Pharmacy Practice News - May 2022

The Best-Read Pharmacist’s News Source

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Tocilizumab alternative

CLINICAL

Hot nutrition trends: new advocacy bill, component shortages, hyperglycemia and more .............................. 6

By Gina Shaw

POLICY

The main barriers to passing provider status legislation ..........

18

Hazardous drug containment: How much is enough? ..........

20

Why CMS put the payment brakes on new Alzheimer’s drug ....................................

24

OPERATIONS & MGMT

Pharmacists should be the OUD experts .......... 28 COVID-19 and the cold chain: lessons learned ..............................

By Gi B Gina Sh Shaw

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edication safety experts worry that the felony conviction of former nurse RaDonda Vaught for a fatal medication error she made in December 2017, while working at Vanderbilt University Medical Center in Nashville, Tennessee, will hinder efforts to advance a systemwide patient safety culture in hospitals that fosters openness and honesty in discussing mistakes, near misses and other safety issues without placing individual blame.

Instead of scapegoating an individual nurse with criminal penalties, they say, the case should be used as a learning opportunity, citing a number of systems-based solutions that could and should be adopted to prevent similar errors and protect other patients.

“This decision is a blow,” said Charlene Hope, PharmD, the chief pharmacy quality and medication safety officer at the University of Chicago Medicine. “Over the past 20-plus years of the patient safety movement, we have made a lot of gains toward developing and encouraging a Continued on page 26

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38

Restoring the Full Diversity of the Gut Microbiome:

Can It Break the Cycle of Recurrent C. Difficile Infection?

See insert after page 12

Boston—Anakinra may be an acceptable alternative to tocilizumab for treating cytokine release syndrome (CRS) after initial management with the latter agent, which continues to be in short supply due to its frequent use as a therapy for patients with severe COVID-19, a new study suggests.

The results are welcome news to pharmacists tasked with rationing tocilizumab (Kineret, Swedish Orphan Biovitrum) during the ongoing pandemic, the investigators reported during the 2022 Hematology/Oncology Pharmacy (HOPA) annual conference.

Finding an effective alternative or adjunctive treatment for CRS is critical, given that CRS is a common

Vaught Verdict a ‘Blow’ To Patient Safety Culture

Continued on page 10

TECHNOLOGY

Pharmacists team up with IBD physicians to standardize use of biologics .....................

Anakinra Helps Relieve Shortage Of COVID-19 Rx

Volume 49 • Number 5 • May 2022

PANDEM Adds More Consensus To Ped ICU Care

New Guideline Aims for Safer Renal Dosing in Cancer Patients

By Bruce Buckley

draft of the new International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) was announced in late March 2022, and a panel of experts at the International Society of Oncology Pharmacy Practitioners (ISOPP) 2022 Virtual Symposium offered a preview of what the oncology community can expect from the document.

The speakers first underscored the need for such a document, given that chronic kidney disease (CKD) has a reported prevalence of up to 53% at cancer diagnosis (JAMA 2018;319[23]:2437-2439). In addition, CKD is associated with significantly worse mortality (Am J Kidney Dis 2014;63[1]:23-30). In the

T

he Society of Critical Care Medicine (SCCM) recently unveiled its groundbreaking clinical practice guidelines for the comprehensive management of critically ill children in the pediatric ICU (PICU), and pharmacists can play a key role in ensuring adherence, experts note.

The PANDEM Guidelines for Children and Infants fill a long unmet need for evidence-based clinical practice recommendations specific to PICU patients, according to the task force.

Continued on page 16

By Gina Shaw

A

Practice Pearl Order amid chaos: how one health system kept meds flowing during the George Floyd unrest.

See page 30

latter study, for every 10-mL/min/1.73 m2 reduction in estimated glomerular filtration rate (eGFR), there was an increase in cancerspecific mortality of 18% (P<0.001).

A panel of multidisciplinary experts developed the ADDIKD guideline to help clinicians lessen those risks. The panel included representatives from oncology, hematology, nephrology, pharmacology and geriatrics, with participation from the leading global kidney disease guidelines group—Kidney Disease Improving Global Outcomes (KDIGO)—as well as the International Society of Geriatric Oncology, the British Oncology Pharmacy Association, the International Society of Oncology Continued on page 14

REDEFINE POSTOPERATIVE PAIN MANAGEMENT With the First and Only Extended-Release Dual-Acting Local Anesthetic (DALA)1-4 ZYNRELEF redefines postoperative pain management by providing superior pain relief for up to 72 hours, with fewer patients experiencing severe pain, and reducing or eliminating the need for opioids in many patients following surgery versus standard-of-care bupivacaine HCl solution.1-4

