Pharmacy Practice News (June 2020) by McMahon Group

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The Best-Read Pharmacist’s News Source

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CLINICAL

A hub for anticoagulation in rural areas .......................

Micronutrients as therapy in the ICU ........

Optimizing nutrition in critically ill children .....

Standardize 4 Safety initiative gains traction .................

POLICY

COVID-19 takes a toll on sterile compounding ...............

A reimbursement checkup at the half-year mark ..............

OPERATIONS & MGMT

Keeping the cold chain strong during COVID-19 ....................... 25 REVIEW ARTICLE

See page 8.

The Need for Biosimilars in Oncology: Challenges In Development See insert after page 14.

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NYU Langone’s Lessons Learned While Fighting COVID-19 Pandemic B

eing at the epicenter of the COVID-19 pandemic, pharmacists at New York University (NYU) Langone Health discovered they had to quickly revamp many of their operating procedures, adapting their staffing ffing and oncall schedules, stocking drug cabinets abinets and purchasing orders to handle le the influx of severely ill patients. But those tasks weren’t the only adjustments the team m had to make. NYU Langonee pharmacists also had to step up their presence on code response teams as patients’’ cardiopulmonary systems crashed rashed under the weight of COVID-19. 9. And they also had to support each h other with stepped-up wellness outreach to address the emotional toll of being front-line responders. As the COVID-19 surge started to mount, scheduling was the main priority. “It became very apparent that we needed to be on the floor to assist iin the direct patient care management

and day-to-day activities of our COVID ICU and acute care units,” said John Papadopoulos, PharmD, the director of clinical pharmacy services at the nearly 1,000-bed Tisch Kimmel campus, in New York City, during an ASHP webinar. He and his team soon realized Y tthis was going to be an “always on” preparedness push. Continued on page 6

Targeting potentially harmful pediatric medications T

Supportive Care After Hematopoietic Cell Transplant

Volume 47 • Number 6 • June 2020

As Beers List for Kids Debuts, New Research Replaces ‘Lore’

he publication of the Beers List in 1991 was a seminal event in the prevention of adverse drug events in older adults. Now, younger patients stand to benefit from a similarly ground-breaking effort in pediatrics. The KIDs (Key Potentially Inappropriate Drugs in Pediatrics) List, published this spring in the Journal of Pediatric Pharmacology and Therapeutics (2020;25[3]:175191), contains 67 drugs and 10 excipients that are potentially inappropriate for prescribing in all or some pediatric patients. David Hoff, PharmD, one of the KIDS List developers, said he first had an inkling of its need about 25 years ago, when he spent

ISMP alert: t:

Remdesivir i i E Error Points to Common Labeling Problem

time focusing on what medications should and should not be used in pediatric patients. In the ensuing years, he developed a list of drugs in his head acquired through the experience of his mentors, passed down like lore. “We learned it through verbal tradition, and took it on faith that what was being told to us was the truth,” said Dr. Hoff, a clinical leader at Children’s Hospitals and Clinics of Minnesota, in Minneapolis. “Over time, I found that research seemed to confirm some of the drugs on my list that you should use with caution or avoid in kids, and seemed to refute others.”

onfusion over remdesivir vial labels was a prime factor in a compounding error that resulted in overdosing multiple COVID-19 patients at one unidentified hospital, according to the Institute for Safe Medication Practices’ weekly Acute Care Medication Safety Alert!. “Like many investigational drug container labels,” the ISMP alert stated, the remdesivir vials were “not clearly labeled” and the information was “crowded and in a small font.”

Continued on page 20

Continued on page 3

COVID-19 Pandemic More coverage: pages 12, 16, 22, 24, 25.

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Ask your Baxter representative for more information and potential cost savings with CLINOLIPID. Brief Summary of Prescribing Information See Package Insert for Full Prescribing Information HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CLINOLIPID safely and effectively. See full prescribing information for CLINOLIPID. CLINOLIPID (lipid injectable emulsion), for intravenous use Initial U.S. Approval: 1975 WARNING: DEATH IN PRETERM INFANTS • Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. INDICATIONS AND USAGE CLINOLIPID is indicated in adults for parenteral nutrition providing a source of calories and essential fatty acids when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: • CLINOLIPID is not indicated for use in pediatric patients because there is insufficient data to demonstrate that CLINOLIPID provides sufficient amounts of essential fatty acids in this population • The omega-3: omega-6 fatty acid ratio in CLINOLIPID has not been shown to improve clinical outcomes compared to other intravenous lipid emulsions DOSAGE AND ADMINISTRATION • Use a 1.2 micron in-line filter when administering to a patient • See full prescribing information for administration and admixing instructions • CLINOLIPID is intended for intravenous infusion. • The recommended dose depends on energy expenditure, clinical status, body weight, tolerance, ability to metabolize and consideration of additional energy given to patient. The usual daily lipid dosage in adults is 1 to 1.5 g/kg/day and should not exceed 2.5 g/kg/day. 1. SCCM/ASPEN Guidelines [Jan. 2016]. 2. Nutrition Therapy in the ICU Patient with COVID-19 Disease Requiring ICU Care (April 2020). Baxter and Clinolipid are trademarks of Baxter International Inc., or its subsidiaries. USMP/CLN/19-0030b 5/2020

DOSAGE FORMS AND STRENGTHS CLINOLIPID 20% is a lipid injectable emulsion. The lipid content is 0.2 grams/mL in 100 mL, 250 mL, 500 mL, and 1000 mL. CONTRAINDICATIONS • Known hypersensitivity to egg and soybean proteins, the lipid emulsion and/or excipients. • Severe hyperlipidemia or severe disorders of lipid metabolism. WARNINGS AND PRECAUTIONS • Preterm infants have poor clearance of intravenous lipid emulsion. • Monitor for signs or symptoms of hypersensitivity reactions. • Monitor for signs and symptoms of infection, fat overload, hypertriglyceridemia and refeeding complications. • Frequent clinical and laboratory determinations are necessary. • The aluminum contained in CLINOLIPID may reach toxic levels with prolonged administration in patients with impaired kidney function. • Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who receive parenteral nutrition for extended periods of time, especially preterm infants.

ADVERSE REACTIONS The most common (5%) adverse drug reactions from clinical trials were nausea and vomiting, hyperlipidemia, hyperglycemia, hypoproteinemia and abnormal liver function tests. To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS The anticoagulant activity of coumarin derivatives, including warfarin, may be counteracted. USE IN SPECIFIC POPULATIONS Hepatic Impaired: Use with caution in patients with preexisting liver disease or liver insufﬁ ciency. Please visit www.baxterpi.com for Full Prescribing Information

Baxter Healthcare Corporation One Baxter Parkway Deerﬁeld, IL 60015 www.baxter.com

Up Front

Pharmacy Practice News • June 2020

ISMP Alert continued from page 1

The confusion was aggravated by the fact that the hospital, which was taking part in a clinical trial of Gilead Sciences’ investigational antiviral for severe COVID-19 patients, stocked two different versions of the drug. One formulation was a lyophilized powder for injection, 100 mg, and the second was an injectable solution with an equivalent 100 mg of the drug. However, the second vial was labeled 5 mg/mL, not 100 mg— and the only clue to the vial’s actual drug quantity was a separate line on the label that read “Contents: 21.2 mL.” The pharmacy technician who made the compounding error used the second formulation to mix the doses. Instead of adhering to the standard remdesivir infusion protocol—a loading dose of 200 mg (two vials) followed by doses of 100 mg (one vial)—the technician mixed 200-mg solutions for the subsequent and loading doses. A pharmacist did not catch the error during the checking process, and the infusions were administered to eight patients. The mix-up came to light at the end of the day during an inventory reconciliation for the drug. The ISMP alert noted that “no adverse reactions” had been reported up to the May 14 publication date. Michael R. Cohen, MS, RPh, the president of ISMP, said the lack of clarity was “typical of what we see with investigational drug labeling,” adding that “university pharmacy researchers who conduct

Investigational Drug Faux Pas

two-part series on medication errors associated with investigational drugs (IDs) by ISMP included the following product-related issues that led to mishaps, among others: Look-alike product identification. Many clinical sites that participate in ID studies are involved in multiple studies by the same sponsor; thus, the sponsor’s abbreviation preceding the identification number adds to ID name similarity. After the sponsor’s abbreviation, the numbers that are used to identify the different drugs may vary by just the last digit (e.g., BMS-123456, BMS-123457, BMS-123458), further contributing to name similarities. Unlabeled products. Some IDs are shipped by the company or a third-party supplier to a clinical site without any labels. While the outer carton and shipping slip may identify the drugs, the individual product containers are unlabeled. Missing, confusing or unnoticeable drug name. The labels on IDs often contain various numbers in nonstandard locations. For example, the label may include the license plate–type number, a study or protocol number, a lot number, and a kit number, making it hard to discern the meaning of each set of numbers. Missing or hard-to-find strength. The product strength or concentration may also be missing or not prominent on ID labels, even if there are multiple drug strengths in use for open-label protocols. Although blinding of the dose may be necessary for some studies, practitioners must be able to select and dispense the correct product strength. International labels. For international studies, paper labels and protocol information in up to 15 different languages may be included behind a peel-off label on the container (see image). With these paper labels, practitioners at clinical sites have complained about how hard it is to access the necessary information, first because the adhesive on the peel-off label is often strong, and then because they must browse through many pages of labels to find the desired language.

investigational drug studies complain about it bitterly.” Some drugs, Mr. Cohen said, “have nothing more than a code number and no instructions. Others have no labels. The carton might be labeled, but when the box is opened, the vials have no labels whatsoever.” This was not the first time ISMP raised the issue. Two years ago, the organization published a two-part series on the way poorly labeled investigational drugs increased the risk for undetected errors

and adverse patient outcomes (bit.ly/ 2TpagVc; bit.ly/2Tmo6Yj) (sidebar).

A Long-Standing Problem Richard Needleman, BSc Pharm, the investigational drug services pharmacist at Temple Health’s Fox Chase Cancer Center, in Philadelphia, said the FDA provides “minimal guidance” for labeling investigational products, unlike its strict oversight of approved commercial drug labels. “Safety is rarely, if ever, a

EDITORIAL BOARD

Late Breaker concern during the design process,” Mr. Needleman said. “In my experience with thousands of oncology clinical trials, I’ve received drug bottles and vials that had no labels, no drug strength, no concentrations and no drug names. “This lack of an acceptable label,” he added, “dramatically increases the medication safety burden at the site and increases the chance of a medication error that can produce a severe adverse patient event, including death.” Mr. Needleman, who is also a member of the Alliance of Dedicated Cancer Centers’ Investigational Drug Services group, said the group “strongly believes that investigational drug labels should have expanded FDA requirements. We have been working with ISMP over the last few years to achieve this legislation.”

Corrective Action Problems with remdesivir labeling have become less of an issue after a third version of the label was issued. That label was applied to vials of the medication used by hospitals for the most severe cases of COVID-19. The type is larger and the labeled contents much clearer. Mr. Cohen suggested that hospitals using the older clinical trial versions of remdesivir—or indeed any investigational drugs with unclear or missing labels— attach their own auxiliary label to the vials, ideally with a barcode that can be scanned “to work within your system.” —Bruce Buckley The sources reported no relevant financial relationships.

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The lowest Dilaudid dose available on the market exclusively from Fresenius Kabi

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INDICATIONS AND USAGE DILAUDID INJECTION is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve DILAUDID 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

DILAUDID INJECTION is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, known hypersensitivity to hydromorphone, hydromorphone salts, sulfite-containing medications, or any other components of the product. 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 in patients with circulatory shock.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness: Monitor for sedation and respiratory depression. Avoid use patients with impaired consciousness or coma.

See full prescribing information for complete boxed warning.

DILAUDID INJECTION contains sodium metabisulfite. There is a risk of anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people.

• DILAUDID 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. • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. • Prolonged use of DILAUDID 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. • 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.

Additional serious adverse reactions: Apnea, circulatory depression, respiratory arrest, shock, cardiac arrest, seizures, withdrawal, anaphylaxis. Most common adverse reactions: Lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. 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 can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, miosis (or mydriasis when hypoxia is present), and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. This Important Safety Information does not include all the information needed to use DILAUDID safely and effectively. Please see full prescribing information, including BOXED WARNING, for DILAUDID INJECTION available at www.simplist-us.com. Please see Brief Summary of Prescribing Information on the following page.

