 facilities answered questions about how they try to prevent errors involving high-alert medications, including chemotherapy, methotrexate, anticoagulants and opioids. Each facility was scored on its processes, with some preventive measures given more weight than others, Ms. Michalek explained. For example, if a facility used barriers, fail-safes or automation/computerization, that improved its score more than strategies that involved education or suggestions to “be careful.” Across all hospitals, prevention efforts vary, with measures that are more robust for some types of medications and less so for others, Ms. Michalek said. Overall, hospitals are doing the

Operations & Management

Pharmacy Practice News • May 2020

Medication Safety most to prevent errors involving moderate/minimal sedation (85/100), magnesium (80/100), and neuraxial opioids and/or local anesthetics (80/100), but they did less to prevent errors with lipid-based medications (61/100) and methotrexate (50/100). When the ISMP separated hospitals with less than 100 beds from the group, smaller hospitals performed slightly better in some categories and but below average for others (Table). It’s clear that smaller facilities are falling behind in certain types of error prevention, Ms. Michalek said, specifically technologies that provide barcoding verification during medication preparation and using independent double checks. This makes sense, she noted. Small facilities may have only one practitioner staffing an area such as the pharmacy, which makes conducting double checks more challenging, and may lack the resources to invest in expensive technology such as IV workflow software systems to help prevent compounding errors (see related story, page 54). There’s still work to be done, Ms. Michalek said. “What keeps me up at night is the worry that we’re going to hear about these errors again and again.”

Where There’s a Will, There’s a Way Smaller facilities may have inherent limitations when trying to prevent errors involving high-alert medications, but there are things they can do. At the ASHP Midyear Clinical meeting, Ms. Sadowski shared the results of the ISMP survey at Deborah Heart. Although the facility is widely recognized, with high ratings from the Centers for Medicare & Medicaid Services and the Society of Thoracic Surgeons, it fell short in several areas of the ISMP medication safety assessment, which it completed in February 2018. “It was kind of an eye-opener,” Ms. Sadowski told Pharmacy Practice News. The center’s overall score on attempts to prevent errors involving high-alert medications was 59/100—lower than that for all hospitals (64/100) and small hospitals (62/100). The center performed better than average compared with all hospitals for neuromuscular blocking agents (89/100 vs. 75/100), concentrated electrolytes injections (82/100 vs. 78/100), and magnesium sulfate injections (84/100 vs. 80/100). However, it performed worse than average compared with all hospitals and smaller facilities in several areas, including moderate sedation (66/100 vs. 84/100 for small hospitals) and anticoagulants (68/100 vs. 76/100 for small hospitals). That last category hit hardest, Ms. Sadowski said, because of her facility’s specialty

‘What keeps me up at night is the worry that we’re going to hear about these errors again and again.’ —Christina Michalek, BS, RPh

in cardiovascular medicine. “This was really an ‘ouch moment,’” she said. “To not score as well on that was a surprise for us, and it said we had work to do.”

Much of pharmacists’ efforts there involved education—making sure nurses always knew when and where to use medications, and in what order, and

including that information on the MAR and EHR. But many of the hospital’s problems lay with the facility’s EHR. Some of the most sophisticated software on the market is not available to hospitals with less than 100 beds, Ms. Sadowski said, so they are unable to incorporate some alerts that help prevent medication errors. Given these findings, the pharmacy at Deborah Heart got creative. For instance, since anticoagulants are contraindicated in patients getting see SMALLER, BETTER, page 46

46 Operations & Management

Pharmacy Practice News • May 2020

Medication Safety

SMALLER, BETTER continued from page 45

epidurals, the facility created a hardstop rule within the EHR that prevents an epidural order and an anticoagulant order from being simultaneously active on a patient’s profile. It also added a feature to the computerized physician order entry that alerts physicians who have ordered antithrombotics if the patient received a dose (including an anticoagulant) within the last 24 hours at the facility. It

also added many low-tech safety features, such as “caution” and “highalert” stickers for heparin and similar medications. Following the near-miss episode with insulin, the hospital ospital knew it needed to make changes. Although the nu urse scanned all the appro opriate barcodes, theyy were missing that patient-specific barcode associating one drug with one

patient. How could they add that? Typically, once a patient was associated with a particular drug, when doses change, the EHR would generate a new order with a new Rx number, requiring staff to relab relabel every pen. “That’s just nott practical for insulin, w which has constant dosing changes,” Ms. Sadowski said. So aagain, the pharmacists got creative: Anytime they received a new

order for short-acting insulin, they created a “dummy order” with the patient’s ID but no dose information, which generated a patient-specific barcode that stayed with that patient, even if dosing information changed. “You can find ways to help increase those layers of safety,” Ms. Sadowski stressed, adding “the lessons we learned are applicable to any hospital at any size.” —Alison McCook The presenters reported no relevant ﬁnancial relationships.

NUZYRA A® (omadacycline) injection for intravenous use NUZYRA A® (omadacycline) tablets, for oral use BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION For complete details, please see Full Prescribing Information.

INDICATIONS AND USAGE Community-Acquired Bacterial Pneumonia (CABP) NUZYRA is indicated for the treatment of adult patients with communityacquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus inﬂuenzae, Haemophilus parainﬂuenzae, Klebsiella pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Acute Bacterial Skin and Skin Structure Infections (ABSSSI) NUZYRA is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by the following susceptible microorganisms: Staphylococcus aureus (methicillinsusceptible and -resistant isolates), Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and Klebsiella pneumoniae. USAGE: To reduce the development of drug-resistant bacteria and maintain the effectiveness of NUZYRA and other antibacterial drugs, NUZYRA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS: NUZYRA is contraindicated in patients with known hypersensitivity to omadacycline or tetracycline-class antibacterial drugs, or to any of the excipients.

WARNINGS AND PRECAUTIONS Mortality t Imbalance in Patients with Community-Acquired Bacterial Pneumonia-Mortality imbalance was observed in the CABP clinical trial with eight deaths (2%) occurring in patients treated with NUZYRA compared to four deaths (1%) in patients treated with moxifloxacin. The cause of the mortality imbalance has not been established. All deaths, in both treatment arms, occurred in patients >65 years of age; most patients had multiple comorbidities. The causes of death varied and included worsening and/or complications of infection and underlying conditions. Closely monitor clinical response to therapy in CABP patients, particularly in those at higher risk for mortality. Tooth Discoloration and Enamel Hypoplasia-The use of NUZYRA during tooth development (last half of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during longterm use of the tetracycline-class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline-class drugs. Advise the patient of the potential risk to the fetus if NUZYRA is used during the second or third trimester of pregnancy. Inhibition of Bone Growth-The use of NUZYRA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if NUZYRA is used during the second or third trimester of pregnancy. Hypersensitivity Reactions-Hypersensitivity reactions have been reported with NUZYRA. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with other tetracycline-class antibacterial drugs. NUZYRA is structurally similar to other tetracycline-class antibacterial drugs and is contraindicated in patients with known hypersensitivity to tetracycline-class antibacterial drugs. Discontinue NUZYRA if an allergic reaction occurs. Clostridium difficile-Associated Diarrhea-Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains off C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Tetracycline-Class Effects-NUZYRA is structurally similar to tetracyclineclass of antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests), have been reported for other tetracycline-class antibacterial drugs, and may occur with NUZYRA. Discontinue NUZYRA if any of these adverse reactions are suspected. Development of Drug-Resistant Bacteria: Prescribing NUZYRA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS: The following clinically signiﬁcant adverse reactions are described in greater detail in the Warnings and Precautions section of the labeling: • Mortality Imbalance in Patients with CommunityAcquired Bacterial Pneumonia