SYNERGISTIC MECHANISM OF ACTION1,5,a

SUPERIOR 72-HOUR PAIN RELIEF1-3,b

OPIOID REDUCTION & ELIMINATION1-3,b

NEEDLE-FREE APPLICATION1

BROAD ACCESS PRICING & FAVORABLE REIMBURSEMENT

Synergistic increases in analgesia compared with meloxicam or bupivacaine alone shown in preclinical and Phase 2 studies.1,5 b Clinical findings were demonstrated in Phase 3 trials for bunionectomy with osteotomy and open inguinal herniorrhaphy comparing ZYNRELEF to both placebo and bupivacaine HCl solution.1-3

a

EXPLORE THE DATA AT ZYNRELEF.COM

Indication

Contraindications

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after foot and ankle, small-to-medium open abdominal, and lower extremity total joint arthroplasty surgical procedures.

ZYNRELEF is contraindicated in patients with a known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDS have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing CABG.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.

IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.

This risk may occur early in treatment and may increase with duration of use.

• ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Warnings and Precautions Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after application of ZYNRELEF. When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours.

Hepatotoxicity: If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient.

Hypertension: Patients taking some antihypertensive medication may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure.

Heart Failure and Edema: Avoid use of ZYNRELEF in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.

Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal failure.

Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.

© 2022 HERON THERAPEUTICS, INC. ALL RIGHTS RESERVED. 4242 CAMPUS POINT COURT, SUITE 200 • SAN DIEGO, CA 92121 • 858-251-4400

PP-HTX011-0557 | 01/22

Chondrolysis: Limit exposure to articular cartilage due to the potential risk of chondrolysis.

Methemoglobinemia: Cases have been reported with local anesthetic use.

Serious Skin Reactions: NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): If symptoms are present, evaluate clinically.

Fetal Toxicity: Due to the risk of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus with NSAIDS, limit use of ZYNRELEF between about 20 to 30 weeks gestation, and avoid use after about 30 weeks.

Use in Specific Populations Infertility: NSAIDs are associated with reversible infertility. Consider avoidance of ZYNRELEF in women who have difficulties conceiving.

Severe Hepatic Impairment: Only use if benefits are expected to outweigh risks; monitor for signs of worsening liver function.

Severe Renal Impairment: Not recommended.

Adverse Reactions Most common adverse reactions (incidence *10%) in controlled clinical trials with ZYNRELEF are constipation, vomiting, and headache.

Report side effects to Heron at 1-844-437-6611 or to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Hematologic Toxicity: Monitor hemoglobin and hematocrit in patients with any signs or symptoms of anemia.

For additional information about ZYNRELEF, please refer to the Brief Summary of Prescribing Information on adjacent page.

Drug Interactions

References: 1. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2021. 2. Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee G-C. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: Phase III results from the randomized EPOCH 1 study. Reg Anesth Pain Med. 2019;44(7):700-706. doi:10.1136/rapm-2019-100531. 3. Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the Phase 3 EPOCH 2 study. Hernia.

2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6. 4. Lachiewicz PF, Lee G-C, Pollak R, Leiman D, Hu J, Sah A. HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized Phase 2b trial. J Arthroplasty.

2020;35(10):2843-2851. doi:10.1016/j.arth.2020.05.044. 5. Ottoboni T, Quart B, Pawasauskas J, Dasta JF, Pollak RA, Viscusi ER. Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain. Reg Anesth Pain Med. 2020;45(2):117-123. doi:10.1136/rapm-2019-100714.

Drugs That Interfere with Hemostasis: Monitor patients for bleeding who are using ZYNRELEF with drugs that interfere with hemostasis (eg, warfarin, aspirin, SSRIs/SNRIs).

ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

ACE Inhibitors and ARBs: Use with ZYNRELEF in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function.

Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects.

REDEFINE POSTOPERATIVE PAIN MANAGEMENT

ZYNRELEF® (bupivacaine and meloxicam) extended-release solution, for soft tissue or periarticular instillation use

Dose-Related Toxicity: The toxic effects of local anesthetics are additive. When using with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours. Monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION

Risk of Use in Patients with Impaired Cardiovascular Function: Patients with impaired cardiovascular function may be less able to compensate for the prolongation of AV conduction. Monitor patients closely for blood pressure, heart rate, and ECG changes.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.

This risk may occur early in treatment and may increase with duration of use • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.