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Simplist DILAUDID INJECTION (hydromorphone hydrochloride) for intravenous, intramuscular, or subcutaneous use, CII BRIEF SUMMARY OF PRESCRIBING INFORMATION This brief summary does not include all the information needed to use DILAUDID INJECTION safely and effectively. Please see full prescribing information, including BOXED WARNING, for DILAUDID INJECTION atwww.fresenius-kabi.com/us. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISK FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse DILAUDID 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 DILAUDID INJECTION and monitor all patients regularly for the development of these behaviors and conditions Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of DILAUDID INJECTION. Monitor for respiratory depression, especially during initiation of DILAUDID INJECTION or following a dose increase. Neonatal Opioid Withdrawal Syndrome Prolonged use of DILAUDID 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 Or Other CNS Depressants 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 DILAUDID 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 DILAUDID INJECTION is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve DILAUDID INJECTION for use in patients for whom alternative treatment options [e.g., non-opioid 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 DILAUDID INJECTION is contraindicated in patients with: • Significant respiratory depression. • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. • Known or suspected gastrointestinal obstruction, including paralytic ileus. • Known hypersensitivity to hydromorphone, hydromorphone salts, sulfitecontaining medications, or any other components of the product. WARNINGS AND PRECAUTIONS (also see BOXED WARNING) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely at initiation, dose titration. See Contraindications for use in patients with bronchial asthma. • 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, wean the patient off of the opioid and treat with physiologic replacement doses of corticosteroids. • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use 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 DILAUDID INJECTION in patients with impaired consciousness or coma. • Risks of Use in Patients with Gastrointestinal Conditions: The hydromorphone in DILAUDID INJECTION may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. • Increased Risk of Seizures in Patients with Seizure Disorders: Monitor patients with a history of seizure disorders for worsened seizure control. • Withdrawal: When discontinuing DILAUDID INJECTION in a physicallydependent patient, gradually taper the dosage. Do not abruptly discontinue therapy in physically-dependent patients. • Risks of Driving and Operating Machinery: DILAUDID 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 DILAUDID INJECTION and know how they will react to the medication. • Sulfites: DILAUDID INJECTION contains sodium metabisulfite. See Contraindications. • Increased Risk of Hypotension and Respiratory Depression with Rapid Intravenous Administration: should be given very slowly. ADVERSE REACTIONS (see Boxed Warning and Warnings and Precautions) Serious adverse reactions: Addiction, abuse, and misuse, lifethreatening respiratory depression, neonatal opioid withdrawal syndrome, interactions with benzodiazepines and other CNS depressants, adrenal insufficiency, severe hypotension, gastrointestinal adverse reactions, seizures, withdrawal, respiratory depression and apnea, circulatory depression, respiratory arrest, shock, and cardiac arrest. Most common adverse reactions: Lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. Less frequently observed adverse reactions: tachycardia, bradycardia, palpitations, blurred vision, diplopia, miosis, visual impairment, constipation, ileus, diarrhea, abdominal pain, weakness, feeling abnormal, chills, injection site uticaria, fatigue, injection site reactions, peripheral edema, biliary colic, anaphylactic reactions, hypersensitivity reactions, increase in hepatic enzymes, decreased

appetite, muscle rigidity, headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence, agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams, urinary retention, urinary hesitation, antidiuretic effects, erectile dysfunction, bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling, injection site pain, urticaria, rash, hyperhidrosis, flushing, hypotension, hypertension, serotonin syndrome, and androgen deficiency. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA at 1-800-551-7176 option 5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. • Lactation: Low levels of opioid analgesics have been detected in human milk. Monitor infants for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydromorphone 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: Patients 65 years of age or older may have increased sensitivity to hydromorphone. 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 patients on one-fourth to onehalf the usual starting dose depending on the degree of impairment and closely monitor during dose titration. DRUG INTERACTIONS Clinically significant drug interactions with DILAUDID INJECTION: benzodiazepines and other CNS depressants, serotonergic and anticholinergic drugs, monoamine oxidase inhibitors (MAOIs), mixed agonist/antagonist and partial agonist opioid analgesics, muscle relaxants, diuretics. OVERDOSAGE Acute overdose with DILAUDID 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, atypical snoring, and death. Marked mydriasis, rather than miosis, may be seen with hypoxia in overdose situations. In case of overdose, reestablish patent and protected airway, institute assisted or controlled ventilation, manage circulatory shock, pulmonary edema, cardiac arrest or arrhythmias, as indicated. Administer opioid antagonists only for clinically significant respiratory or circulatory depression. Carefully monitor the patient until spontaneous respiration is reestablished. Administration of opioid antagonist in aphysically dependent patient should be initiated with care and by titration with smaller than usual doses of the antagonist. For full Prescribing Information please go to www.simplist-us.com

6 Clinical

Pharmacy Practice News • June 2020

COVID-19 Pandemic

Langone’s Lessons Learned continued from page 1

Dr. Papadopoulos said his team’s COVID-19 presence had to be seven days per week, including both a regular day shift and a second evening shift from 4 p.m. to midnight. His team, which included 20 clinical pharmacy managers and clinical pharmacotherapy specialists, and six pharmacy residents, quickly mapped out a schedule. With a “tremendous influx of patient volume, our ED was extremely busy, and our hospital leadership was very nimble in placing patients into newly designed floors both at the acute care and ICU levels,” Dr. Papadopoulos said. The pharmacy team then determined they needed a two-system model of care: For ICUs, pharmacists were made available on the floors. For acute care floors, pharmacists provided remote coverage, contacting providers by telephone or a secure chat platform to communicate their recommendations and assist with care plans. “No one had a road map for how to deal with a pandemic,” Dr. Papadopoulos said. “I think we were proactive, and we did the best we could on a day-to-day basis.” The pandemic led to many rapid changes for the pharmacy team, among them the on-call schedule. Dr. Papadopoulos happened to be on call during the first week of March, and said it felt like he got about four hours of sleep that week due to the volume of COVID-19-related requests for help in clinical care. It became unfeasible for one person to handle calls each week under such circumstances, he said, so the team divided the campus into sections, with five people per week taking charge of calls and medication requests, one for each section. They distributed a guidance document about the revised schedule to all providers, so they would know exactly who to call with questions. Additionally, the infectious diseases pharmacists put together an action plan for COVID-19 antivirals, he said. They also provided on-the-spot guidance for any pharmacotherapy specialist who was not ICU trained, including how to round in an ICU and help manage critically ill patients. They also developed action plans for stockouts and drug shortages, as well as how to assess the increase in information being published online in the medical literature about COVID-19, such as on cytokine release syndrome and venous thromboembolism prophylaxis. The team had a daily check in the afternoon to assess their plans and activities for the day, and pushed for honest communication to share feelings about the emotional and physical toll they were experiencing. “I was very open about speaking with anyone who had issues or just wanted to

talk; it’s important for us to also focus on our staff wellness,” Dr. Papadopoulos said. As new COVID-19 units were announced, the team determined how to optimize their staffing and their automated drug cabinets (ADCs), said Cristian Merchan, PharmD, a clinical pharmacy manager with NYU Langone. They noted who needed N95 face masks and other personal protective equipment (PPE), and came up with a plan for ADC stocking, medication deliveries, deployment of centralized pharmacy technicians and pharmacists available for code responses. Residents also were given assignments, with second-year residents assisting in ICUs, and first- and second-year residents asked to help with code responses and operational needs such as preparing IVs and stocking medication cabinets. The team also created a standardized medication list for COVID-19 patients, which included investigational antivirals and medications necessary to manage mechanically ventilated patients, Dr. Merchan said. The list included all drugs recommended to replace those on shortage, and pharmacists provided many of these medications to be readily available on the floors for use.

Optimizing ADCs Pharmacists also developed a multipronged approach to stocking the ADCs, starting by removing low-use medications, which freed up capacity for more commonly needed drugs. They increased their restocking efforts from one to three times per day by redeploying pharmacy technicians from closed units, with some additional restocks necessary for controlled substances and continuous infusions. If a default product was out of stock at the ADC, pharmacists automatically directed users to an equivalent product in stock in that cabinet. Order entry was another technology that required some tweaking. Focusing mainly on antivirals, investigational agents for COVID-19, continuous infusions and anticoagulants, the team made guidance documents available in their order entry system to make it easier for providers to confer with pharmacists, Dr. Merchan said. Patient lab results and echocardiogram readings were made visible on the order entry and pharmacy verification screens. The team also performed a systemwide update to smart pump libraries, centered on concentration changes, dosing sedatives and opioids, allowing boluses, and adding new drugs in case of a severe shortage. The huge volume of critically ill patients with COVID-19 triggered shortages of several medications, said Serena Arnouk, PharmD, a clinical pharmacotherapy

At the height of the COVID-19 pandemic, NYU Langone experienced a 10-fold increase in the usage of sedatives and vasopressors, “which was absolutely eyeopening,” said Serena Arnouk, PharmD, who works with the surgical ICU.

specialist who works in the surgical ICU. “At the height of the pandemic, we experienced a 10-fold increase in the usage of sedatives and vasopressors, which was absolutely eye-opening,” she said.

Innovating on Drug Shortages The medical center’s drug shortage committee increased communications from weekly to daily “purchasing huddles,” Dr. Arnouk said. There, inventory personnel from all campuses discussed what products they had difficulty acquiring and what they could redistribute among one another. Front-line clinical pharmacists communicated with operational and procurement teams regarding the projected number of patients per day and how the pharmacotherapy picture was dynamically changing. They also had to clearly communicate with vendors to provide justification for larger inventory purchases, especially for controlled substances used in the ICU, she said. To store the extra medications, the team identified extra storage space and purchased additional refrigerators, Dr. Arnouk noted. The informatics group created a report on the quantity at hand of the top 20-plus essential medications, noting stock in ADCs and products stored manually, and updated it daily. Medications they struggled to acquire consistently included sedatives, analgesics, paralytics, vasopressors and diuretics. The team ran a report in the electronic health record each day to see how many patients had orders for commonly used ICU infusions, and sent emails to rounding pharmacists informing them. They realized there was no single approach to sedation and paralysis that could be widely adopted without depleting their supplies, so they got creative. For IV fentanyl, rounding pharmacists helped ensure that half of patients were on the medication and half were given hydromorphone to avoid leaning on any single agent, Dr. Arnouk said. They also used some nontraditional agents to decrease the use of IV infusions, such as hydromorphone tablets, fentanyl patches, phenobarbital or enteral adjunctive agents such as gabapentin and

antipsychotics. This adaptation necessitated a clinical pharmacy presence to educate the staff and manage drug interactions and titrations, she said. “It’s definitely different and feels strange at times, but we’re doing what we need to do with the resources available to optimize our patients’ pharmacotherapy plans to safely sedate them, achieve ventilator synchrony and hope for a positive outcome,” Dr. Arnouk said. Overall, Dr. Papadopoulos said, “I am very proud of my entire team. We put aside all of our collective fears and concerns, we all put on our PPEs and went to the floors. At the peak of our COVID surge, we had 12 ICUs, 18 acute care units, the pediatric ICU and a busy [emergency department], and we covered these units as best as we could.”

Going on Overdrive ‘25/8’ The current crisis isn’t the first adverse situation to hit the New York City area, which also had to handle 9/11 and Hurricane Sandy. “But in this situation, they had to take the ball and run with a quickly evolving pandemic,” said session moderator Lisa Lifshin, BSPharm, the senior director of pharmacy technician program accreditation and residency services for ASHP. “It’s almost like they were going on overdrive 25/8.” Ms. Lifshin said she was very impressed by the pace in which the team got colleagues not used to handling ICU patients up to speed, learned about new drugs and ensured drug information was accurate and appropriate, and maintained their drug stock and storage, and by how they maintained professionalism in an extremely stressful situation. “They kept it together and used all of their resources to continue rounding, and maintain a level of care above and beyond that they’re accustomed to and that all members of the interdisciplinary team are used to having,” she said. “That doesn’t always happen in crisis situations.” —Karen Blum The sources reported no relevant financial relationships.

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8 Clinical

Pharmacy Practice News â&#x20AC;˘ June 2020

Educational Review

Pharmacologic Recommendations for

Supportive Care After Hematopoietic Cell Transplant AMANDA GERBERICH, PHARMD, BCPS Clinical Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

pproximately 23,000 hematopoietic cell transplants (HCTs) are performed in the United States annually for the treatment of malignant and nonmalignant diseases.1 The most common malignant

indications for HCT include multiple myeloma, non-Hodgkin lymphoma (NHL), and acute myelogenous leukemia (AML).1 Nonmalignant indications include diseases characterized by an abnormal lymphohematopoietic system, such as aplastic anemia and sickle cell disease.2,3

During HCT, recipients are given an infusion of stem cells to rebuild their lymphohematopoietic system, typically preceded by a myeloablative chemotherapy conditioning regimen that targets the underlying malignancy. Hematopoietic stem cells are harvested from a donorâ&#x20AC;&#x2122;s bone marrow, umbilical cord, or peripheral blood, with the donor being either the recipient (autologous HCT) or a human leukocyte antigen (HLA)-matched donor (allogeneic HCT). The majority of HCTs in the United States are autologous.4 Approximately 20% to 30% of allogeneic and 5% of autologous HCT recipients experience transplant-related death.2 Mortality can be caused by graft rejection, disease relapse, and transplant-related complications.2,3 Allogeneic HCT patients experience higher mortality from graft-versus-host disease (GVHD) that occurs due to HLA mismatching. Other complications affecting both autologous and allogeneic HCT recipients include immunosuppression, infection, and chemotherapy-induced toxicities. Pharmacologic supportive care can decrease complications associated with GVHD, immunosuppression, and infections.2,3 Recommendations for supportive care differ by transplantation source and patient risk factors. Pharmacologic options consist of immunosuppressive therapy for GVHD prophylaxis, colony-stimulating factors (CSFs) for myelosuppression, and antimicrobial prophylaxis for infections.

Graft-Versus-Host Disease Prophylaxis for GVHD should be given to all allogeneic HCT recipients immediately after transplantation.5,6 Prophylactic regimens typically consist of 2 immunosuppressive agents with

varying mechanisms of action to inhibit immune cell activation (Table 1).2,5,6 Although no US guidelines recommend a preferred prophylactic regimen, standard of care typically consists of a calcineurin inhibitor, such as tacrolimus or cyclosporine, in combination with a short course of methotrexate. Methotrexate is associated with hepatotoxicity and mucositis, which may limit the number of doses a patient can receive. As an alternative to a methotrexate-containing regimen, a regimen of sirolimus in combination with tacrolimus is comparable in preventing the occurrence of grades 2 to 4 GVHD and GVHD mortality. Although tacrolimus plus sirolimus is associated with less mucositis than methotrexate-containing regimens, sirolimus is associated with hypercholesterolemia, hypertriglyceridemia, elevated creatinine, and endothelial injury syndromes.5,6 For patients receiving a reduced-intensity conditioning

regimen before HCT, mycophenolate mofetil may be used in combination with either tacrolimus or cyclosporine for prophylaxis. Other agents used for GVHD prevention include pentostatin, cyclophosphamide, rabbit anti-thymocyte globulin, and alemtuzumab (Campath, Genzyme).2 Prophylaxis of GVHD with immunosuppressive agents may contribute to delayed white blood cell recovery, which is seen to a greater extent with methotrexate-containing regimens.7 Prophylactic agents typically are tapered beginning 50 to 100 days after HCT and are completely discontinued 180 days post-HCT.2 Treatment of GVHD usually involves topical and/or systemic steroids in addition to the immunosuppressive therapy used during prophylaxis.2,8 Immunosuppressive agents should be restarted in patients who have been tapered off prophylactic Text continues on page 10

Table 1. Common Immunosuppressive Agents Used for GVHD Prophylaxis Agenta

Administration

TDM Goal Trough

Tacrolimus

Initiate 1-3 days before HCT

5-15 mcg/Lb

Cyclosporine

Initiate 1-3 days before HCT

150-450 mcg/Lb

Sirolimus

Initiate post-HCT day 1

3-12 mcg/Lc

Methotrexate

Give post-HCT days 1, 3, 6, 11

Not routine

Mycophenolate

Initiate on day of HCT

Not recommended

GVHD, graft-versus-host disease; HCT, hematopoietic cell transplant; TDM, therapeutic drug monitoring a Agents are used in combination. Common regimens include methotrexate plus cyclosporine or tacrolimus, tacrolimus plus sirolimus, and mycophenolate mofetil plus tacrolimus or cyclosporine. b

Check level 72 h after initiation, then 2 to 3 times per week until stable.