• Inhibition of Bone Growth

• Tooth Development and Enamel Hypoplasia

• Tetracycline-Class Effects

• Hypersensitivity Reactions

Clinical Trials Experience-Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overview of the Safety y Evaluation of NUZYRA: NUZYRA was evaluated in three Phase 3 clinical trials (Trial 1, Trial 2 and Trial 3). These trials included a single Phase 3 trial in CABP patients (Trial 1) and two Phase 3 trials in ABSSSI patients (Trial 2 and Trial 3). Across all Phase 3 trials, a total of 1073 patients were treated with NUZYRA (382 patients in Trial 1 and 691 in Trials 2 and 3) of which 368 patients were treated with only oral NUZYRA. Imbalance in Mortality: y In Trial 1, eight deaths (2%) occurred in 382 patients treated with NUZYRA as compared to four deaths (1%) in 388 patients treated with moxifloxacin. All deaths, in both treatment arms, occurred in patients >65 years of age. The causes of death varied and included worsening and/or complications of infection and underlying conditions. The cause of the mortality imbalance has not been established [see Warnings and Precautions (5.1)]. Serious Adverse Reactions and Adverse Reactions Leading g to Discontinuation: In Trial 1, a total of 23/382 (6.0%) patients treated with NUZYRA and 26/388 (6.7%) patients treated with moxifloxacin experienced serious adverse reactions. Discontinuation of treatment due to any adverse reactions occurred in 21/382 (5.5%) patients treated with NUZYRA and 27/388 (7.0%) patients treated with moxifloxacin. Most Common Adverse Reactions: Table 4 lists the most common adverse reactions occurring in ≥2% of patients receiving NUZYRA in Trial 1. Table 4: Adverse Reactions Occurring in ≥2% of Patients Receiving NUZYRA in Trial 1 NUZYRA (N = 382)

Moxiﬂoxacin (N = 388)

Alanine aminotransferase increased

3.7

4.6

Hypertension

3.4

2.8

Gamma-glutamyl transferase increased

2.6

2.1

Insomnia

2.6

2.1

Vomiting

2.6

1.5

Constipation

2.4

1.5

Nausea

2.4

5.4

Aspartate aminotransferase increased

2.1

3.6

Headache

2.1

1.3

Adverse Reaction

COVID-19 Pandemic 47

Pharmacy Practice News • May 2020

OCHSNER’S PLAN continued from page 25

meant we had to open 25 of the 2-mL vials or 10 of the 5-mL vials,” she said, and IV production increased.

In-House Compounding Helps As the COVID-19 caseload surged and more patients needed ventilators, “our pharmacies had to increase on-site compounding of IV drips,” Dr. Simonson said. “To support our largest facility to prepare the IV drips, we moved our non-drip

p od pr duc ucti tion ti on,, in incllu ud dingg an anti tibi ti biot bi ottic ics, s,, intto O hsner’’s 50 Oc 503A 3A compoundi dingg facil di i it il ity.”” Dr. Si D Simonson said id pharmacy h also l worked with nurses and doctors to develop drug administration guidance to limit the number of times nurses had to go into patient rooms. Guidance also was developed for respiratory therapists for the use of metered-dose inhalers for COVID-19 patients who didn’t need to be intubated. As the number of critical care beds expanded to meet the COVID-19 surge, Ochsner had to find sources for more ventilators, infusion pumps and automated

‘We were amazed and thankful that the Ochsner pharmacy team, while managing the surge in patients, was able to develop a ventilation medication demand projection tool to accurately estimate needs over a four-week period by drug and drug class.’ —Dan Kistner, PharmD dispensing cabinets. “Our supply chain team was very busy,” Dr. Simonson said.

NUZYRA A® (omadacycline) injection for intravenous use NUZYRA A® (omadacycline) tablets, for oral use Serious Adverse Reactions and Adverse Reactions Leading g to Discontinuation: In the pooled ABSSSI trials, serious adverse reactions occurred in 16/691 (2.3%) of patients treated with NUZYRA and 13/689 (1.9%) of patients treated with comparator. Discontinuation of treatment due to adverse events occurred in 12 (1.7%) NUZYRA treated patients, and 10 (1.5%) comparator treated patients. There was 1 death (0.1%) reported in NUZYRA treated patients and 3 deaths (0.4%) reported in linezolid patients in ABSSSI trials. Most Common Adverse Reactions: Table 5 includes the most common adverse reactions occurring in ≥2% of patients receiving NUZYRA in Trials 2 and 3. Table 5: Adverse Reactions Occurring in ≥2% of Patients Receiving NUZYRA in Pooled Trials 2 and 3 Adverse Reaction

NUZYRA (N = 691)

Linezolid (N = 689)

Nausea*

21.9

8.7

Vomiting

11.4

3.9

Infusion site reactions**

5.2

3.6

Alanine aminotransferase increased

4.1

3.6

Aspartate aminotransferase increased

3.6

3.5

Headache

3.3

3.0

Diarrhea

3.2

2.9

*In Trial 2, which included IV to oral dosing of NUZYRA, 40 (12%) patients experienced nausea and 17 (5%) patients experienced vomiting in NUZYRA treatment group as compared to 32 (10%) patients experienced nausea and 16 (5%) patients experienced vomiting in the comparator group. One patient (0.3%) in the NUZYRA group discontinued treatment due to nausea and vomiting. *In Trial 3, which included the oral loading dose of NUZYRA, 111 (30%) patients experienced nausea and 62 (17%) patients experienced vomiting in NUZYRA treatment group as compared to 28 (8%) patients experienced nausea and 11 (3%) patients experienced vomiting in the linezolid group. One patient (0.3%) in the NUZYRA group discontinued treatment due to nausea and vomiting. **Infusion site extravasation, pain, erythema, swelling, inﬂammation, irritation, peripheral swelling and skin induration. Selected Adverse Reactions Occurring g in Less Than 2% of Patients Receiving g NUZYRA in Trials 1,, 2 and 3: The following selected adverse reactions were reported in NUZYRA-treated patients at a rate of less than 2% in Trials 1, 2 and 3. Cardiovascular System Disorders: tachycardia, atrial ﬁbrillation; Blood and Lymphatic System Disorders: anemia, thrombocytosis; Ear and Labyrinth Disorders: vertigo; Gastrointestinal Disorders: abdominal pain, dyspepsia; General Disorders and Administration Site Conditions: fatigue; Immune System Disorders: hypersensitivity; Infections and Infestations: oral candidiasis, vulvovaginal mycotic infection; Investigations: creatinine phosphokinase increased, bilirubin increased, lipase increased, alkaline phosphatase increased; Nervous System Disorders: dysgeusia, lethargy; Respiratory, Thoracic, and Mediastinal disorders: oropharyngeal pain; Skin and Subcutaneous Tissue Disorders: pruritus, erythema, hyperhidrosis, urticaria.