These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events

INDICATIONS AND USAGE ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after foot and ankle, small-to-medium open abdominal, and lower extremity total joint arthroplasty surgical procedures.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.

DOSAGE AND ADMINISTRATION Important Dosage and Administration Information: ZYNRELEF is intended for single-dose administration only. Avoid intravascular administration of ZYNRELEF. ZYNRELEF should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurologic or cardiac toxicity. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. The safety of concomitant administration of ZYNRELEF and other NSAID medications has not been evaluated. If additional NSAID medication is indicated in the post-operative period, monitor patients for signs and symptoms of NSAID toxicity.

ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit. See ZYNRELEF Instructions for Use included in the kit for complete administration instructions.

ZYNRELEF should not be administered via the following routes: epidural, intrathecal, intravascular or intra-articular, regional nerve blocks, and pre-incisional or pre-procedural locoregional anesthetic techniques.

Administration Instructions: ZYNRELEF is applied without a needle into the surgical site using a Luer lock cone-shaped applicator attached to the syringe following final irrigation and suction of each layer and prior to suturing. Only apply ZYNRELEF to the tissue layers below the skin incision and not directly onto the subdermal layer or skin. Use only the amount necessary to coat the tissues, such that ZYNRELEF does not leak from the surgical wound after closure.

Dosing Instructions: As a general guidance in selecting the proper dosing of ZYNRELEF, the following examples of dosing are provided: − Foot and ankle surgical procedures, such as bunionectomy: up to 2.3 mL to deliver 60 mg/1.8 mg. − Small-to-medium open abdominal surgical procedures, such as open inguinal herniorrhaphy: up to 10.5 mL to deliver 300 mg/9 mg. − Lower extremity total joint arthroplasty surgical procedures, such as total knee arthroplasty: up to 14 mL to deliver 400 mg/12 mg.

Hepatotoxicity: Bupivacaine should be used cautiously in patients with hepatic disease because of their inability to metabolize local anesthetics normally. NSAIDs are associated with elevations of ALT or AST and rare, sometimes fatal cases of severe hepatic injury. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur, perform a clinical evaluation of the patient. The risk of these events following single-dose local application of ZYNRELEF is uncertain.

Hypertension: NSAID use in patients taking ACE inhibitors, thiazide, or loop diuretics may result in impaired blood pressure control.

Monitor blood pressure.

Heart Failure and Edema: NSAID use in patients with heart failure may increase the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed with NSAIDs. Avoid use in patients with severe heart failure unless the benefits outweighs the risk of worsening heart failure; if used, monitor for signs of worsening heart failure. The risk of these events following single-dose local application of ZYNRELEF is uncertain.

Renal Toxicity: NSAIDs may cause a dose-dependent reduction in renal blood flow and overt renal decompensation. Additionally, the metabolites of meloxicam are excreted by the kidney which may hasten the progression of renal dysfunction in those with renal disease. Correct dehydration and hypovolemia prior to initiating ZYNRELEF. Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.

Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.

Anaphylactic Reactions: Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs.

Chondrolysis: Limit exposure to articular cartilage due to the potential risk of chondrolysis. Intra-articular infusions of local anesthetics have been associated with chondrolysis.

Methemoglobinemia: Local anesthetics have been associated with methemoglobinemia. Treat with supportive care, and, if necessary, methylene blue, exchange transfusion, or hyperbaric oxygen.

Exacerbation of Asthma Related to Aspirin Sensitivity: NSAIDs are contraindicated in patients with aspirin-sensitive asthma. When ZYNRELEF is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for exacerbation of asthma symptoms.

Serious Skin Reactions: NSAIDs can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, which can be fatal. If symptoms present, evaluate clinically.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): NSAIDs may cause DRESS. If signs or symptoms are present, evaluate the patient immediately and treat as clinically indicated.

Fetal Toxicity: NSAIDs may cause fetal renal dysfunction leading to oligohydramnios at about 20 weeks gestation and premature closure of the fetal ductus arteriosus at about 30 weeks gestation or later.

Limit use between about 20 to 30 weeks gestation, and avoid use after about 30 weeks.

Hematologic Toxicity: NSAIDs may cause anemia due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), SSRIs and SNRIs may increase this risk. Monitor these patients’ hemoglobin and hematocrit and for signs or symtoms of anemia.

See full Prescribing Information for all important dosage and administration information, preparation instructions and compatibility considerations.

Masking of Inflammation and Fever: NSAIDs reduce inflammation, and possibly fever, which may diminish detection of infections.