Check level 24 h after initiation, then 2 to 3 times per week until stable.

Based on references 2, 5, and 6.

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Educational Review Text continued from page 8

therapy and reescalated in patients undergoing a taper at the time of GVHD diagnosis. Treatment is continued until the patient responds, at which point treatments can be tapered. Additional agents, such as alemtuzumab, may be added in the setting of steroid-refractory GVHD.2,8 Therapeutic drug monitoring (TDM) should be done to ensure the patient has appropriate drug levels of cyclosporine, tacrolimus, and sirolimus.

prophylaxis and treatment with immunosuppressive agents, and in those with compromised barriers related to high-dose chemotherapy. The most prevalent infections in HCT recipients that require prophylaxis include gram-negative bacteremia, Candida or Aspergillus fungal infections, and reactivation of herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) (Table 3).12-14 Antibacterial Prophylaxis

Myelosuppression Myelosuppression occurs in HCT recipients because of preparative conditioning regimens, underlying disease states, and GVHD immunosuppressive therapy.2 Immediately after transplantation, patients experience neutropenia and low white blood cell counts from preparative conditioning regimens that can persist for 2 to 4 weeks until engraftment.2,7 The use of CSF to promote growth and differentiation of myeloid and erythroid cells after transplant may help facilitate neutrophil recovery and decrease the degree of neutropenia. The use of CSFs after autologous HCT and high-dose chemotherapy has been shown to speed neutrophil recovery.9 Despite the faster neutrophil recovery, studies have been inconclusive as to whether CSF changes the length of post-HCT hospital stay, infections, and survival.9 In contrast, after allogeneic HCT, use of CSFs for supportive care potentially can worsen patient outcomes by increasing the incidence of GVHD.9 One exception is after umbilical cord stem cell transplantation, which tends to have slower neutrophil recovery times and benefits from CSF administration.9 The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) recommend the use of a CSF (filgrastim or pegfilgrastim) after autologous HCT or cord blood transplant as supportive care for a low neutrophil count.9,10 The NCCN recommends administering daily filgrastim beginning 5 days after transplantation until the absolute neutrophil count recovers to more than 1,500/mcL for 2 consecutive days. The ASCO guideline also provides a weak recommendation that CSFs may be considered after allogeneic HCT. The NCCN guideline for hematopoietic growth factors notes that biosimilar products may be substituted for reference filgrastim or pegfilgrastim, although they are not considered interchangeable by the FDA.9 To date, there are 2 FDA-approved filgrastim and 3 pegfilgrastim biosimilars (Table 2).9-11 In addition to biosimilars, tbo-filgrastim can be substituted for the reference filgrastim product.9 Tbo-filgrastim was approved as an original biologic product and has similar outcomes to filgrastim in preventing febrile neutropenia, but because it was not approved as a biosimilar, it has more limited indications than filgrastim biosimilar products.

Infection Myelosuppression due to HCT increases infection risk in patients, especially during periods of neutropenia.7 The risk for certain infections persists for several months after resolution of neutropenia, until the immune system fully recovers. Infection risk is higher in patients receiving GVHD

Recommendations for antibacterial prophylaxis vary among guidelines.12,13 The NCCN recommends that antibacterial prophylaxis be considered during periods of neutropenia for both autologous and allogeneic HCT recipients as well as for patients with GVHD on long-term immunosuppression.12 The

Infectious Diseases Society of America (IDSA) and ASCO jointly recommend antibacterial prophylaxis p ponly for allogeneic HCT recipe eients with neutropenia after a myeloablative conditioning regimen.133 This guideline notes that there may be limited benefit for antibacterial prophylaxis in patients receiving dmatched-related HCT and reducedT intensity myeloablative regimens. The y ylaxrecommended therapy for prophylaxdoxime as is is a fluoroquinolone, with cefpodoxime an alternative.12,13 The NCCN prefers use of levofloxacin, and recommends sulfamethoxazoletrimethoprim as an additional alternative agent.12

Table 2. Granulocyte Colony-Stimulating Factor Agents Reference Product

Approval Date

Biosimilar Product

Approval Date

Filgrastim (Neupogen, Amgen)

February 20, 1991

Tbo-filgrastima (Granix, Sicor Biotech)

August 29, 2012

Filgrastim-sndz (Zarxio, Sandoz)

March 6, 2015

Filgrastim-aafi (Nivestym, Hospira)

July 20, 2018

Pegfilgrastim-jmdb (Fulphila, Mylan)

June 4, 2018

Pegfilgrastim-cbqv (Udenyca, Coherus)

November 2, 2018

Pegfilgrastim-bmez (Ziextenzo, Sandoz)

November 4, 2019

Pegfilgrastim (Neulasta, Amgen)

January 31, 2002

Not technically considered a biosimilar; approved through original biologic pathway.

Based on references 9-11.

Table 3. Overview of Antimicrobial Prophylaxis Recommendations Infection

Indications for Prophylaxis

Recommended Regimen

Durationa

Bacterial

Allogeneic: during neutropenia; GVHD on IST Autologous: during neutropenia

Fluoroquinolone (alternatives: cefpodoxime, sulfamethoxazole-trimethoprim)

Until neutropenia resolution

CMV

Allogeneic: recipient or donor seropositive for CMV IgG; GVHD on IST Autologous: not indicated

Surveillance with weekly PCR (alternative: letermovir)

1-6 mo

HSV

Allogeneic and autologous: seropositive for HSV, during neutropenia

Acyclovir, famciclovir, or valacyclovirb

Until neutropenia resolution; may be extended in GVHD or history of frequent infections

VZV

Allogeneic and autologous: seropositive for VZV

Acyclovir, famciclovir, or valacyclovirb

Allogeneic: at least 12 mo Autologous: at least 6-12 mo May be extended in GVHD on IST

Antifungal

Allogeneic: during neutropenia; GVHD on IST Autologous: during neutropenia with mucositis

GVHD: posaconazole No GVHD: fluconazole or micafungin (alternatives: posaconazole, voriconazole, amphotericin B)

Until neutropenia resolution; may be continued for up to 75 d post-allogeneic HCT

PJP

All patients immediately after HCT; GVHD on IST

Sulfamethoxazole-trimethoprim (alternatives: atovaquone, dapsone, pentamidine)

Allogeneic: 6 mo Autologous: 3-6 mo GVHD on IST: until IST discontinued

CMV, cytomegalovirus; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplant; HSV, herpes simplex virus; IgG, immunoglobulin G; IST, immunosuppressive therapy; PCR, polymerase chain reaction; PJP, Pneumocystis jirovecii pneumonia; VZV, varicella zoster virus a

Duration expressed as time post-HCT.

Dosing differs for HSV and VZV.

Based on references 12-14.

Clinical 11

Pharmacy Practice News • June 2020

Educational Review Antiviral Prophylaxis A Approximately 80% of HSV-seropositive patients will experience rreactivation of HSV follo o lowing transplantation, wi w with the highest risk during p periods of neutropenia 7,12,13 and mucositis. m Prophylaxis for HSV is recommended by the NCCN and ASCO/IDSA guidelines during periods of neutropenia in both autologous and allogeneic HCT recipients who are HSV-seropositive.12,13 Extended HSV prophylaxis can be considered in patients with GVHD or a history of frequent HSV episodes. The ASCO and IDSA guideline recommends continuing prophylaxis until resolution of mucositis, if neutropenia resolves before mucositis. The recommended agents for HSV prophylaxis include acyclovir, famciclovir, and valacyclovir. Prophylaxis for VZV is recommended after autologous and allogeneic HCT in patients who are seropositive for VZV.12,13 The risk for VZV reactivation is higher in the initial period of neutropenia after engraftment. Prophylaxis is recommended with acyclovir, famciclovir, or valacyclovir for at least 6 to 12 months after autologous HCT and 12 months after allogeneic HCT. A longer duration may be used in patients with GVHD on immunosuppressive therapy. Allogeneic HCT recipients may be at high risk for CMV reactivation if the recipient or donor is immunoglobulin (Ig)G-seropositive for CMV or if the recipient has GVHD on immunosuppressive therapy. The NCCN recommends surveillance in these patients using weekly polymerase chain reaction (PCR) testing for at least 1 to 6 months and possible primary prophylaxis with letermovir (Prevymis, Merck) in CMV IgG-positive allogeneic HCT recipients.12 If CMV reactivation is detected on PCR, the NCCN recommends preemptive therapy using either oral valganciclovir or IV ganciclovir (with IV foscarnet or cidofovir as possible alternatives) until CMV is no longer detectable on PCR. Antifungal Prophylaxis Primary antifungal prophylaxis for Candida or Aspergillus species is indicated in the setting of expected prolonged neutropenia, such as immediately following HCT.12,13 The NCCN recommends prophylaxis during neutropenia in autologous HCT recipients with mucositis and allogeneic HCT recipients.12 Fluconazole or micafungin is recommended for prophylaxis, and the NCCN recommends posaconazole, voriconazole, and amphotericin B as alternative agents for allogeneic HCT recipients. Prophylaxis should be continued until neutropenia resolution and may be continued for up to 75 days following allogeneic HCT. Drug–drug interactions should be monitored because there are significant known interactions between conditioning regimen agents and posaconazole or voriconazole. Fungal infections occurring in the late-stage period after allogeneic transplant commonly are caused by invasive mold organisms; therefore, a mold-active agent, such as posaconazole, is recommended for patients with GVHD.12,13 Secondary prophylaxis with a mold-active agent may

be indicated for patients with a history of fungal infection during periods of immunosuppression. Pneumocystis jirovecii pneumonia prophylaxis is indicated in all patients after HCT, according to the NCCN.12 The organization recommends prophylaxis for 6 months in allogeneic HCT recipients and for the duration of immunosuppressive therapy in patients with GVHD, and suggests prophylaxis in autologous HCT recipients for 3 to 6 months after transplantation. Sulfamethoxazole-trimethoprim is the preferred prophylactic agent, and atovaquone, dapsone, or pentamidine may be considered as alternatives per ASCO/IDSA.13 Vaccination Patients undergoing HCT typically lose immunity conferred by previously administered vaccinations and require revaccination.12,15 Because immunization requires the host to mount an immune response, vaccination should not occur during immunosuppression, such as in patients with GVHD or those receiving prednisone doses greater than 20 mg per day. In addition, live vaccines should not be administered to immunosuppressed patients. The CDC recommends waiting 24 months to administer varicella, live zoster, and measles/mumps/rubella vaccines.15 Both the NCCN and CDC recommend readministration of inactivated virus vaccines (ie, diphtheria/tetanus/acellular pertussis, Haemophilus influenzae type b, pneumococcal, hepatitis A, hepatitis B, meningococcal conjugate vaccine, inactivated polio, and HPV) beginning 6 months after HCT.12,15 The inactivated influenza vaccine can be given as early as 4 to 6 months after HCT, but the CDC recommends considering a second dose if administered after 4 months.12,15

The Pharmacist’s Role Given the complexity of pharmacologic supportive care after HCT, the American Society for Blood and Marrow Transplantation published recommendations on the role of pharmacists in managing HCT patients as part of an interdisciplinary team.16 Pharmacist responsibilities include medication management, transitions of care, patient education, and scholarship activities, such as research and teaching. For medication management, pharmacists play a key role in TDM, antimicrobial stewardship, and revaccination, as well as monitoring comorbid disease states.

Conclusion Significant morbidity and mortality are associated with HCT. Pharmacologic supportive care can be used to reduce complications associated with myelosuppression, GVHD, and infections. In the setting of autologous HCT, CSF is recommended to reduce neutropenia duration post-HCT, and antimicrobial prophylaxis is recommended based on patient characteristics. Patients undergoing allogeneic HCT are at higher risk for infection and GVHD; therefore, supportive care encompasses prophylactic therapy to prevent these complications. Use of CSF agents is recommended only for umbilical cord transplants. Given the number of agents involved in HCT supportive care, pharmacists can play a key role in ensuring compliance with guideline recommendations and optimizing transitions of care for HCT patients.

References 1.

D’Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR Summary Slides, 2019. www.cibmtr.org. Accessed April 1, 2020.