DRUG INTERACTIONS

during mating and early pregnancy resulted in embryo loss at 20 mg/kg/day; systemic exposure based on AUC was approximately equal to the clinical exposure level. Results of studies in rats with omadacycline have shown tooth discoloration. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15-20%. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. Lactation: Risk Summary y—There is no information on the presence of omadacycline in human milk, the effects on the breastfed infant or the effects on milk production. Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including omadacycline, by the breastfed infant is not known. Because there are other antibacterial drug options available to treat CABP and ABSSSI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with NUZYRA and for 4 days (based on half-life) after the last dose. Females and Males of Reproductive Potential Contraception p Females: NUZYRA may produce embryonic or fetal harm. Advise patients to use an acceptable form of contraception while taking NUZYRA. Infertility y Males: In rat studies, injury to the testis and reduced sperm counts and motility occurred in male rats after treatment with omadacycline. Females: In rat studies, omadacycline affected fertility parameters in female rats, resulting in reduced ovulation and increased embryonic loss at intended human exposures. Pediatric Use-Safety and effectiveness of NUZYRA in pediatric patients below the age of 18 years have not been established. Due to the adverse effects of the tetracycline-class of drugs, including NUZYRA on tooth development and bone growth, use of NUZYRA in pediatric patients less than 8 years of age is not recommended. Geriatric Use-Of the total number of patients who received NUZYRA in the Phase 3 clinical trials (n=1073), 200 patients were ≥65 years of age, including 92 patients who were ≥75 years of age. In Trial 1, numerically lower clinical success rates at early clinical response (ECR) timepoint for NUZYRA-treated and moxifloxacin-treated patients (75.5% and 78.7%, respectively) were observed in CABP patients ≥65 years of age as compared to patients <65 years of age (85.2% and 86.3%, respectively). Additionally, all deaths in the CABP trial occurred in patients >65 years of age. No significant difference in NUZYRA exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg IV dose of NUZYRA. Hepatic Impairment-No dose adjustment of NUZYRA is warranted in patients with mild, moderate, or severe hepatic insufficiency (Child-Pugh classes A, B, or C). Renal Impairment-No dose adjustment of NUZYRA is warranted in patients with mild, moderate, or severe renal impairment, including patients with end stage renal disease who are receiving hemodialysis.

Anticoagulant Drugs-Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage while also taking NUZYRA. Antacids and Iron Preparations-Absorption of oral tetracyclines, including NUZYRA, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron containing preparations.

OVERDOSAGE No speciﬁc information is available on the treatment

USE IN SPECIFIC POPULATIONS

Distributed by: Paratek Pharmaceuticals, Inc. Boston, MA, USA

Pregnancy: Risk Summary y—NUZYRA, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. The limited available data of NUZYRA use in pregnant women is insufﬁcient to inform drug associated risk of major birth defects and miscarriages. Animal studies indicate that administration of omadacycline during the period of organogenesis resulted in fetal loss and/or congenital malformations in pregnant rats and rabbits at 7 times and 3 times the mean AUC exposure, respectively, of the clinical intravenous dose of 100 mg and the oral dose of 300 mg. Reductions in fetal weight occurred in rats at all administered doses (see Data). In a fertility study, administration to rats

of overdosage with NUZYRA. Following a 100 mg single dose intravenous administration of omadacycline, 8.9% of dose is recovered in the dialysate. To report SUSPECTED ADVERSE REACTIONS, contact Paratek Pharmaceuticals, Inc. at 1-833-727-2835 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

PARATEK K® and the hexagon logo are registered trademarks of Paratek Pharmaceuticals, Inc. NUZYRA A® and its design logo are registered trademarks of Paratek Pharmaceuticals, Inc. For patent information: www.paratekpharma.com/products/patent p p /p /p . © 2019 Paratek Pharmaceuticals, Inc. All rights reserved.

US-NUA-0166 07/19

“Pharmacy’s job was to ensure we got the needed pumps and dispensing cabinets for the new beds opening. “I picked up the phone and called BD. ‘We’re going to be opening beds rapidly, and I need you to be able to provide me with the automated dispensing cabinets and pumps as quickly as they’re needed,’” she recalled saying. There was a very short turnaround for getting a dispensing cabinet, and it turned out that another hospital was upgrading to the latest models but had not yet installed them, so they became available for Ochsner’s rapidly expanding critical care beds. “The BD team was great, and we got what we needed.’’ Early on, Dr. Simonson’s team developed a calculator for predicting ventilator medication needs “to help us stay ahead of the curve.” The tool was given to Vizient for use in any hospital experiencing a patient surge. Dan Kistner, PharmD, Vizient’s group senior vice president of pharmacy solutions, said, “We were amazed and thankful that the Ochsner pharmacy team, while managing the surge in patients, was able to develop a ventilation medication demand projection tool to accurately estimate needs over a four-week period by drug and drug class. They shared that tool with Vizient, and we have now posted it to our Disaster Response page on our public website.” At CivicaRx, which came to Ochsner’s assistance in the fentanyl shortage, Heather Wall, the chief commercial officer, said: “As we have hospital members all over the country, we are receiving direct COVID-19-related treatment information from many of the hot spot areas, including from Dr. Simonson and her team. We have seen an increase in demand for broad-spectrum antibiotics, sedation medications, pain management medications, neuromuscular blocking agents and medications needed to treat comorbidities. “In the past few weeks,” Ms. Ford added, “we have had the privilege to deliver daily, overnight and on weekends, increased supplies of the medications being actively used to treat COVID-19 patients.” —Bruce Buckley The sources reported no relevant ﬁnancial relationships.

48 Operations & Management

Pharmacy Practice News • May 2020

Nutrition

Optimizing Home Nutrition continued from page 1

home with ... a smooth transition,” said Reid A. Nishikawa, PharmD, the coordinator of clinical services and director of research at Nutrishare Inc. “A smooth transition for the patient is one that is safe, reduces stress, and promotes independence,” Dr. Nishikawa told the online attendees. He added that physicians, nurses, pharmacists, dietitians, social workers and case managers all play important roles. Before the patient even leaves the hospital, many considerations can be made to reduce the risk for complications. Dr. Nishikawa noted the importance of identifying the type of intestinal failure affecting the patient, such as short bowel syndrome or intestinal dysmotility. “It is necessary to anticipate the duration of PN, review medical problems, assess laboratory data, evaluate drug therapy and review the remaining intestinal anatomy to design an optimal PN formulation for the patient,” he said. Dr. Nishikawa also underscored the need to ensure adequate inpatient training, especially regarding catheter care, dressing changes, medication administration and self-monitoring. A review of the medical and surgical histories, as well as recent laboratory results, is critical to the formulation of safe PN. Catheter information is important, as is the tip location for safe administration. Most patients will receive an ambulatory infusion pump, which requires training and instructions to set up. Also crucial is a suitable PN preparation area in the home, “away from animals, ceiling fans, heater vents, children running back and forth, birds flying in the air,” Dr. Nishikawa said. “I think I’ve seen all of it.” Furthermore, the home environment should have an organized supply storage area, a dedicated refrigerator and a way to properly dispose of medical waste. “And handwashing technique is especially important in this day and age,” he noted.

Patient-Specific PN Needed The standard PN formulation is “not for everyone,” Dr. Nishikawa said. Modifications should be based on a number of factors, such as gastrointestinal (GI) losses, medications, other disease states and organ function. Depending on what factors are at play, levels of potassium, magnesium, sodium chloride and phosphate may need to be increased or decreased. “If there is any evidence of diabetes, glucose management is important,” he added, noting that levels of potassium and phosphate may specifically need to be adjusted. Fluid requirements may vary based on GI or urinary losses.

Other PN components include calories, amino acids and IV lipid emulsions (ILE). ASPEN guidelines detail acceptable concentrations of amino acids, dextrose and ILE, with values varying based on specific products being used for the compounding of PN (bit.ly/2JNYWN1). “Until recently, we only had one lipid emulsion. Things were simpler,” said Dr. Nishikawa, referring to the ILE composed of 100% soybean oil. Today, additional options are available that include medium-chain triglycerides, olive oil and fish oil, which can be less inflammatory than soybean oil. “Now that we have multiple ILEs, we have to take into consideration what stability and compatibility data exist. These issues are critical to a safe PN formulation.” Dr. Nishikawa outlined additional concerns with medication compatibility and stability in PN, a complex issue also due to the multiple types of available formulations, amino acids, doses of electrolytes and trace elements. Parenteral drugs may be added directly to the PN formulation or administered via the Y-site. However, when adding any parenteral drugs to PN, he cautioned, “binding to the bag, pH, extended beyond-use dating [BUD], refrigerated temperature, continuous infusion and the use of an in-line filter must be considered.” Vanessa Kumpf, PharmD, BCNSP, a clinical pharmacist specialist at Vanderbilt Center for Human Nutrition, in Nashville, Tenn., suggested that one common PN–drug interaction occurs when a medication causes an electrolyte abnormality. Loop diuretics may trigger potassium wasting, for example. “This may require adjustment in the electrolyte content of the PN formula,” said Dr. Kumpf, who was not involved in the session. More direct interactions also can occur, such as warfarin with the vitamin K content in the PN formula. Dr. Kumpf outlined further scenarios that could pose compatibility issues, such as with medications used to help control diarrhea in patients receiving PN for short bowel syndrome. “The effective use of antidiarrheals will influence IV fluid requirements and volume of the PN formula required to maintain adequate hydration,” she said. “The hospital discharge medication list should, therefore, be reviewed by the infusion pharmacist and any medication changes after discharge home communicated by the patient.” Specific to the home PN patient is the potential loss of stability when certain medications or nutrients are added to the PN formula in a batch fashion. “We

‘Not all medications can be safely added to PN. As a general rule, if compatibility and stability data are not reported, it is not safe to administer a parenteral drug with PN.’ —Reid A. Nishikawa, PharmD know that multivitamin injection and insulin are not stable when added to the PN formula in advance of administration,” Dr. Kumpf said. “They, therefore, need to be added to the bag by the patient just prior to infusion.”

Incompatible Drugs Worth Watching Dr. Nishikawa listed several parenteral drugs that have been shown to be incompatible with PN formulations: ampicillin, ganciclovir, imipenem, midazolam, pantoprazole and sodium bicarbonate. Drugs incompatible with Y-site administration into PN, he added, include acetazolamide, acyclovir, amphotericin, ampicillin, caspofungin, dopamine, doxycycline, ganciclovir, lorazepam, midazolam and nalbuphine. “Not all medications can be safely added to PN,” Dr. Nishikawa warned. “As a general rule, if compatibility and stability data are not reported, it is not safe to administer a parenteral drug with PN.” When assessing PN formulations for stability or compatibility, he said visual assessment is “totally inadequate” to determine a safe admixture. “Visual compatibility is not proof of chemical compatibility. We have to realize that we have approximately a 50-micron limit to what we can see with the

naked eye. That’s significant because the diameter of the pulmonary capillary is approximately 5 to 7 microns. So, [even] if you can’t see a precipitate [that] is under 50 but greater than 5 to 7 microns, ... it will not be a safe drug to add to the PN formulation.” Attention also should be paid to unexpected events, such as natural disasters and drug shortages, with the latter often stemming from the former. Emergency preparedness, including for natural disasters, requires advance planning. Dr. Nishikawa recommended ensuring the patient has all necessary emergency telephone numbers—for their physician, nurse, hospital and pharmacy—as well as at least a three-day supply of all essential items for PN administration. This stock will include IV fluids and back-up batteries for their infusion pump to administer PN. Despite all these considerations, Drs. Nishikawa and Kumpf emphasized keeping in mind the patient’s quality of life. “Remember that the patient or caregiver will often be overwhelmed,” Dr. Kumpf said. “Try to simplify your treatment plan as much as possible.” —Lynne Peeples Drs. Nishikawa and Kumpf reported no relevant ﬁnancial relationships.

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50 Operations & Management

Pharmacy Practice News • May 2020

Oncology

OSU Pilots Cancer Drug Repository Program I

n Ohio, cancer patients who have a supply of prescription drugs they can no longer use—for example, because their treatment plan or dosage has changed—can now donate their surplus medications to other patients in need via a new drug repository program at the Ohio State University Comprehensive Cancer Center (OSUCCC) Arthur G. James Cancer Hospital, the institution announced. In October 2019, the Ohio Board of Pharmacy revised its rules and expanded a program that allows institutions such as hospitals and pharmacies to receive eligible donated drugs that they can, in turn, provide to financially strapped patients. The program now includes orally administered cancer drugs.

involving two drugs: temozolomide (Temodar, Merck) and capecitabine (Xeloda, Roche). “After a review period to assess what are the highestneed medications for the pilot phase of this program, we selected these drugs because of their widespread use in a lot of tumor types as well as a high level of need involved, with patients often encountering high copays or long prior authorization processes,” Dr. KennerlyShah said. The first patient received drugs dispensed through the program in February 2020. OSUCCC plans to monitor the program for 60 days to assess volume and other operational issues, before scaling it up to include other oncology medications.