2. Liewer S, Perkins J. Hematopoietic stem cell transplantation. In: DiPiro JT, Yee GC, Posey LM, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. McGraw-Hill; 2019. https://accesspharmacy.mhmedical. com/content.aspx?bookid=2577&sectionid=236063698. Accessed February 20, 2020. 3. Applebaum FR. Hematopoietic cell transplantation. In: Jameson J, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill; 2018. accessmedicine.mhmedical. com/content.aspx?bookid=2129&section id=192018534#1156755348. Accessed February 20, 2020. 4. Center for International Blood and Marrow Transplant Research, a contractor for the CW Bill Young Cell Transplantation Program operated through the US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau. US Transplant Data by Center Report, Transplants by donor type. bloodstemcell.hrsa.gov/sites/ default/files/bloodstemcell/data/transplant-activity/ transplants-donor-type.pdf. Last updated December 12, 2018. Accessed February 20, 2020. 5. Hamilton BK. Current approaches to prevent and treat GVHD after allogeneic stem cell transplantation. Hematology Am Soc Hematol Educ Program. 2018;2018(1):228-235. 6. Sung AD, Chao NJ. Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment. Stem Cells Transl Med. 2013;2(1):25-32. 7. Mueller SW, Fish DN. Infections in immunocompromised patients. In: DiPiro JT, Yee GC, Posey LM, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. McGraw-Hill; 2019. https://accesspharmacy.mhmedical. com/content.aspx?bookid=2577&sectionid=224361683. Accessed February 20, 2020. 8. National Comprehensive Cancer Network. Hematopoietic cell transplantation (HCT): pre-transplant recipient evaluation and management of graft-versus-host disease. Version 1.2020. www.nccn.org/professionals/physician_ gls/pdf/hct.pdf. Updated October 30, 2019. Accessed February 20, 2020. 9. National Comprehensive Cancer Network. Hematopoietic growth factors. Version 2.2020. https://www.nccn.org/ professionals/physician_gls/pdf/growthfactors.pdf. Updated January 27, 2020. Accessed January 27, 2020. 10. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(28):3199-3212. 11. FDA. Drugs@FDA. FDA-approved drugs. www.accessdata. fda.gov/scripts/cder/daf/. Accessed February 20, 2020. 12. National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. Version 1.2020. www.nccn.org/professionals/physician_gls/pdf/ infections.pdf. Updated December 17, 2019. Accessed January 27, 2020. 13. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36(30):3043-3054. 14. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238. 15. Kroger AT, Dunchin J, Vazquez M. General best practice guidelines for immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). www.cdc.gov/vaccines/hcp/acip-recs/general-recs/ immunocompetence.html. Updated December 26, 2019. Accessed February 20, 2020. 16. Clemmons AB, Alexander M, DeGregory K, et al. The hematopoietic cell transplant pharmacist: roles, responsibilities, and recommendations from the ASBMT Pharmacy Special Interest Group. Biol Blood Marrow Transplant. 2018;24(5):914-922.

12 Clinical

Pharmacy Practice News • June 2020

Bleeding Disorders

Centralized Anticoagulation Hub Appears Promising for VA

pilot program by the Department of Veterans Affairs to provide pharmacist-directed, centralized anticoagulation services is helping streamline care for patients in some rural areas and free up time for clinicians in regional VA centers to manage other patients. The Centralized Anticoagulation Services Hub (CASH) provides warfarin management services for about 1,100 patients in four Veterans

Integrated Service Networks comprising 11 states in the Upper Midwestern United States, Heather L. Ourth, PharmD, the national program manager for clinical pharmacy practice program and outcomes assessment, told Pharmacy Practice News. Three VA medical centers are active participants, with a fourth to join in January. CASH is based at the Edward Hines, Jr. VA Hospital in Chicago. There,

clinical pharmacy specialists and technicians work together to manage patients. Pharmacists, some of whom work remotely, call patients by phone to address nontherapeutic international normalized ratios (INRs), and complete education and risk–benefit assessments. Some patients who are more stable may receive letters instead of calls. Pharmacists also review and co-sign pharmacy technician notes when needed.

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Pharmacy technicians who are based onsite review new patient requests, address therapeutic INRs, triage patients to pharmacists when necessary, and review incoming calls and messages, retrieve lab results and contact no-shows. A dashboard database helps assist with identifying patients to contact, and tracks metrics and quality monitors.

Success and Expansion Now one year into a two-year pilot, the program has increased the percentage of time in therapeutic range from 70.7% to 77% over a 14-month enrollment period. The program initially hired three clinical pharmacy specialists and two technicians, with plans to hire additional staff as the program grows. CASH was created in an effort to streamline care for patients, especially those in rural areas, and to better use health professionals’ time in regional centers, Dr. Ourth said. While the majority of patients taking warfarin were cared for in pharmacist-run anticoagulation clinics, some in rural areas were being managed by physicians and nurses, or by clinical pharmacy specialists working in primary care settings. “We felt there could be operational efficiencies that could be gained by piloting this virtual care model that optimizes the role of both the pharmacist and the technician,” she said, “and free up physician providers, nurses and

Clinical

Pharmacy Practice News • June 2020

Bleeding Disorders therapy, and if we can utilize pharmacists and pharmacy technicians in a way that supports more of the patient population who receives these drugs and keeps them out of harm’s way, that’s a huge step forward.”

‘We felt there could be operational efficiencies [from] piloting this virtual care model that optimizes the role of both the pharmacist and the technician and free up physician providers, nurses and primary care pharmacists to be able to see more patients.’ —Heather L. Ourth, PharmD primary care pharmacists to be able to see more patients and address chronic disease state management, mental health needs and pain management.” Although the centralized anticoagulation program hasn’t yet done formal patient satisfaction surveys, Dr. Ourth said, “the feedback that hub staff has given us is the patients like it and it’s convenient for them. They still have to get their labs done, but then they don’t have to make another appointment. They know the pharmacists are going to call them with their results and any further instructions.” The program has helped alleviate the workload of providers at the participating VA centers, she added. The goal is to add additional patients to CASH to reach a target sample of 3,300 by June 2020, Dr. Ourth said. Then, they can spend the last six months of the pilot studying the strongpoints and successes to be able to scale it larger. Additional VA centers have asked to participate.

‘A Huge Step Forward’ In anticoagulation therapy, management by phone, telemedicine and related tools has been proven to be as successful

as face-to-face encounters, commented John Fanikos, RPh, the executive director of Pharmacy Services at Brigham and Women’s Hospital, in Boston. “The important part of this study

—Karen Blum

was the inclusion and expansion of the role of pharmacy technicians, which is a wonderful advancement,” Mr. Fanikos said. “There are lots of patients on anticoagulant and antiplatelet

The sources reported no relevant financial relationships. Dr. Ourth presented a poster (1-013) about the VA’s centralized approach to anticoagulation at the ASHP 2019 Midyear Clinical Meeting, in Las Vegas.

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14 Clinical

Pharmacy Practice News • June 2020

Nutrition

Beyond supplementation:

Micronutrients as Therapy in the ICU M

icronutrient supplementation as a therapy for critically ill patients is receiving increasing attention. However, although excellent mechanistic data support potential benefits, clinical trial data are lacking, according to a presentation at the ASPEN20 Virtual Conference in March. “Everyone was super excited about the potential for vitamin D, vitamin C, selenium, thiamine and other micronutrients to improve outcomes mes in the ICU. But it’s been very difficult lt to demonstrate the benefits that everyone believed there was going ng to be,” said Keith Miller, MD, a trauma and critical care surgeon at the University of Louisville Hospiital, in Kentucky. “There havee been a lot of big, expensivee trials with less than excit-ing results” (N Engl J Med d 2019;381[26]:2529-2540; N Engl ngl J Med 2013;368[16]:1489-1497). ). Dr. Miller and other session presenters highlighted some data that suggest improved outcomes with supplementation of certain micronutrients for some subgroups of patients. “With any nutrition study, it is hard to see positive effects of an intervention for all patients,” Christian Stoppe, MD, a critical care consultant at Aachen University in Germany, and another session presenter, told the online attendees. Phil Ayers, PharmD, the chief of clinical pharmacy services at Baptist Medical Center, in Jackson, Miss., said there may be a legitimate role for some micronutrients in critically ill ICU patients—particularly when used in higher than recommended daily doses of some micronutrients. “Vitamin C, vitamin D, selenium and thiamine are promising micronutrients for adjuvant therapy in severe acute illness,” said Dr. Ayers, who was not involved in the session. “Early supplementation should be considered to prevent or treat deficiency.” But he added that “dosing should be interpreted in light of the limitations of the primary literature.”

Dialing in Vitamin D Vitamin D is known to be critical for bone health and metabolism of calcium and phosphorus. Research over the past 15 years has elucidated several additional roles for vitamin D in human health, particularly related to the immune response during illness. “There are vitamin D receptors on nearly every cell in the body,” Dr. Miller said.

‘Vitamin C, vitamin D, selenium and thiamine are promising micronutrients for adjuvant therapy in severe acute illness. [But] dosing should be interpreted in light of the limitations of the primary literature.’

—Phil Ayers, PharmD

Growing enthusiasm for the vitamin has resulted in studies of its potential role in critical illness. “There are nutrients that have excellent theoretical benefit that have not been well flushed out in trials,” Dr. Miller said. “Vitamin D, however, has been extremely well studied.” Vitamin D deficiency, defined as calcifediol, or 25(OH)D, less than 20 ng/mL, is extremely common in the general population: More than 40%, according to a U.S. study in 2005 and 2006 (Nutr Res 2011;31[1]:48-54). Not surprisingly, it is more common among critically ill patients, and is “certainly associated with poor outcomes,” Dr. Miller noted (Crit Care 2014;18[6]:660). A handful of randomized clinical trials have evaluated the effect of vitamin D supplementation, generally administered enterally as a bolus dose of 540,000 IU. In the VIOLET trial, investigators found no difference in 90-day all-cause mortality for vitamin D–deficient patients given a dose of vitamin D compared with a placebo (N Engl J Med 2019;381[26]:2529-2540). An earlier trial found that administration of highdose vitamin D did not reduce mortality

overall compared with placebo, but did result in a significant decrease in patients with severe vitamin D deficiency— defined as 25(OH)D less than 12 ng/mL (JAMA 2014;312[15]:1520-1530). “A big problem in critical care trials is the heterogeneity of the ICU patient population,” said Dr. Miller, noting how young patients who may have gunshot injury or had surgery are grouped with older patients, such as those with pneumonia. “Because vitamin D deficiency is so common, you may be less likely to see a benefit if you give the vitamin to everyone in the ICU. You are more likely to see a benefit in specific subgroups.” Another trial investigating the role of the vitamin, VITDALIZE, is ongoing (ClinicalTrials.gov Identifier: NCT03188796). “That will help clarify and target in on some of the subgroups that a lot of clinicians believe would benefit from supplementation,” Dr. Miller said. “Enterally administered vitamin D is cheap and amazingly safe,” he added. Except for a few cases of hypercalcemia, researchers have not noted many adverse events. “A large, randomized clinical trial demonstrating broad clinical benefit

is not yet out there,” he added. “But I think there’s a place for it.”

Vitamin C, Thiamine Data A Mixed Bag Despite the proven importance of D vitamin C in immune function and vita as an antioxidant, research also is mixed on whether supplementation with the vitamin may improve outcomes in critically ill patients, o according to Todd Rice, MD, an assoa ciate professor of medicine in the c Division of Allergy, Pulmonary and D Critical Care Medicine at VanderCr bilt bi University School of Medicine, in Nashville, Tenn. Nas sh study stirred interest when A 2017 2 thee authors reported that supplementation with hydrocortisone, thiata mine and vitamin C lowered hosm pital mortality rates compared with a placebo in patients with severe sepsis and septic shock: 8.5% versus 40.4% (P<0.05) (Chest 2017;151[6]:1229-1238). But tthe study was criticized for its methods that may not have adjusted me for aall potential confounders. The VITAMINS trial, a more recent randomized study conducted in Australia, did not show any differences in vasopressor-free days, mortality or ICU length of stay between patients receiving hydrocortisone, thiamine and vitamin C and those given hydrocortisone alone (JAMA 2020;323[5]:423-431). “There are some not very good data that says vitamin C improves outcomes in patients with septic shock,” Dr. Rice told the online attendees. “There are other data, also generally flawed, that has not been able to demonstrate improved outcomes. That leaves us in a bit of an area of unknown.” While the medical community awaits further data, should these micronutrients be supplemented in the ICU? Dr. Rice said no supplementation is totally free of risk. Too much vitamin C can cause kidney stones in the urinary tract, for example. “But the bigger issue is that vitamin C interferes with a bunch of assays,” Dr. Rice said. Vitamin C can elevate the glucose readings of some glucometers due to ascorbate oxidation on the surface of electrochemical strips contained in these devises. This can force lab tests and risk a non-hyperglycemic patient receiving insulin (Chest 2018;154[1]:228-229). Dr. Rice noted that this accuracy issue does not occur with the spectrophotometric or calorimetric-based methods used in clinical core laboratories. The role of thiamine level alone in critical care also is murky. “We don’t know a ton about thiamine supplementation in critical illness,” said Dr. see MICRONUTRIENTS, page 16

Clinical

Pharmacy Practice News • June 2020

Nutrition

Toward Better Nutrition Care of Critically Ill Children A

ssessing, prescribing and delivering nutrition to critically ill children is crucial for optimizing outcomes. It also remains a significant challenge, as presenters detailed during a session at the ASPEN20 Virtual Conference. “Younger patients are the most susceptible population in terms of malnourishment,” said Ann-Marie Brown, PhD, an assistant clinical professor at Emory University Nell Hodgson Woodruff School of Nursing, in Atlanta, and a session presenter. Indeed, growing evidence indicates that without an adequate plan for providing proper feeding, the nutritional status of sick children deteriorates during the course of hospitalization (Nutrients 2019;11[2]:236). Determining the best feeding protocol, including when to initiate enteral nutrition (EN) versus parenteral nutrition (PN), is difficult due to limitations, such as inconsistencies in published outcomes. “While there is evidence to say a feeding protocol helps, there’s not enough evidence to show the best starting point,” Dr. Brown said. More studies are emerging to provide better direction, including about how to find the balance between overfeeding and underfeeding, which Dr. Brown referred to as the “Goldilocks dilemma”: “We’re looking for not too much, not too little, but just enough,” she said.

incidence of overfeeding (83%) and a cumulative energy excess of up to 8,000 kcal per week, especially in children younger than 12 months of age (Pediatr Crit Care Med 2011;12[4]:398-405). Meanwhile, underfeeding may result in a cumulative energy and protein deficit that can lead to loss of muscle mass and poor clinical outcomes (Am J Clin Nutr 2015;102[1]:199-206). “This is particularly true in patients who are already malnourished or have very low reserves prior to critical illness,” he added.

Assessing Status To establish the correct protocol for a pediatric ICU patient, a key first step is determining their nutritional status as they are admitted. While there is no perfect nutrition assessment technique, Dr. Mehta noted, he suggested multiple techniques, including a history of recent nutrient intake; a physical exam to determine nutritional deficiencies and anthropometry, such as weight, height, skinfold thickness and mid–upper arm circumference; and specialized devices to measure body compartments, such as bioelectric impedance assessment, CT scan or ultrasonography. Each technique has its own limitations. “Anthropometry can be challenging in the critically ill child with fluid shifts. Edema and increased total body water can alter many of the common-

‘Newer techniques are being studied to assess [pediatric] nutrition requirements and composition goals. This will help individualize nutrition therapy for these patients.’ —M. Petrea Cober, PharmD Overfeeding critically ill children can raise the risk for hyperglycemia and triglycerides, explained session presenter Nilesh Mehta, MD, the director of critical care nutrition at Boston Children’s Hospital (J Pediatr Surg 2018;53[9]:1688-1691). It also can result in increased carbon dioxide production from the metabolism of the excess carbohydrate, which places an increased burden on the respiratory system (Pediatr Crit Care Med 2015;16[6]:e157-164). “This may be associated with poor function outcomes in patients who already have respiratory compromise or difficulties,” Dr. Mehta said. Such overfeeding often results because the equations used in standard feeding approaches overestimate the energy expenditure of children, he noted. In a 2011 study co-authored by Dr. Mehta, standard feeding resulted in a high

ly used anthropometric tests, such as weight, triceps skinfold thickness and mid–upper arm circumference,” he said. “Specialized devices that measure body compartments are either not adequately validated in this population or may also be inaccurate in the setting of fluid shifts and edema.” The latest guidelines from the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition offer insights on the provision and assessment of nutrition support therapy in pediatric critically ill patients. Published in 2017, the guidelines suggest use of indirect calorimetry to accurately measure resting energy expenditure (JPEN J Parenter Enteral Nutr 2017;41[5]:706-742). “Accurate assessment of energy needs by using indirect calorimetry is the first step in prescribing optimal energy dose

A poorly tailored nutrition regimen resulted in a

high incidence of overfeeding (83%) and an

energy excess of up to 8,000 kcal per week, especially in children younger than 12 months of age. Source: Pediatr Crit Care Med 2011;12(4):398-405.

and avoiding underfeeding or overfeeding in this population,” Dr. Mehta said. Lori J. Bechard, PhD, RD, a clinical research manager at Boston Children’s Hospital, acknowledged that indirect calorimetry can be difficult for some centers to use given its size and expense—in the tens of thousands of dollars. A standardized equation is a good alternative, she said. “BMI is a simple enough tool for most patients,” Dr. Mehta added (Crit Care Med 2016;44[8]:1530-1537). He suggested using the equation only to identify children who are malnourished on admission and, therefore, require particular attention to their nutritional intake. “Although BMI is not perfect, it’s discriminatory power is attractive,” he said. “BMI will not be used to develop energy prescriptions.”

Emerging Evidence Many of the recommendations for energy goals and nutrition prescription strategies for this patient population are based on low quality of evidence. “There’s still a big research gap,” Dr. Bechard said. Katherine Chessman, PharmD, a pharmacy professor at the Medical University of South Carolina in Charleston, agreed that guidelines are largely based on weak evidence. “Methods of assessment are largely unvalidated and additional research is needed,” said Dr. Chessman, who was not involved in the session. Dr. Bechard highlighted what can be gleaned from the evidence available, including the benefits of early EN. A 2014

study found that children who received early EN, defined as the provision of 25% of goal calories enterally over the first 48 hours of admission, were less likely to die than those who did not (odds ratio, 0.51; P=0.001) (JPEN J Parenter Enteral Nutr 2014;38[4]:459-466). Dr. Mehta agreed that EN is the “preferred mode of nutrient delivery in the critically ill. EN may be started in small amounts soon after initial resuscitation and stabilization of the critically ill patient.” The timing of PN also can be critical. The PEPaNIC trial, published in 2016, remains widely referenced in the debate over use of early versus late PN upon admission to the pediatric ICU, Dr. Bechard noted (N Engl J Med 2016;374[12]:1111-1122). The trial found that children who receive late initiation of PN fared better: Fewer had new infections (10.7% vs. 18.5%; P<0.001), and they averaged shorter ICU lengths of stay (6.5 vs. 9.2 days; P=0.002) than those who received early PN. But the study had a significant shortcoming: Patients either received PN within 24 hours or on day 8. “They either got it really early or really late,” Dr. Bechard said. “In the real world, there’s a lot of opportunity between day 1 and day 8. And that might be where the sweet spot is for the best use of PN as a supplement to EN in practice.” She suggested the continuing need for a valid nutrition risk assessment score that identifies children at risk for nutritional deterioration, optimal methods for assessing muscle wasting and see CRITICAL CARE, page 16

16 Clinical

Pharmacy Practice News • June 2020

Nutrition

Nutritional Connections to COVID-19

ome data indicate that selenium may play a role in preventing and treating COVID-19, according to Christian Stoppe, MD, a critical care consultant at Aachen University in Germany. Selenium deficiency leads to more oxidative stress and may decrease specific immune response, activate the complement system and increase the viral replication rate, he explained. Studies on influenza viruses have underscored such effects (Antioxid Redox Signal 2012;16[7]:705743). These relationships also

MICRONUTRIENTS continued from page 14

Rice, pointing to one study that found a lower mortality rate among patients given thiamine for septic shock (Crit Care Med 2018;46[11]:1747-1752). “But we need a prospective trial to see if thiamine really works.” Meanwhile, thiamine, also known as vitamin B1, does not appear to pose any risk for adverse effects. “So giving thiamine is probably not unreasonable,” Dr. Rice said. “But with the conflicting data, we don’t use it as a treatment.”

Uncertainty Over Selenium Yet more uncertainty surrounds supplementation with selenium, according to Dr. Stoppe. Research has linked low selenium levels with organ failure

CRITICAL CARE continued from page 15

energy and protein goals, and an understanding of the impact of low- versus high-protein intake as well as of feeding protocols on outcomes.

PINS 3 Data Dr. Bechard is a co-author on a series of multicenter trials aimed at helping to clarify optimal feeding protocols. The latest of those studies, the 3rd Pediatric International Nutrition Study of Critically Ill Children (PINS 3), remains in the analysis phase and is the first to look at practices since release of the 2017 guidelines (ClinicalTrials.gov Identifier: NCT03223038). Compared with the findings of PINS 1 and 2, she noted, emerging data now suggest more dedicated dietitians are involved in pediatric critical care as well as a greater use of feeding protocols. PINS 3 data also point to a decline in energy prescriptions and more prevalent use of EN: earlier and with less PN, all recommendations in the guidelines. M. Petrea Cober, PharmD, a clinical coordinator in the neonatal ICU

have been shown between selenium deficiency and higher rates of viral mutations (Biol Trace Elem Res 2011;143[3]:1325-1336). “Interestingly, in the region of Hubei, [China,] where COVID-19 originally spread from, the population had selenium deficiency,” Dr. Stoppe said (FASEB J 2001;15[10]:1846-1848). “It is important in these times to think [openly] about potential strategies

in ICU patients (R2=0.42; P<0.01) (Br J Anaesth 2007;98[6]: 775-784). The relationship was more pronounced when organ failure was associated with an infection such as severe sepsis. A 2013 review found selenium supplementation reduced the relative risk (RR) for death by 17% among critically ill patients with sepsis (RR, 0.83; 95% CI, 0.70-0.99; P=0.04) (PLoS One 2013;8[1]:e54431). A more recent meta-analysis found no significant differences in mortality among ICU patients (Crit Care 2016;20[1]:356) in the 21 randomized controlled trials that met inclusion criteria (RR, 0.98; 95% CI, 0.90-1.08; P=0.72). Parenterally administered selenium also did not have any demonstrable effect in

to improve outcomes,” he added. “It is inexpensive. There’s a low risk for any side effects. Why not try to optimize selenium levels in patients with COVID19 if we can further support their specific immune response?” Meanwhile, a couple of trials are currently investigating whether vitamin C supplementation might benefit COVID-19 patients. “We don’t yet know the answer,” said Todd Rice, MD, an associate professor of medicine at

a subgroup analysis of patients with infections. There was no positive or negative effect on length of stay in the ICU or hospital, renal function, or ventilator-days (RR, 0.95; 95% CI, 0.88-1.02; P=0.15), the researchers found. These results are surprising, given that selenium enhances the body’s most powerful antioxidant and antiinflammatory response mechanisms, Dr. Stoppe said. “Yet clearly, clinical data in general ICU patients could not demonstrate significant benefits, and nutrition guidelines don’t recommend its general use” (Clin Nutr 2019;38[1]:48-79; Crit Care Med 2016;44[2]:390-438). Despite the negative findings, data suggest there may be specific

at Akron Children’s Hospital in Ohio, noted that the recent improvements have helped improve patient outcomes. “Newer techniques are being studied to assess nutrition requirements and composition goals. This will help individualize nutrition therapy for these patients,” said Dr. Cober, who was not involved in the ASPEN20 session. “More research is needed for optimal nutrition in pediatric critically ill patients.”

Nailing Down Protein Delivery The optimal amount of protein delivery is another key consideration in pediatric nutrition. In general, Dr. Mehta noted, protein delivery is often inadequate, and the 2017 guidelines recommend 1.5 g/kg of protein prescription daily in critically ill children. “You still really need to consider the individual patient and how they are presenting,” he said. “The pediatric ICU is a really heterogeneous place.” “Some will have chronic diseases, some will be malnourished, and others will be previously healthy,” Dr. Chessman added. “So a one-size-fits-all approach to nutrition support in the critically ill child is not appropriate. Institution-specific

feeding protocols, developed by an interdisciplinary team of providers, will likely help to ensure safe and appropriate nutrition support in critically ill children. who was not involved in the session.”

Bolus or Continuous? Nutritionists also have been debating the merits of bolus versus continuous dosing. “Historically, people in the U.S. have been reluctant to use bolus as a starting point for fear of emesis and aspiration,” Dr. Brown said. Although few studies have compared continuous and bolus head-to-head, research by her team and others has demonstrated not only equivalent safety but also improved nutrition delivery with bolus feeds (JPEN J

Vanderbilt University School of Medicine, in Nashville, Tenn. Supplementation with vitamin D also might be a reasonable strategy, particularly in areas where deficiencies of the vitamin are common, noted Keith Miller, MD, a surgeon at the University of Louisville Hospital, in Kentucky. “There’s no high-quality evidence to suggest that vitamin D supplementation will prevent COVID-19 or reduce morbidity if you’re infected,” Dr. Miller said. “Despite the lack of evidence, it would be disingenuous for me not to admit that I have started supplementing vitamin D where I had previously not been doing so.” —L.P.

populations that may benefit from selenium supplementation. For example, Dr. Stoppe is researching the effects of selenium supplementation in high-risk patients undergoing cardiac surgery in the SUSTAIN CSX trial (Trials 2014;15:339. doi. org/10.1186/1745-6215-15-339). He said he anticipates data from the trial by the end of the year. “We may just have to focus on the sickest patients,” Dr. Stoppe said. “It’s a point that comes out more and more in clinical trials.” —Lynne Peeples Dr. Rice reported consulting for Baxter and Nestlé. Dr. Miller reported serving as a faculty member on an educational clinical nutrition fellowship sponsored by Nestlé. Drs. Stoppe and Ayers reported no relevant financial relationships.

Parenter Enteral Nutr 2019;43[6]:750758). One possible explanation for the difference is that bolus feeds mimic periods of typical gastric rest that have been associated with improved gastric motility, she noted. Interruptions, Dr. Brown added, are a key barrier to effective EN for pediatric patients (JPEN J Parenter Enteral Nutr 2010;34[1]:38-45). One of the most common reasons that people halt EN, she explained, is feeding intolerance, which is typically measured via gastric residual volume. But the thresholds used for testing are “all over the place,” she said. “Recent studies in adult and pediatric ICUs find that routine measurement of gastric residual volume does not predict emesis or aspiration, but just causes us to artificially hold feeds” (Clin Nutr 2020;39[3]:685693). In other words, it provides no safety net and actually impedes the delivery of food. “We need to have an organized approach to feeding,” she said. “And we need to stop routinely checking gastric residual volume.” —Lynne Peeples The sources reported no relevant financial relationships.