Branch spent two years developing rules to govern the program. When applications to participate in the state pilot drug repository program went out, Dr. Page’s cancer center was the first to apply and receive approval. “We have been receiving some drugs over the last year, but the process for redistributing them to patients has not yet been fully worked out so that we can implement it,” Dr. Page said. “We are currently working with the pharmacy school at the University of North Texas Health Science Center to get the process established so that these drugs can be dispensed to the patients who need them. It’s really hard to throw away an unused bottle of chemotherapy drug that cost $12,000 or $15,000 for a month’s supply.”

‘It’s really hard to throw away an unused bottle of chemotherapy drug that cost $12,000 or $15,000 for a month’s supply.’

original packaging, whereas Ohio’s does not. So OSUCCC has established a multiple-point inspection process for any drugs that do not arrive in their original sealed manufacturer packaging to ensure there is no evidence of adulteration or tampering, moisture, or inappropriate storage. Inspection also verifies that tablets or capsules are intact, checks whether the drug is a controlled substance or a drug sample, and confirms the drug identification number. Although individuals receiving donated drugs must be patients of the OSU health system, donors do not. All drugs must be donated directly by the patient to the health system, not through an intermediary such as a local physician.

42% of patients depleted their life savings within

2 years of a cancer diagnosis Source: Am J Med. 2018;131[10]:1187-1199.e5.

—Ray Page, DO, PhD

“Day after day, our physicians and pharmacists have patients bring in full or partial bottles of their oral chemotherapy medications, often unopened and sometimes still sealed, saying: ‘My therapy changed and I just received this in the mail,’ or ‘My dose was reduced, and I just picked this up from the pharmacy yesterday, but I can’t use it,’” said Julie Kennerly-Shah, PharmD, the associate director of pharmacy at the James Cancer Hospital, in Columbus. “Oncology patients are acutely aware of the financial toxicity that a cancer diagnosis brings upon them, and on others like them. Many had barriers accessing these drugs in the first place, such as high copays and long waits for prior authorization. They want to do something with these drugs to help other people, rather than just waste them.”

Pilot Program With 2 Drugs OSUCCC began collecting donations for its cancer drug repository program in January, with a small pilot initiative

On Feb. 19, 2020, the American Society for Clinical Oncology (ASCO) released a position statement outlining its support for drug repository programs solely for oral medications, provided they are maintained within a closed system. ASCO noted that 13 states have laws that permit repository programs for unused cancer drugs, supplies and devices. Nevertheless, besides OSUCCC, it appears that few, if any other medical centers or pharmacies have significantly invested in developing a cancer drug repository.

Texas Center Working On a Program Ray Page, DO, PhD, a medical oncologist and hematologist at The Center for Cancer and Blood Disorders in Fort Worth, Texas, and the immediate past chair of ASCO’s Clinical Practice Committee, has been advocating for the creation of a cancer drug repository in the state for several years. Legislation was passed in 2017, after which the Department of State Health Services’ Pharmacy

Staff Required for Redispensing Establishing a full-scale cancer drug repository at OSUCCC will require a significant investment from a personnel and facilities standpoint, Dr. Kennerly-Shah said. “This process requires a lot of inspections to ensure that medications are safe to dispense to another patient but also space for them to be stored and inventoried … to be redispensed. While we don’t yet have enough data to know how much staff time this will require, we are anecdotally anticipating that the program will need a pharmacist and technician dedicated to it, with the ability to also have flextime to support the general retail pharmacy operation. As the program grows, it may require the full-time support of the pharmacist and technician, but we won’t know that until we have enough experience with the inspection and redispense process.” Drug repository laws vary by state. Texas law, for example, requires that donated medications be in their

“The response has been tremendous so far,” Dr. Kennerly-Shah said. “We are hearing from patients all over Ohio and even outside the state, asking if they can donate their medication to us.” The significance of cancer drug repository programs as a resource for patients in need is underscored by a 2018 study finding that 42% of patients had depleted their entire life savings within two years after a cancer diagnosis ((Am J Med d 2018;131[10]:1187-1199.e5). “Patients are switching to less optimal therapies or even skipping doses and avoiding appointments, engaging in risky behaviors to limit their costs,” Dr. Kennerly-Shah said. “Financial toxicity is an enormous burden on cancer patients and their families, and we want to do everything we can to reduce additional stressors for them so they can focus on getting well.” —Gina Shaw The sources reported no relevant ﬁnancial relationships.

Technology

Pharmacy Practice News • May 2020

Disaster Preparedness

Trying Telepharmacy? Here’s What You Need to Know E

very American health facility is scrambling to figure out the best way to fight the COVID-19 pandemic. Recently, the CDC suggested that providers use telemedicine whenever possible (bit.ly/2Uklk5x; bit. ly/2U3yrsN). For pharmacists accustomed to treating patients in a traditional brick-and-mortar setting, a rapid transition to telepharmacy may seem daunting. Indeed, there are many barriers that prevent pharmacists from quickly providing all services to patients in a remote fashion, but even simple phone calls enable pharmacists to remotely check in on patients and answer their questions, said Timothy P. Stratton, PhD, RPh, a professor of pharmacy practice at the University of Minnesota College of Pharmacy in Duluth. “For patients, telepharmacy can be provided through a number of different formats.”

Learn From What Works For nearly one year, David Bush, RPh, has been working as a telepharmacist and the owner of Medicap in Hancock County, Ind., serving rural patients who don’t have easy access to a traditional pharmacy. Patients travel to a designated building that contains an iPad they can use to video chat with Dr. Bush directly; he watches as the onsite pharmacy technician prepares the prescriptions. There are many advantages to telepharmacy, Dr. Bush told Pharmacy Practice News: It saves patients and providers time, and enables him to reach patients he couldn’t otherwise. “I think that’s huge.” Some rural hospitals have reported that the rate of errors has improved since they began using telepharmacists ((Am J Health Syst Pharm 2010;67[13]:1085-1092). But there are many reasons why traditional pharmacists can’t quickly switch all their services to a remote format, he said. The main barrier is that any communications between provider and patient—video chat, emails and text messaging—have to be compliant with HIPAA, and that isn’t easy to do. His telepharmacy contains tablets with proprietary encryption software that ensures any communications are secure. (Of note: President Donald Trump’s administration recently extended telehealth services to Medicare patients, and would stop enforcing some aspects of HIPAA that might impede remote communications [for more information, see page 43].) Still, telepharmacists who want to

use more than a telephone will have to do some research, because regulations vary state by state ((J Pharm Pract 2020;33[2]:176-182). In Minnesota, for example, pharmacies can use the Department of Human Services’ statewide Vidyo video conferencing network to provide telepharmacy services, such as medication therapy management, to patients who have a mental health diagnosis, Dr. Stratton said. “But to do so, the pharmacy may need to purchase hardware that is compatible with the state system.” In the future, pharmacists who want to work from home possibly could do service-level work with minimal complications, said Dr. Bush, such as calling patients to check on their adherence, and ensure they are taking their medicines appropriately. “I can do all kinds of different things. I don’t have to dispense products; I am just providing services on the other side.”