18 Clinical

Pharmacy Practice News • June 2020

Medication Safety

Are You Ready to Standardize 4 Safety? T he massive national interprofessional effort to release agreedupon standardized concentrations for most medication doses is nearing completion. Standardize 4 Safety (S4S), an initiative funded by the FDA and led by ASHP, released its first set of standardized concentrations, for adult continuous infusions, in October 2016. The next set, for pediatric continuous infusions,

has been in the comment and review period for almost a year, and a final release is expected before summer of 2020, according to Michael Ganio, PharmD, ASHP’s director of pharmacy practice and quality. The standardized concentrations will ultimately include: • concentrations and dosing units for IV continuous medications for adult patients;

• concentrations and dosing units for IV continuous medications for pediatric patients; • concentrations for compounded oral liquid medications; • doses for oral liquid medications; • concentrations for IV intermittent medications; and • concentrations for patient-controlled analgesia and epidural medications. “By the end of 2020, ideally we would

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like all of the standardized doses to be either complete in final form, or at least released in draft form, and be in the comment or comment review phase,” Dr. Ganio told Pharmacy Practice News. Prior to S4S, no agreed-upon national standards for medication concentrations existed, leaving patients vulnerable to medication errors, particularly during transitions of care from an ambulance to the hospital, between hospitals or different levels of care within the same hospital, or at discharge. For example, in an ambulance, a patient might receive 360 mg/200 mL (1.8 mg/mL) of the antiarrhythmic drug amiodarone. At the local hospital’s emergency department, their usual concentration of amiodarone might be 300 mg/250 mL (1.2 mg/mL). When the patient is moved to that same hospital’s tertiary care ICU, he or she might receive a concentration of 750 mg/250 mL (3 mg/mL). “Hospital pharmacies and community pharmacies use different compounding recipes based on the availability of formulations, ingredients, duration of therapy [e.g., limited doses in the inpatient setting and multidose bottles for outpatients], ease of preparation, and reimbursement issues,” said Scott Ciarkowski, PharmD, the manager of quality and safety for Michigan Medicine, in Ann Arbor, which began its own standardized concentration effort even before ASHP’s national initiative. For example, a statewide survey conducted in Michigan to determine the degree of variation in oral liquid compounding found that approximately 53% of medications had three or more different concentrations compounded in the state (J Am Pharm Assoc 2014;54[4]:383-389). “The potential for errors is evident,” said Rhonda Liberto, PharmD, a system medication safety officer at Ochsner Health, in New Orleans, who presented a continuing education session on preparing for S4S at the

Clinical 19

Medication Safety In a recent Michigan survey,

53% of compounded oral liquids were mixed using 3 or more different concentrations. Source: J Am Pharm Assoc 2014;54[4]:383-389

ASHP 2019 Midyear Clinical Meeting, in Las Vegas. The S4S recommended concentrations have been developed by expert panels consisting of physicians, nurses and pharmacists from specialties including critical care, anesthesia, emergency/trauma, medication safety and information technology. Guiding principles for the concentrations chosen include patient clinical needs, the availability of FDA-approved commercial products, and operational considerations such as cost and waste. They aim to use a single concentration whenever

possible—although more may be needed based on factors such as tenuous patients and fluid status—and to use more concentrated doses when possible. “This effort is about more than just concentrations: It’s about reduction in clinical variability,” Dr. Liberto said. “It’s an opportunity to step back and look at all of the medications that are impacted and your error risk, and make sure your medical record build and all your processes are as clean, concise, consistent and standardized as possible.”

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Preparing for the New Standards So how can your institution prepare to implement the new standards? “First, it is important for institutions to fully consider where and how the medications involved are used, and what pieces of technology include those concentrations,” Dr. Liberto said. When standardizing your institutional concentrations to match S4S, consider: • the electronic health record; • the smart infusion pump library; • operating room labeling technology; • code carts; • other infusion devices, such as those in operating rooms, MRI suites and clinics; and • other labeling technology. “If you are a multihospital health system, are practices standard across the board?” Dr. Ganio asked. “Will implementation be as straightforward as changing a concentration in a database shared by all locations, or will you have to harmonize concentrations in a locationby-location manner? You should involve the leadership of the P&T [pharmacy and therapeutics] committees at all hospitals in reviewing the standards as they come out, and identifying where the standards already approved or proposed might conflict with your current practice.” Dr. Ciarkowski advised putting a pharmacy lead in charge of the overall effort to make the S4S changeovers. “You need someone planning and leading those changes; it’s labor-intensive,” he said. “That person also needs to communicate clearly and regularly with prescriber and nursing partners about the plan and time line for doing this. It can’t come as a surprise to anyone. And take the approach of anticipating that an error could happen when you make the changeover. These aren’t little changes that you’re making.” The latest updates on the S4S initiative, including all proposed and finalized standard concentrations across all categories, can be found on the ASHP website at www.ashp.org/PharmacyPractice/Standardize-4-Safety-Initiative. —Gina Shaw The sources reported no relevant financial relationships.

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20 Clinical

Pharmacy Practice News • June 2020

Medication Safety

Beers List for Kids continued from page 1

It wasn’t long before Dr. Hoff had a short list of drugs he believed shouldn’t be used in some or all of the pediatric population, but he never saw a formal guideline of such drugs, like the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. So he set out to create his own. He and his resident, R.C. Hellinga, PharmD, now at the University of New Mexico Hospital,

in Albuquerque, initially searched the literature to compile a list for their own hospital. The work was good, Dr. Hoff thought, but more needed to be done. About 2.5 years ago, he approached the board of the Pediatric Pharmacy Association (PPA) to ask whether they would commission such a guideline. They loved the idea, and it eventually culminated in the KIDS List.

A table lists the drugs in alphabetical order, stating the risk/rationale for their inclusion, recommendations on which age groups they apply to, the strength of their recommendations, and quality of evidence. The most frequently cited groups included antiinfectives, antipsychotics and gastrointestinal agents. Most drugs (85%) required a prescription.

Dopamine Antagonists One of the largest classes with a strong recommendation to use cautiously in

children was dopamine antagonists, said lead study author Rachel Meyers, PharmD, a clinical associate professor of pharmacy practice and administration at Rutgers Ernest Mario School of Pharmacy, in Piscataway, N.J., and a pediatric clinical pharmacist at St. Barnabas Medical Center, in Livingston, N.J. “The risk for dystonias and dyskinesias [from the agonists] is higher in children, particularly in infants than in older kids,” Dr. Meyers said. Chloramphenicol, which can lead to gray baby syndrome in neonates,

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also had strong evidence for adverse effects and caution in children. Other drugs, such as salicylates, didn’t exhibit strong evidence, she said: “We know about the historical connection [of salicylates] with Reye syndrome, but the data definitively connecting them wasn’t as strong as we’d like.” As a result, salicylates are listed as a class to use with caution in children with suspicion of viral illness, but the recommendation is just a weak one at this point, she said. Many drugs proposed for inclusion did not make the final list because of weak evidence, such as over-thecounter pediatric cough and cold preparations and fluoroquinolones, Drs. Hoff and Meyers said. Selective serotonin reuptake inhibitors also weren’t included, because the authors believed

This program is supported by an independent educational grant from the Opioid Analgesic REMS Program Companies. See https://ce.opioidanalgesicrems.com/RpcCEUI/rems/pdf/resources/List_of_RPC_ Companies.pdf for listing of REMS Program Companies. This activity is intended to be fully compliant with the Opioid Analgesic REMS education requirements issued by the US Food and Drug Administration.

Jointly provided by AKH Inc., Advancing Knowledge in Healthcare and Warrior Centric Healthcare Foundation

Distributed by CMEZone.com

And send your Twitter handle to editor David Bronstein at davidb@mcmahonmed.com so we can follow you.

Clinical

Pharmacy Practice News • June 2020

Medication Safety ‘I hope [the KIDS List] is used for new learners as a starting point in their training, [is] adopted into practice at health systems, [and] reduces [adverse drug reactions] in kids.’ —David Hoff, PharmD the medications are clinically beneficial to many pediatric patients. As for fluoroquinolones, “we classically teach our pharmacy students to avoid

Gray baby syndrome is a rare, lifethreatening condition that can develop in infants and premature babies up to the age of 24 months.

Canada. “We’ve been talking about it since I started 25 years ago.” Katie Hughes, PharmD, a pediatric pharmacist with Riley Hospital for

Children at Indiana University, in Indianapolis, said she was really excited to see an email notification about the study from the PPA, and immediately pulled up the study. “There’s a lot of ways I personally would utilize this,” Dr. Hughes said. “It is an easy way for me to give all of the residents and students that come through for rotation a quick eye-opener of how different pediatrics is than adults.” She said she wished the document contained more information on pharmacokinetic and pharmacodynamic differences in children, but overall thought the

summary was good. “I like how they hit all of the high points we see, but I also like the strength of recommendation and quality of evidence because it’s not black and white,” she said. “The way it’s presented makes it a lot cleaner to know this is a strong recommendation we shouldn’t use something, so that’s an easy way to get this information quickly versus having to do a literature search on your own.” —Karen Blum The sources reported no relevant financial relationships.

Supporting Pharmacy Efficiency g Product Family With a Growing

The condition has been linked to

overdoses of chloramphenicol

Liquid Unit Dose

administered either to the mother or the infant, and the drug is one of the potentially inappropriate medications included in the KIDS List.

them in children under 18,” Dr. Meyers said, due partly to a link between the drugs and adverse musculoskeletal effects. “But we found the data has shown the risks are there for adults as well, so we didn’t find the justification to put them on this list to avoid in children specifically. While we should be careful using them in children just like we always did, that risk and that concern is there in the adult population as well.” The KIDS List is intended to be a work in progress that can be updated as necessary, Dr. Meyers noted. There is a lot of room for enhancing the strength of recommendations for these and other drugs through added research, Dr. Hoff said. “I hope this is used for new learners as a starting point in their training, and I hope it’s adopted into practice at health systems,” he said. “[My hope] is that it reduces [adverse drug reactions] in kids.” The KIDs List “takes the first steps in a new direction to enhance drug safety for children, and to provide guidance to clinicians and direction and inspiration to our next generation of pediatric pharmacy and drug therapy researchers,” according to an accompanying editorial in the journal. “It’s a very good document for people to refer to, and I hope that this stimulates other pediatric pharmacists and clinical pharmacologists around the world to expand the list,” said a co-author of the editorial, David Knoppert, MScPhm, MSc, a retired neonatal pharmacist in

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22 Policy

Pharmacy Practice News • June 2020

Sterile Compounding

COVID’s Impact on the Compounding Supply Chain I

ncreased demand for and shortages of personal protective equipment (PPE) and other supplies have left many hospitals across the country struggling to maintain the integrity and safety of their sterile compounding operations, experts say. “I’ve had many calls from former and current clients for whom I have built cleanrooms, about supplies they’re running out of or are about to run out of. They want to know what to do in order to remain compliant,” said Jerry Siegel, PharmD, a managing partner at Safe Medication Management Associates and the former senior director of pharmacy for the Ohio State University Wexner Medical Center, in Columbus. In recognition of the extraordinary situation, USP has published a new guidance document addressing operational concerns regarding sterile compounding during the COVID-19 pandemic (bit.ly/ 3br2xMj). The document suggests that state boards and other regulators temprarily use “risk-based enforcement discretion” related to the implementation of USP compounding standards. The guidance, which was prepared without USP’s usual comment period, states that facilities may consider delaying recertification of primary and secondary engineering controls if they are served by a continuous monitor, but that increased environmental monitoring and application of shorter beyond-use dates should be considered if certification is delayed. It also notes that “in consideration of the current resource constraints and increased waste of drugs, compounders should apply Beyond-Use Dates (BUDs) conservatively based on both chemical and physical stability and microbiological considerations.” (See box.) USP stressed, however, that the guidance document “is for informational purposes only and is intended to address operational considerations during the COVID-19 pandemic. Parties relying on the information in this document bear independent responsibility for awareness of, and compliance with, any applicable federal, state, or local laws and requirements.”

Different Sites, Different Stories Such caveats aside, hospitals are taking seriously the need to adjust their approaches to sterile compounding due to COVID-19-related equipment shortages. The degree of adjustments needed varies widely from day to day and from institution to institution. At Beth Israel Deaconess Hospital– Needham, in Massachusetts, a 59-bed facility that is part of a larger 12-hospital system, the sterile compounding area is part of an older pharmacy space

that is awaiting final approval from the state department of health for a buildout compliant with the new USP General Chapter <797> requirements, originally slated for implementation in December 2019 and now pending review. “When COVID first hit, our big focus was initially on preserving PPE with strategies such as sterilizing and reusing our N95 masks, and only using N95 masks when there was a possibility of aerosolization,” said Joseph Giovangelo, MSPharm, the hospital’s director of pharmacy. “We have also focused on protecting our staff. We have 15 FTEs [full-time equivalents] in the pharmacy, with typically one certified technician and one registered pharmacist in compounding per shift, except at night, when we have just one pharmacist on [duty] who is responsible for all compounding. We have now divided our pharmacy staff into four teams and cross-trained all pharmacists to work in the compounding area, so that we have sufficient coverage.” Because four pharmacy employees have had to take leave, either because of exposure to the disease or to care for sick family members, the hospital is relying on per-diem pharmacists to supplement its existing staff, Mr. Giovangelo added. But nearby at UMass Memorial Medical Center, in Worcester, PPE shortages have not affected sterile compounding. “We are closely watching surgical masks, N95 masks and gowns, but so far our supply chain operation has been able to procure what we need,” said Neil Gilchrist, PharmD, MBA, the senior director of pharmacy services. “The bigger impact on our compounding operation has related more to the increasing number of patients on ventilators and the requirements for the use of sedatives, analgesics and paralytics. We have considered compounding strategies, such as using different bag sizes and different concentrations.” Weeks Medical Center, in Lancaster, N.H., has so far avoided major supply chain issues resulting from the pandemic. “We had a pretty good stock of PPE materials before this hit, because we are so busy with a large chemotherapy practice that we try to keep ahead of supply needs,” said John Eddy, RPh, the manager of pharmacy services. “Right now we have sufficient equipment. If we are going to run out of something, it might be chemo-type gowns; those are now hard to come by and could pose a problem if this continues for very long.” Weeks has begun to run short on some of its cleaning supplies. “Our whole hospital uses the Super Sani-Cloth ‘purple top’ disinfectant wipes daily, and we can no longer purchase that, although we still have a couple of containers left,” Mr. Eddy said. “We have some more of the

Some hospitals are starting to run short of cleaning supplies that are crucial to maintaining sterile compounding conditions.

orange top wipes, which we typically only use once a month, but if we have to, we could use that every day. If this carries on, though, we will have to make bleach solution for cleaning.”