More Barriers Telepharmacy has a long way to go before it becomes an easy way to work, Dr. Stratton said; beside the issues with HIPAA compliance, there are problems with reimbursement. “Many states do not pay pharmacists for providing telepharmacy services, nor are all private insurers willing to pay pharmacists for providing telepharmacy services.” Although telepharmacy often can save providers time, they may struggle with time management, noted Dr. Stratton, because telepharmacists are often juggling other responsibilities. For instance, St. Luke’s Hospital in Duluth serves as the hub hospital for the “Wilderness Coalition,” a consortium of small critical access hospitals throughout Northeast Minnesota’s Arrowhead Region. Eight of these small

hospitals used St. Luke’s pharmacists to remotely review orders during nights and weekends and then release medications through automated dispensing cabinets at the remote hospitals—all while keeping up with their regular duties at St. Luke’s.

“The hospital had to ensure that those shifts were adequately staffed that the telepharmacist would be able to focus on the needs of the remote hospitals when needed,” Dr. Stratton said. Some patients who want to temporarily switch from a traditional pharmacy to a telepharmacy outlet during the pandemic may wish to do so, but the remote system can’t handle too many new patients at once, Dr. Bush cautioned. “If we took everyone out of big-box pharmacy and dumped them all to telepharmacy, I don’t think anyone working in telepharmacy would be staffed sufficiently to handle large volumes.” For now, he recommended that patients who don’t have easy access to a telepharmacy outlet can maintain their social distancing by using the drive-through window. —Alison McCook The sources reported no relevant ﬁnancial relationships.

52 Technology

Opinion

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12 Reasons for the Lag In Pharm Tech Adoption Jerry Fahrni, PharmD

4. Regulatory requirements.

Founder, Jerry Fahrni Consulting Fresno, California

The pharmacy field is heavily regulated. Regulations are continuously added and changed with no hope of relenting anytime soon. Dealing with these changes to ensure compliance requires a disproportionate amount of pharmacy time and personnel, often usurping limited resources that could be used for other projects. Understanding that regulatory changes are ongoing and repetitive, it is in the best interest of pharmacy leadership to consider this a unique and separate operational role, requiring a dedicated resource.

s part of the Information Age, technology has become indispensable. Standardization and interoperability of systems are no longer optional. Yet pharmacy continues to lag in adopting and implementing new technologies. The explanation for this discrepancy is unclear. Here we explore some of the barriers that pharmacies face as they attempt to enter the technology revolution, as well as some strategies for breaking through them.

1. Lack of capital or budget. As a pharmacy technology consultant, I’ve conducted more than 100 interviews with pharmacy personnel, from the executive level on down, and cost is perhaps the No. 1 reason cited for failing to implement new technology. On the surface, this is logical. However, consider for a moment that 1) technology has the potential to save money over the long term, and 2) many technologies are relatively inexpensive when compared with some routine operating costs. Given these realities, the cost barrier, at least in some cases, needs to be reconsidered.

2. Limited resources. Beyond financial resources, pharmacies often lack time and personnel to plan for, implement and maintain technologies. It is not uncommon for medical centers—and by extension, pharmacies—to plan only for the immediate resources necessary to maintain routine operations while failing to plan for future expansion and optimization. But as noted below, the right planning can help solve the resource problem and get a project off the ground.

3. Lack of well-trained support staff and expertise. In their sim-

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Pharmacy Practice News • May 2020

plest form, projects have three distinct phases: planning, implementation and post-implementation. It is frustratingly common for groups to fail to include post-implementation support for projects. Availability and expertise of resources after implementation are key to the success of the project. Regardless of how well a project is planned, there is a high likelihood that issues will arise following the “go-live” phase. For this reason, it is imperative to have dedicated, well-trained support personnel with a deep understanding of the system available to troubleshoot issues and answer questions. Doing so prevents small problems from becoming big ones, and keeps staff frustration from growing.

5. Product and vendor immaturity and usability. Technologies used by pharmacies are not new. Barcode scanning, gravimetric analysis, radiofrequency identification (RFID), remote temperature monitoring, automated carousels, inventory management software, highspeed unit-dose packagers, and more have been around for many years, and in some cases decades. However, not all these technologies have been optimized for pharmacies, which can lead to products that are difficult to use, impossible to integrate with existing systems, and have questionable reliability and support. These gaps, in turn, can make the product objectionable to decision makers. As a result, it is best to manage expectations and provide perspective. Technology is continuously evolving and improving. Even in their current state, many technologies offer opportunities for improved operations and patient safety.

6. Lack of interoperability. Accessing, processing and using data are key components of pharmacy practice. The need for interoperability is greater than ever before, especially with the adoption of electronic health record systems. Unfortunately, much of the data that clinicians need resides in isolated “information silos.” Few of the technologies used in pharmacy operations offer true interoperability and integration between systems. The inability to connect systems severely limits their value. Unfortunately, this is a longstanding problem with no quick or easy solution in sight. Each pharmacy will have to decide for itself how best to prioritize this functionality.

7. Lack of health care technology research. Pharmacists have traditionally referenced journals and books to stay abreast of practice changes. This approach has not worked well for technology. Current literature models suffer from two significant flaws:

Technology

Pharmacy Practice News • May 2020

Opinion 12. Expectations, usability and experiences. Our personal lives

Gravimetric analysis, radiofrequency identification (RFID) and remote temperature monitoring are among the pharmacy technologies with uneven adoption rates.

1. Wide ranges of health care technology are treated as “generic.” Some articles on general topics can be found, but almost none on specific systems and workflows. 2. Existing literature publication models are too slow to keep up with changes in technology. Every year brings more literature, but much of it is outdated by the time of publication. Failure of the modern literature model has resulted in a lack of depth and breadth of knowledge regarding the use of technology in pharmacy operations. Alone, technology can do nothing. Experience gained from both successes and failures must be focused on, amplified and explored.

8. Obsolete practice modes. The basic model for pharmacy medication distribution is simple: Get medications to patients as safely, efficiently and costeffectively as possible. Unfortunately, the pharmacy distribution model has not kept up with technological advances in purchasing, materials handling, logistics, transportation, inventory control, and supply chain management. A 2009 vision statement by the ASHP Section of Pharmacy Informatics and Technology underscored this challenge: “Pharmacy practice, especially practice within the acute care setting, is largely unchanged from what it was 30 years ago. … [Too] many pharmacists continue to practice in the acute care settings that provide roughly the same services, using the same practice model now, that they did in 1976.”1 Put simply, introducing technology into an outdated practice model is unworkable.

9. Poorly defined benefit and an uncertain return on investment. Undefined best practice plus an outdated practice model equals an uncertain return on investment (ROI) for many pharmacy technologies. An ROI can take many forms: decreased overall operational costs, decreased labor and increased efficiency, decreased drug waste, and so on. Unfortunately, without a solid understanding of a given technology and how best to use it, it is difficult to calculate or even estimate a true ROI. Such uncertainty makes

justifying the investment in these systems nearly impossible. Anecdotally, technology brings increased efficiency, cost savings and improved safety. Although useful in some circumstances, anecdotal evidence requires additional quantitative data to provide value.

10. Lack of strategic planning and failure to prioritize. In an article highlighting the difficulties inherent in automating the medication use process, Troiano et al points to two major challenges: getting stakeholder input and building enough advanced planning into the process. 2 “In order to gain the benefits from [technologies],” the authors stated, “the implementation requires organizational commitment with extensive user input to change work processes as well as the wise use of a range of supporting tools. This commitment must include short- and long-term strategic goals that advance pharmacy practice through the use of technology.” Unfortunately, organizations are inundated with similar needs for many departments. Given the number of requests, it is difficult for executive leadership to prioritize. Sometimes the choice is made easy due to a patient safety issue, broken equipment or new regulatory requirements that necessitate change. At other times, prioritization is based on the organization’s operational strategy. Regardless of the reason, prioritizing pharmacy projects is necessary to ensure continued growth and efficiency of pharmacy operations.

11. Resistance to change. Change in health care is “even harder than in most industries,” Brickman et al noted in an article exploring how to get health care employees onboard with change.3 “Clinical and administrative staff often view their work as a vocation as much as a profession, and they are historically suspicious of senior administrators and resistant to strategic agendas.” However, change is essential for growth and development. It is important that leadership teams show commitment, be positive, demonstrate persistence and perseverance, have patience, and be honest, i.e. never try to package a negative change as positive. Although it is nearly impossible to eliminate fear of change, there are many excellent books on change management to help guide one through the process.

are filled with technology, from our smartphones to our home appliances. Experiences with these technologies often carry over into the workplace. This can lead to unrealistic expectations, or in some cases, negative user experiences. Unfortunately, researchers have discovered that negative memories are more resistant to decay over time than their positive counterparts. Elizabeth Kensinger, PhD, of Boston College’s Department of Psychology, wrote in her research that “negative memories may edge out positive ones: It really does matter whether [an event is] positive or negative in that most of the time, if not all of the time, negative events tend to be remembered in a more accurate fashion than positive events.”4

Conclusion When viewed individually, the challenges and barriers discussed above seem relatively straightforward. There are various resources and techniques available to easily handle each. However, when taken together, the path to overcome such obstacles becomes less clear, which may explain, at least partially, why pharmacy continues to

lag behind other industries in adopting technology. Despite these challenges, it remains in the best interest of pharmacies to work through each barrier to introduce technology into existing operations to create safer, more efficient and cost-effective workflows. Dr. Fahrni provides consulting services for medication use, pharmacy operations and health care information technologies. His specialty areas include pharmacy systems integrator, systems design, operational workﬂows, health care informatics, pharmacy informatics and distribution systems, electronic health records, electronic medication administration records and mobile health.

References 1. ASHP. Technology-enabled practice: a vision statement by the ASHP Section of Pharmacy Informatics and Technology. Am J Health Syst Pharm. 2009;66(17):1573-1577. 2. Troiano D, Morrison J, Federico F, et al. Safely automating the medication use process: not as easy as it looks. J Healthc Inf Manag. 2009;23(4):17-23. 3. Brickman J. How to get health care employees onboard with change. Harvard Business Review. November 23, 2016. bit.ly/3bzUmOH. Accessed April 23, 2020. 4. Kensinger E. Negative emotion enhances memory accuracy. Curr Dir Psychol Sci. 2007;16(4):213-218.

54 Technology

Pharmacy Practice News • May 2020

Medication Safety

Push Is On to Make IV-Workﬂow Systems Universal I

n December 2014, a 65-year-old woman was at home in Bend, Ore., recovering from brain surgery she recently had undergone in Seattle. After experiencing bouts of anxiety, she went to the ER at a local hospital, where the doctor ordered IV fosphenytoin, a low-risk antiseizure medication that also frequently is used to treat anxiety. The order was sent to the pharmacy, where it was reviewed and sent to the cleanroom. The bag was prepared, labeled with a barcode, and checked by the pharmacist. It was then delivered to the ED, where the attending clinician scanned the patient’s wristband and the IV bag; they matched. The bag was hung, a drip was started, and 30 minutes later, Loretta McPherson was brain-dead. Forensic analysis revealed that instead of fosphenytoin, the pharmacy technician accidentally had pulled the paralytic agent rocuronium. A few hours’ north on I-5, in Bellevue, Wash., medication safety technology expert Mark Neuenschwander read the headline about McPherson’s death with horror. For the past two decades, he had been a passionate advocate of bedside barcoding in hospitals, helping to lead the push for the FDA to require all immediate drug packages to be labeled with scannable barcodes. However, a scannable barcode could not save McPherson. “I realized that bedside barcoding can neither detect nor intercept preparation errors in the pharmacy,” Mr. Neuenschwander said. This medication error inspired Mr. Neuenschwander to organize a new movement aimed at placing IV workflow management systems (IV-WMS) in all health care facilities where medications are compounded. After

exceed criteria outlined in “THRIV’s Technology Checklist” (see page 4) but also to require health care providers to use them when preparing IVs.

Nearly 1 in 10 Preparations Incorrect

several years of organizational effort, the THRIV Coalition for IV Accuracy was formed officially in 2019, with its website (www.thrivcoalition.org) launched at the ASHP 2019 Midyear Clinical meeting in Las Vegas. “We must use proven technologies that make it harder for pharmacy technicians to mix things wrong and easier to mix them correctly, [that]