Making Do With What You Have At many institutions, sterile alcohol is in short supply. Are there any alternatives for appropriately sterilizing cleanrooms? First, Dr. Siegel recommended reserving the sterile alcohol for only International Organization for Standardization (ISO) class 5 areas. “Don’t use it to clean the floors,” he said. “Disinfection of the ISO 5 biosafety cabinets and the vial stoppers is the most critical use of this product.” It is also possible to make your own sterile alcohol by filtering nonsterile 70% isopropyl alcohol (IPA) with a 0.2-micron filter, suited specifically to the alcohol type, in a biological safety cabinet (BSC). Dr. Siegel noted, however, that you must first wipe down all the components with either any remaining sterile alcohol or a 50/50 mixture of hydrogen peroxide. “A second method is to add enough 3% hydrogen peroxide to 70% nonsterile IPA to make a 0.0125% solution,” he said. “This small amount of hydrogen peroxide will kill bacterial and fungal spores, but the solution will need 72 hours to be effective. The outside of the container will need to be wiped down with 50/50 peroxide before placing into the ISO 5 environment.” Many hospitals use PeridoxRTU (Contec Healthcare) for hazardous drug (HD) removal in BSCs and on ceilings, walls and floors, but that product also has been on back order. “You need an oxidizing agent to clean your hazardous chemo rooms, but it doesn’t have to be that one,” Dr. Siegel said. “Bleach is a very effective

oxidizing agent in strengths greater than 4%, but it will ‘pit’ stainless steel if not rinsed off. Sodium thiosulfate is also an excellent oxidizing agent but may also be more difficult to obtain. Hydrogen peroxide at 3% can also be used if available, but needs to be rinsed with sterile water because it will cause staining and streaking if left on surfaces without rinsing.” Dr. Siegel warned against mixing vinegar and hydrogen peroxide as a cleaning agent. “This combination will make peroxyacetic acid, which is very corrosive.” To preserve PPE in the sterile compounding operation, Dr. Siegel and Fred Massoomi, PharmD, the senior director at Visante, offered the following recommendations: Redefining anteroom space. “Many facilities typically have a very small ‘dirty’ side in their anteroom, where everyone garbs and then wears PPE all day long,” Mr. Siegel said. “In the current circumstances, you should reverse that, making your clean side a very small area where you garb just prior to entering the buffer room.” This is done, he said, “so pharmacists are not garbed in the main work area and instead only change prior to going into the buffer room. Slow and deliberate movement in the anteroom and limiting personnel will allow you to maintain the ISO 8 status of the anteroom.” Reduce dust accumulation. This can be done by adding sticky mats for use by all personnel entering the room, but not in ISO-rated room spaces or segregated compounding area perimeter spaces. Wear scrubs in compounding rooms and hair covers. Mask are not necessary in this new ‘dirty space.’ “This saves a tremendous amount of PPE,” Dr. Siegel said. Conserve shoes. Another type of PPE that has begun to run short: shoe covers.

Policy

Pharmacy Practice News • June 2020

Sterile Compounding

4 BUD Cues During COVID-19 “We are starting to see increased use of shoe covers in ICUs and other areas where COVID-19 patients are cared for, so there has been more and more shortages of those. That’s something we need in the sterile compounding world,” Dr. Massoomi said. If you run short on shoe covers, preserve your supply by reserving them for the HD compounding room only, Dr. Siegel suggested. Reuse gowns—but heed regulations. USP’s new garbing guidance states that disposable gowns can be reused by a single user unless they are soiled or torn. “The stated preference is to discard them at the end of the day, but you can actually use a gown for up to one week for nonhazardous compounding if you do not turn it inside out, hang it up so it doesn’t touch the floor, and keep it away from the sink where it might get wet,” Dr. Siegel said. “For hazardous compounding, it is best never to reuse a gown since it can have hazardous residue, and you absolutely cannot take it out of the hazardous room. But if you have a real shortage, you could possibly reuse the gown to the end of the shift and then destroy it. Never use it beyond that, and never turn it inside out or let it touch the floor or a water source.” As you remove the gown, keep in mind that its purpose is to contain matter from your body, such as hair and flaked skin, and keep it away from the product as you are making it. “You want to remove the gown in an area where those particles can be removed away from the HD space, and vented out,” Dr. Massoomi said. “Make sure you don’t contaminate and further damage it while taking it off, and store it in the anteroom on the dirty side of the room and ideally near a room exhaust/return vent, away from the dirtier area.”

Beware of Bogus N95 Masks One of the biggest and most problematic shortages of PPE has involved N95 masks. “They are in shortage everywhere,” Dr. Siegel said. These masks are intended to protect the wearer by removing 95% of viral particles and nonvolatile HDs. “For nurses taking care of COVID-19 patients in the ICU, those masks will save their lives, while sterile surgical masks will not, so we need to preserve the N95 masks for caregivers on the front line.” The National Institute for Occupational Safety and Health (NIOSH) has put out a warning to health care providers about counterfeit N95 masks, available online at bit.ly/2zvW45G. “You can’t tell if a mask is counterfeit just by a cursory examination,” Dr. Massoomi said. “Look for the stamp indicating that this is a NIOSH-certified N95 mask. You would think companies that make and sell counterfeit masks would not fake a NIOSH stamp because that is illegal and they know it can lead to a lot more trouble; however, I would not count on that epiphany of honesty. If you’ve ever

USP’s guidance on operational concerns for sterile compounding during the COVID-19 pandemic includes four key recommendations governing beyonduse dates (BUDs). These BUDS, the group notes, may be assigned “if compounding does not otherwise deviate from General Chapter <797> standards”: 1. Low- and medium-risk compounded sterile preparations (CSPs) prepared in a segregated compounding area: Apply BUDs conservatively, not to exceed: • 12 hours at controlled room temperature • 24 hours in a refrigerator 2. Low- and medium-risk CSPs prepared in a cleanroom suite: Apply BUDs conservatively, not to exceed: • 4 days at controlled room temperature • 10 days in a refrigerator for medium-risk CSPs • 14 days in a refrigerator for low-risk CSPs • 45 days in a solid frozen state at −25° C to −10° C or colder 3. A single-dose container that is entered or punctured only in International Organization for Standardization class 5 or cleaner air. In such cases, BUDs may be used up to: • 12 hours after initial entry or puncture, as long as the storage requirements during that 12-hour period are maintained; opened single-dose ampules must not be stored for any time period. 4. When assigning these BUDs, considerations should be given to: • ensuring personnel monitoring (e.g., gloved fingertip and thumb sampling) is successfully completed every 6 months; and • increasing frequency of surface sampling in the primary engineering control to determine effectiveness of cleaning procedures and work practices. “If we are unable to get pieces of garb and cannot meet the standards USP has put forward, we have to shorten the BUDs to protect our patients. That is paramount,” said Fred Massoomi, PharmD, the senior director at Visante.

held an N95, you know that they are structured, well made and fit well. If the materials look cheap—for example, the bands around the ear—it’s probably not a real N95 NIOSH-certified mask.” Dr. Siegel recommended that in the compounding area, N95 masks should “only” be used for the monthly cleaning of the BSC below the deck. “The accumulation of HD below the deck can be significantly higher than the areas above the deck and warrant this higher level of protection,” he said. Dr. Massoomi recommended a powered air-purifying respirator or controlled air-purifying respirator, if available, for BSC/compounding aseptic containment isolator (CACI) cleaning. “I’ve had the opportunity to clean many of BSCs/ CACIs, and once you start to add a cleaning liquid back onto that dried material, products like cyclophosphamide and 5-FU [5-fluorouracil], they can go from a liquid form to a vapor. When cleaning the cabinet, you don’t know what residues reside under the work surface, so assume the worst. If you’re concerned about vapors, USP <800> advises checking in with the site on respirators.” Where N95 or better respirators really shine in the compounding areas, Dr. Massoomi said, is in exposure to powders. “If you have a vial of a product of any active pharmacy ingredient (cyclophosphamide, hydrocortisone, alum, cefazolin, etc.) and it hasn’t been reconstituted, if the vial breaks or the powder spills or comes in a shipping tote that’s broken, an

N95 respirator is essential to protecting the individual(s) by keeping particulate matter from being inhaled.” Although Althoug N95 and N99 masks used for viral protection can be cleaned and sterilized with cle UV-C light or steamed U peroxide, that process does not remove the HD residue from these masks when they are used for HD cleaning purposes. H Paper masks used for this P purpose must be disposed pur of afterward. “You can also use afte either i h a P or R NIOSH-rated mask— those are very hard to come by but the best you can use—or a respirator for cleaning under the deck,” Dr. Siegel said. For further guidance on PPE preservation and reuse beyond the USP and FDA guidance documents visit the CDC’s resource on that topic at bit.ly/ 2WpCm4h, as well as downloadable flyers and guides from NETEC (Emory University, University of Nebraska Medical Center, and The City of New York; bit.ly/35R3D2U). —Gina Shaw The sources reported no relevant financial relationships.

24 Policy

Pharmacy Practice News • June 2020

Reimbursement Matters

You’re halfway there!

Focus on the Upcoming Payment Year W

e’re more than halfway through the FY2020 reimbursement year with some of the proposed rules for 2021 already released! These rules also affect contracts your facility has with the key payors in your area, and thus present an opportune time to craft any language you would like your system’s negotiating team to include in the new contracts. What are some of the services that you have developed during the COVID-19 pandemic response that you would like to continue to provide and be reimbursed for? Look to professional organizations for the support they can offer as you develop these services (box). The groups offer diverse information and have online discussion sections that provide an opportunity to share with, and ask questions from, your peers. All have active lobbying sections, as well, to help gain traction for payment for the services that you provide. Also see my May column on COVID-19 reimbursement (bit.

health care interoperability, developed by the Office of the National Coordinator for Health Information Technology and mandated by the 21st Century Cures Act, requires that electronic health data be made available to patients at no cost and defines exceptions to data blocking (www.healthit.gov/curesrule). Are you actually making headway and changing what you do? Going beyond the status quo? Changing mindsets? Being innovative? Incorporating new strategic options? How much of that are you going to fight to keep? It’s more than just speaking the words.

Prior Authorization Updates These new CMS requirements on prior authorization (PA) for certain hospital outpatient department services were part of the OPPS 2020 rules (Table). Although their start was delayed, the PA requirements take effect nationwide for dates of service on or after July 1, 2020. This PA process applies to five

Table. Selected Outpatient Services That Require Prior Authorizationa

Code(ii)

Botulinum Toxin Injection

64612

Injection of chemical for destruction of nerve muscles on one side of face

64615

Injection of chemical for destruction of facial and neck nerve muscles on both sides of face

J0585

Injection, onabotulinumtoxina, 1 unit

J0586

Injection, abobotulinumtoxina

J0587

Injection, rimabotulinumtoxinb, 100 units

J0588

Injection, incobotulinumtoxin a

Extracted from Table 65, Federal Register (go.cms.gov/2yTM4D4).

ly/2TueTgt). You may have a new group of residents or fellows in your department who need introductions to this aspect of health care, so reach out to them. It’s clear that the COVID-19 pandemic disruption is causing resets in how health care is delivered and that some of these may be permanent welcome innovations. Telehealth and the push for interoperability are two terrific examples of that. In early May, a new regulation to spur

categories of hospital outpatient department services, including blepharoplasty, botulinum toxin injections, panniculectomy, rhinoplasty and vein ablation. How robust is your PA process? Does it adequately cover these very expensive products that are not prepared by pharmacy but are being dispensed/supplied in these treatment areas? What’s the trigger for recognizing that PA now applies to Medicare patients? Details, links and submission guidelines are in the CMS document, Prior Authorization for Certain Hospital Outpatient Department (OPD) Services (go. cms.gov/364Pe3n).

More Noteworthy Changes Several additional developments affecting reimbursement should be on your radar as we approach the midyear mark: Nebulizers and Related Drugs. CMS has a helpful Medicare Learning Network fact sheet that offers advice and suggestions on these products and the requirements for reimbursement

(go.cms.gov/2YWFl65). Self-Administered Drug Exclusion List (A53127). This local coverage article has been revised as follows: “Due to the current public health emergency, the effective date for the addition of Tremfya® (J1628) and Stelara® (J3357) will be deferred until 45 days after the public health emergency ends” (go.cms. gov/2YW7HNL). 2021 FY Proposed Rule Sets. CMS operates on both FY and CY schedules for its payment rules. OPPS is the only one to follow the calendar, and its proposed 2021 rules are anticipated in a few weeks. Others that follow the FY schedule have been published and are available for your facility to comment on. In all cases, comments will be considered before the final sets are published later this summer. In addition to the IPPS proposed rules covering inpatients, in light of the COVID-19 pandemic, your relationship with some of these other facilities may have changed significantly. If so, knowing their payment rule sets will be essential. FY2021 IPPS Proposed Rule (CMS1735-P). Among the multiple changes, these are most pertinent to pharmacy: • Certain payment rate updates are tied to reporting quality data and are meaningful to EHR users. • Disproportionate share hospital payments have been reduced by $500 million to $7.8 billion. • Efforts to promote price transparency continue, building on the rule finalized last year requiring hospitals to list their median payor-specific negotiated rates for inpatient services by MS-DRG. • There is a new DRG for chimeric antigen receptor T-cell therapy based on available Medicare claims data, to provide a predictable rate. • There are new technology add-on payments for certain antimicrobials approved under the FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs (LPADs). To allow eligible antimicrobial products to begin receiving the add-on payment sooner, CMS proposed conditional approval for antimicrobial products that meet the criteria for add-on payment but don’t receive FDA approval in time for final rule consideration. FY2021 LTC: Net payments for LTCs would decrease by 0.9% (–$36 million), largely due to a reduction in payment for site-neutral cases (25% of all cases). FY2021 Hospice Payment Rate Update Proposed Rule (CMS-1733-P). This update is focused on FY2021 Medicare payment rates and the wage index for hospices serving Medicare beneficiaries. It provides model examples of the

“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

hospice election statement and hospice election statement addendum that reflect the changes finalized in the FY2020 hospice final rule for elections on or after Oct. 1, 2020 (fact sheet: go.cms.gov/2Wpvfc6; proposed rule: bit.ly/35RkUsM). FY2021 SNF Proposed Payment And Policy Changes (CMS-1737-P) For FY2021. CMS said it published this proposed rule “consistent with the legal requirements to update Medicare payment policies for skilled nursing facilities (SNFs) on an annual basis. CMS recognizes that the entire healthcare system is focused on responding to the COVID-19 public health emergency. As a result, the proposed rule includes proposals required by statute and that affect Medicare payment to SNFs, as well as proposals that reduce provider burden and may help providers in the COVID-19 response” (fact sheet: go.cms.gov/2Ao9Tn5; proposed rule: bit.ly/2STX62b). FY2021 IRF PPS Proposed Rule. This change updates payment policies and rates for IRFs. In recognition of the significant impact of the COVID-19 public health emergency and limited capacity of health care providers to review and provide comment on extensive proposals, CMS said it limited annual IRF rulemaking required by statute to essential policies, including proposals that reduce provider burden and may help providers in the COVID-19 response (fact sheet: go.cms.gov/3brQcHC; proposed rule: bit.ly/3csv0mo). FY2021 IPF PPS Proposed Rule (CMS-1731-P). This change updates payment rates by better aligning the rates for IPFs with the costs of providing care (fact sheet: go.cms.gov/3ctreZM; proposed rule: bit.ly/3fLavmM). ■

Association Aid ACCC: www.accc-cancer.org AMCP: www.amcp.org APhA: A Pharmacist’s Guide to Outpatient Fee-for-Service Billing: pharmacist.com/billing-primer ASHP: ASHP.org

A Reimbursement Lexicon CMS, Centers for Medicare & Medicaid Services; CY, calendar year; EHR, electronic health record; FY, fiscal year; IPF, inpatient psychiatric facility; IPPS, Inpatient Prospective Payment System; IRF, inpatient rehabilitation facility; LTC, long-term care; MS-DRG, Medicare Severity Diagnosis Related Group; OPPS, Outpatient Prospective Payment System

Operations & Management

Pharmacy Practice News • June 2020

Specialty Pharmacy

Keeping the Cold Chain Strong During COVID-19 P

harmaceutical manufacturers and accreditors will scrutinize coldchain packaging and processes more closely in the COVID-19 and post-COVID eras, according to Jon Pritchett, PharmD, the pharmacy program director at the Accreditation Commission for Health Care (ACHC), in Cary, N.C. Some manufacturers already go so far as to show specialty pharmacies the precise package materials and packout configurations they’ve validated to optimize temperature integrity of highvalue medications and ensure patient safety, Dr. Pritchett added. “They even state the size of cooling packs and how to layer them in the box to maintain temperature for specific medications for set time periods,” he told Pharmacy Practice News. COVID-19 has added further pressure to pack out and ship or courier properly because insurers now approve 90-day prescriptions for patients sheltering at home. The 90-day extension is being applied to refrigerated nonspecialty items such as insulin, and patients want their medications dropped off at their doorstep while carriers struggle to meet delivery demand for all kinds of merchandise.

even as some ship beyond their geography due to the demands of limited and sole distribution networks. “Packages that go from, say, New York to Arizona or Alaska, for example, must thermally protect medication efficacy under widely diverse environmental conditions year round,” Dr. Pritchett explained. Accreditors are on top of this. The Utilization Review Accreditation Commission (URAC), in Washington, D.C., raised its Performance Qualification testing standards last October to twice a year from once for all medications— refrigerated, frozen and room temperature—for each packout size and shipment method. Meanwhile, ACHC is “waiting to see how finalization of USP [Chapters] <800>, <797> and <795> standards flesh out before we issue a more prescriptive standard for cold chain,” Dr. Pritchett said. Until that happens, it’s critical for pharmacies to do as much as they can to ensure they are following optimal cold chain strategies, he stressed. “If a medication doesn’t work, you want to know that it’s a pharmacological issue with the drug rather than it went out of temperature in transport.”

More Cold Chain Rigors

UIC’s Approach

Specialty pharmacies address this added complexity in different ways,

To comply with the new URAC standards, the specialty pharmacy at

University of Illinois Hospital, in Chicago (UIC), has as validated a room m temperature medidication packout for the 55° to 105° F tememperature range, using room temperaturee ice packs instead of refrigerated and frozen en ice packs, and less insulating material—in their heir case, case bubble wrap, explained Lisa Kumor, PharmD, the accreditation coordinator for UIC’s specialty pharmacy services. “We’re still working on the proper amount of insulation for room temperature packouts less than 55° F, and we need to educate patients not to refrigerate room temperature medications despite our new packouts,” Dr. Kumor said. Room temperature packouts “will be a hurdle for specialty pharmacies overall because they generally haven’t yet done extensive testing to make sure they’re maintaining controlled room temperature requirements,” said Katie Kraverath, a senior business development manager at Temptime. “There will be an increase in mail-order medications in light of COVID-19, and guidelines will continue to tighten to make sure they’re protected.”

Resources for Temperature Integrity o optimize temperature, noise and energy performance to safely store medications, vaccines and pharmaceuticals. Microprocessor controlled, some models have alarms, event logs, color touch screen and password protection. Contact: (800) 743-5637; C www.helmerinc.com w

Accreditation Commission for Health Care (ACHC) Nonprofit accrediting organization Contact: (855) 937-2242; www.achc.org

Coldchain Technology Services SHIP2Q service reclaims high-performance ship-pers from pharmacies/health care practitioners after initial use, then prepares them for reuse with a safe, hygienic irradiation performance process and qualification using ultraviolet light to decontaminate and sanitize, and fitness-tests compoomponents to ensure continued high performance. Closedloop system amortizes cost of shippers over many trips. Because these containers are often 40% to 50% the cubic size and weight of foam coolers with comparable payload areas, the program is cost-neutral or cost-positive, eliminates waste, and improves product safety and security. More than 700,000 reclamations since 2009 have kept about 2 million tons of shipper waste out of landfills. Contact: (888) 687-2553; info@coldchain-tech.com

Green Cell Foam U.S.-grown, non-GMO cornstarch is the primary raw material in KTM’s thermal insulating, shock-absorbing, biodegradable, single-use packaging alternative to polystyrene, polyurethane and polyethylene coolers. Contact: (517) 703-9140; info@ktmindustries.com

Helmer Scientific Medical grade forced-air pharmacy refrigerators

LogTag USA L US data loggers monitor wide USB ranges of time, temperature and humidity, including freeze and vaccine transport indicators. They issue PDF reports and have companion software. Contact: www.logtagrecorders.com.

Packaging Technology Group TRUEtemp Naturals Cellulose line of curbside recyclable and repulpable products adds a new dual-temperature pharmaceutical shipper. The sustainable thermal solution enables medications and therapies with different temperature requirements to travel together in the same container, and saves on shipping costs and assembly training. Contact: (508) 673-1300; www.packagingtech.com

‘If a medication doesn’t work, you want to know that it’s a pharmacological issue with the drug rather than it went out of temperature in transport.’ —Jon Pritchett, PharmD Hospital-Based Specialty Pharmacies Innovate “The COVID crisis sheds light on our need to be very local and patient-specific,” said JoAnn Stubbings, BSPharm, a clinical associate professor of pharmacy practice at UIC College of Pharmacy, referring to the UIC specialty pharmacy where she recently retired from the post of associate director. “Our conciergestyle courier service has served us phenomenally well during this crisis. The pharmacy experienced zero disruption to timely deliveries with temperature integrity, and 75% to 80% of what we ship needs to be refrigerated.” Ms. Stubbings added that “it was almost overkill when we set up this service in 2016. But when COVID hit, nothing changed in our ability to serve patients.” Part of that historical success was see COLD CHAIN, page 26

The liners are made with renewable, traceable raw materials, fold flat for efficient shipping, can be custom branded, and bear the “widely recyclable” designation from how2recycle.org. Contact: (888) 647-3630; www.temperpack.com

Temptime TransTracker visual temperature indicators are single-use devices that change color to signal whether a particular temperature threshold has been exceeded for a period during transport. No activation required, they are easy to read, easy for pharmacists to use and patients to understand, and come in different temperature threshold options to monitor for heat and freeze events. Also, app-driven EDGE programmable data loggers track temperature wirelessly to further ensure integrity; these Bluetooth sensors can be used to conduct seasonal qualification tests with packaging and medication monitoring during storage and transport. Contact: (973) 630-6000; www.temptimecorp.com and www.zebra.com

TimeStrip Single-use, self-adhesive, power-free, instantly readable Timestrip PLUS temperature indicators show whether temperatures have breached a defined threshold and for how long. Indicators respond to different threshold temperatures, so users should select the ones most suited to their needs. Contact: (516) 441-0133; www.timestrip.com

TemperPack ClimaCell high-performance thermal-insulating box liners are fully customized to a client’s box size, shipping logistics, thermal profile and packing operation.

URAC Nonprofit accrediting organization. Contact: (202) 216-9010; www.urac.org

26 Operations & Management

Pharmacy Practice News • June 2020

Specialty Pharmacy

COLD CHAIN continued from page 25

due to the use of a refrigerated van, which helped ensure no wasteful packouts at the pharmacy. Fast forward to the pandemic, with social distancing and a “no-touch” approach to cold chain management, and adjustments were needed, such as full cold chain packs. The pharmacy also monitors the van’s temperature in real time while en route, Ms. Stubbings noted. Mike Gannon, PharmD, a business coordinator of specialty pharmacy services at UIC, pointed to another key driver of cold chain success, one that may well be unique to health systems: the fact that such facilities have medical centers near its patients. That type of structure, he noted, adds “value when you consider [their specialty] pharmacy’s ability to integrate with the medical record, which expedites the prior authorization process and allows for better communication across health care providers.” Successful cold chain management also requires dedicated partners, and for UIC, one was the local courier Webber Logistics, which averaged about 20 daily deliveries to specialty pharmacy patients in southwestern Chicago in March 2020. Courier owner Bryant Webber said the average delivery time was three hours, 44 minutes. But speed is not the only service goal, he stressed. It’s also important to take a few extra customer service steps, such as calling or texting patients when a delivery is imminent. That way, Mr. Webber noted, patients can be ready to retrieve and store their medications properly upon no-contact delivery.

The Pandemic Effect “If COVID and sheltering at home continue to scale, the need for people to receive medication deliveries will increase,” said Stephen F. Eckel, PharmD, the associate dean of global engagement and a clinical associate professor at the University of North Carolina Eshelman School of Pharmacy, in Chapel Hill. In such a scenario, “a health system’s cold chain capabilities is what to worry about most,” Dr. Eckel said. “Specialty pharmacies need to educate patients to treat them like their perishable groceries, something they could easily relate to.” About 30% of the 800 to 1,200 prescriptions mailed every day by the UNC Shared Services Center Specialty Pharmacy, also in Chapel Hill, require cold chain packaging, according to director of pharmacy Jeff Reichard, PharmD. The pharmacy attaches a temperature tag to each product so patients can see if it deviated from “normal” conditions by 2° to 8° C; a color change on the tag would indicate a short, moderate or extended excursion period. The pharmacy also uses advanced

tracking services to “rescue” packages at risk for being exposed to suboptimal conditions—for example, refrigerated items not delivered within 24 hours of their packout, Dr. Reichard said.

Top Priorities Specialty pharmacies that are able to comply with evolving thermal protection standards, save on shipping space and labor and materials

costs on packouts, and keep the environment safer would come out on top while keeping pace in an era of increasing

medication shipments. To this end, both Dr. Eckel and Ms. Stubbings said they would welcome

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.

Operations & Management

Pharmacy Practice News • June 2020

Specialty Pharmacy clearer packout guidelines from pharmaceutical manufacturers, and more feasible, affordable solutions to show temperature variations from suppliers. Approaches by some vendors, among them two distinctive paths toward sustainability and shipping efficiencies, are being made (sidebar, page 25). Jed Dutton, the vice president of marketing at TemperPack, in Richmond, Va., pointed to one key trend in cold chain materials and policy. “Styrofoam bans exist in many parts of the country. The National Institutes of Health

has said styrene is a probable carcinogen to humans [Mutagenesis 2011;26(5):583584]. Shipping lifesaving drugs in 70-yearold technology associated with cancer puts pharmaceutical makers and pharmacies in an uncomfortable position,” Mr. Dutton said. The company’s ClimaCell box liners, made largely of starch and paper, are a recyclable alternative. Additionally, TemperPack’s thermal transport lab, which he said is certified by the International Safe Transit Association, emulates external shipping conditions, which enables it to test and qualify packaging

solutions that meet temperature range and shipping specifications for each user. Meanwhile, the shipper reclamation system by Coldchain Technology Services (CTS), in Spring Branch, Texas, allows pharmaceutical manufacturers to pay a variable cost for boxes as they use them, rather than purchasing and storing them. Specialty pharmacies with multiple sites “can use our pre-engineered systems to establish a uniform shipping and packout protocol across their organization, which decreases risk, improves product security and

HyperRAB

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

HIGHLIGHTS OF PRESCRIBING INFORMATION

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

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

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

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

3054805 Revised: 11/2019

helps with accreditations,” said Scott Bullard, the company’s director of business development. KabaFusion, a Cerritos, Cal.–based chain of 28 URACand ACHC-accredited home infusion specialty pharmacies across the nation, “plans to deploy” the CTS shipping solution this summer, said Frank Esposito, RPh, the vice president of operations. —Al Heller The sources reported no relevant financial relationships other than their stated employment.

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

When protecting your patients with HRIG

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

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

HIGH-POTENCY FORMULA

REDEFINING HRIG ADMINISTRATION REDEFINING HRIG ADMINISTRATION

LOWEST VOLUME PER DOSE

MORE RABIES ANTIBODIES PER mL

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

#1 Prescribed HRIG in the US

March 2020

US-HB3-2000016