MUSC: An Early Adopter

ne enthusiastic supporter of THRIV’s efforts is Jeff Brittain, PharmD, the director of pharmacy support services at the Medical University of South Carolina (MUSC), in Charleston. “I’m 100% behind THRIV,” Dr. Brittain said. “It can be hard to understand the advantages of IV-WMS until you see them in your own pharmacy, because most pharmacies don’t realize how inaccurate they really are. You can do a lot of education, add manual steps, and put on high alert stickers, but those are not forcing functions. They don’t necessarily have that much effectiveness. There’s a better way.” MUSC first began exploring IV workflow systems in late 2009 and early 2010, when the market was still in its infancy. Dr. Brittain and his team reviewed the three different IV workflow products that were then on the market, and ultimately selected Baxter’s DoseEdge. MUSC went live with its IV-WMS in September 2011, rolling the technology out in the children’s hospital the first week, the cancer center the second week, and then other areas of the hospital. Approximately 2,200 IV preparations go through the IVWMS across MUSC Health daily. Dr. Brittain reported that the scanning process identifies and rejects about 3% to 5%

don’t allow preparers to proceed to the next item on an order’s checklist until the previous item is fulfilled correctly,” Mr. Neuenschwander said. Although the coalition advocates for health care institutions to voluntarily adopt IV-WMS, THRIV also is pushing for standards, compliance and accrediting bodies to not only accept workflow management systems that meet or

of items for dose preparation as inappropriate. “If you get into the hood where the scanner is, we assume you intend to use that ingredient to make the dose, so when an incorrect scan is recorded at that stage, we count it as a prevented error and attribute the prevention to the system,” he said. “At the pharmacist level, we now have less than 0.3% of scans rejected. Before we had an IV-WMS, we saw roughly a 5% rejection rate when preparations came to the pharmacist for verification. So we are eliminating many potential errors before we even open the vial. That reduces waste as well.” There have been other benefits, Dr. Brittain said. “We have used the data to narrow down the number of concentrations that we have. We get data out of the system on each step of the preparation, which provides a whole new world of metrics to help us adjust things like workflow, staffing and the times batches run.” Other IV-WMS systems include ARxIUM’s RIVA, BD Pyxis IV Prep, ConsortiEx Assure-Trak, Equashield, Grifols Kiro and PharmacyKeeper, ICU Medical’s Diana, and Omnicell IVX Workflow. Some electronic health records also have introduced workflow modules, such as Epic’s DispensePrep. —G.S. The sources reported no relevant ﬁnancial relationships.

How often do IV preparation errors occur? An observational study of accuracy in compounding IV formulations at five hospitals found a 9% error rate ((Am J Health Syst Pharm 1997;54[8]:904-912); most of the errors involved wrong ingredients and/or volumes. “Imagine if Amazon fulfilled one in every 10 packages incorrectly, or Delta lost one of every 10 bags checked,” Mr. Neuenschwander said. “And nobody’s ever been killed by a late bag or getting the wrong package.” A more recent systematic review of published evidence on IV admixture preparation errors found a substantial variation in error types and reported rates: wrong drug (approximately 0%-4.7%), wrong diluent solution (0%49.0%), wrong label (0%-99%), wrong dose (0%-32.6%), wrong concentration (0.3%-88.6%), wrong diluent volume (0.06%-49%), and inadequate aseptic technique (0%-92.7%) (BMJ ( Open 2017;7:e015912). Research consistently suggests that IV-WMS reduce errors. For example, evaluation of such a system at Boston Children’s Hospital found that 23% of the errors detected would not have been identified by the pharmacy’s previous practices ((Am J Health Syst Pharm 2014;71[15]:1311-1317). Meanwhile, only about 20% to 25% of hospitals report that they are now using IV-WMS. “Many of those either have systems that don’t meet THRIV’s minimum criteria or they are using the systems to prepare a low percentage of their IV medications,” Mr. Neuenschwander said. “In fact, the hospital in Bend had IV workflow technology in their pharmacy [that] faithfully intercepted errors but had to suspend its use due to upgrading [of ] its hospital information system. The adoption rate is low and the utilization is shallow. THRIV’s goal is to get to the point where these safety systems are expected of hospitals by regulatory and accrediting bodies. We don’t believe we will get near universal adoption until [these systems] are required.” According to ASHP’s 2019 hospital survey, cost is the No. 1 barrier to IV workflow management adoption. “This I do not understand, because IV-WMS are relatively inexpensive,” Mr. Neuenschwander said. “A 200-bed hospital could easily spend a million dollars or more to comply with USP’s

Technology

Pharmacy Practice News • May 2020

Medication Safety Chapter <797> sterility requirements, while IV workflow technologies that meet or exceed THRIV’s standards could be obtained for considerably less than $100,000.” The survey cited lack of space as the second barrier. “Perhaps respondents were thinking of large robotic workflow devices,” said Mr. Neuenschwander, but he noted that small, semiautomated tabletop components (tablets, scanners, camera, scales) can achieve all the same safety goals as large robotic systems. Also, many pharmacists experience

THRIV’s 5 MustHave IV-WMS Technologies 1. Workflow Management Software Software that guides compounders and/or robotics step-by-step through IV mixtures: • Linked with medication order systems to populate user interfaces with up-to-date IV orders, which may be re-queued as urgency requires. • Guiding compounders stepby-step through each mixture with specific instructions and forcing functions that do not allow proceeding to next steps until previous steps have been completed and verified.

2. Barcode Scanning • Scanning barcodes to ensure all components/ingredients are correct.

3. Volume Verification Employing a combination of proven technologies that verify volumes of base solutions and additives are correct, which include: • In-process image capture (or live video): requiring and enabling a second set of eyes to verify right drugs and right volumes were used. • Gravimetrics: weighing ingredients before and after draws and fills to verify volumes and final products. • Flowmetrics: technologies that automatically release, measure and verify delivered volumes. • Optical volume recognition: employing technological eyes to auto-verify syringe draws.

4. Auto Labeling • Barcoded labels produced or verified and activated for final preparations.

5. Auto Documentation • Concurrently auto documenting and time-stamping each preparation step.

“sales fatigue” from requesting funding from institutional leadership to acquire these systems, he conceded. “I have not yet met a pharmacist who does not believe in IV workflow technology. They know it’s the right thing, but they are weary from having their repeated requests routinely turned down. THRIV seeks to motivate, encourage and equip pharmacists to not let up, to influence their hospitals to voluntarily implement these systems now, and not wait until they are mandatory.” The Institute for Safe Medication

Practices (ISMP) is a THRIV organizational advocate. “Barcode verification and gravimetrics coupled with real-time alerts created by workflow management systems can detect and prevent many potentially serious medication errors that would not have been recognized with traditional verification methods,” said Michael R. Cohen, RPh, the president of ISMP. “We strongly support their use, but ISMP doesn’t have any enforcement power. We need an organization that has the force of law to take this up and

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 p 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 p 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. Postmarketingg Experience p 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 p 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 p Local Anesthetics EXPAREL should not be admixed with local anesthetics other than bupivacaine. Nonbupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. There are no data to support administration of other local anesthetics prior to administration of EXPAREL.

Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior to administration. Water and Hypotonic yp Agents g 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 Summaryy 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 Summaryy 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 g 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

[mandate compliance]. “Realistically, it will take time to make these standards mandatory,” Mr. Cohen said. “But IV workflow errors are among the most dangerous errors we see in hospitals. In the meantime, I would really hope that people would go to the THRIV website, download the guidelines, and make sure they are compliant.” —Gina Shaw The sources reported no relevant ﬁnancial relationships.

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 g 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 g Analgesia g 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

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 A id additional dditi l use off llocall anesthetics th ti within ithi 96 h hours ffollowing ll i 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.

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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.