CONTRAINDICATIONS

The safety of ZYNRELEF has been evaluated in a total of 1067 patients undergoing various surgical procedures across 7 randomized, double-blind, bupivacaine- and placebo-controlled studies designed to investigate ZYNRELEF to reduce postoperative pain for 72 hours and the need for opioid analgesics. Among 504 patients who received ZYNRELEF in single doses of 60 mg/1.8 mg to 400 mg/12 mg via instillation into the surgical site, the most common adverse reactions (incidence greater than or equal to 10%) following ZYNRELEF administration were constipation, vomiting, and headache. The most common adverse reactions (* 5% and higher than placebo) in the following 3 studies were:

ZYNRELEF is contraindicated in patients with known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing coronary artery bypass graft (CABG) surgery.

WARNINGS AND PRECAUTIONS Cardiovascular (CV) Thrombotic Events with NSAID Use: To minimize the potential risk of CV thrombotic events, do not exceed the recommended dose. Monitor for serious CV events. Aspirin does not mitigate the risk of these thrombotic events. In patients with a recent MI, avoid the use of ZYNRELEF unless the benefits are expected to outweigh the risk, and if used, monitor patients for signs of cardiac ischemia. The risk of these events following single-dose local application of ZYNRELEF is uncertain.

Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID Use: To minimize the risk of GI bleeding, do not exceed the recommended dose and avoid using more than one NSAID at a time. If additional NSAID medication is indicated in the post-operative period, monitor patients for signs and symptoms of NSAID-related GI adverse reactions. In high-risk patients, evaluate if the benefits outweighs the risk of bleeding, remain alert for GI ulcerations and bleeding, and promptly evaluate and treat suspected serious GI adverse events. In patients using concomitant low-dose aspirin, monitor for GI bleeding.

ADVERSE REACTIONS

• Bunionectomy: 157 patients received ZYNRELEF 60 mg/1.8 mg and the most common adverse reactions were dizziness, incision site edema, headache, incision site erythema, bradycardia, impaired healing, and muscle twitching. With the exception of muscle twitching, these events were also higher for bupivacaine HCl compared to placebo. A total of four subjects had delayed bone healing (assessed by X-ray on Days 28 and 42), with no clinically meaningful difference between treatment groups. Additional local inflammatory adverse events observed at a higher incidence for ZYNRELEF compared to placebo or bupivacaine HCl included incision site cellulitis, wound dehiscence, and incision site infection.

• Herniorrhaphy: 163 patients received ZYNRELEF 300 mg/9 mg and the most common adverse reactions were headache, bradycardia, dysgeusia, and skin odor abnormal. With the exception of skin odor abnormal, these events were also higher for bupivacaine HCl compared to placebo.

• Total knee arthroplasty: 58 patients received ZYNRELEF 400 mg/ 12 mg and the most common reactions were nausea, constipation,

vomiting, hypertension, pyrexia, leukocytosis, and pruritus. With the exception of hypertension, these events were also higher for bupivacaine HCl compared to placebo.

DRUG INTERACTIONS Bupivacaine Drug Interactions: Local anesthetics: In clinical studies, other local anesthetics (including ropivacaine and lidocaine) have been administered before, during, or after application of ZYNRELEF without evidence of local anesthetic systemic toxicity. Administration of ZYNRELEF with other formulations of local anesthetics (ie, bupivacaine liposome injectable suspension) has not been studied. Drugs associated with methemoglobinemia: Bupivicane may increase risk of methemoglobinemia when concurrently used with nitrates, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other methemoglobinemia-associated drugs.

Meloxicam Drug Interactions: Drugs That Interfere with Hemostasis: Meloxicam use with anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Monitor patients with concomitant use of ZYNRELEF with anticoagulants, antiplatelet agents, SSRIs, and SNRIs for signs of bleeding. ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Meloxicam may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ACE Inhibitors and ARBs: Meloxicam use with ACE inhibitors and ARBs in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, adequately hydrate and monitor for signs of worsening renal function. Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy, including antihypertensive effects. Digoxin: NSAIDs increase the serum concentration and prolong the half-life of digoxin. Monitor serum digoxin levels. Lithium: NSAIDs elevate plasma lithium levels and reductions in renal lithium clearance. Monitor for signs of lithium toxicity. Methotrexate: NSAIDs use with methotrexate may increase risk for neutropenia, thrombocytopenia, and other methotrexateassociated toxicities. Monitor for signs of methotrexate toxicity Cyclosporine: NSAIDs use with cyclosporine may increase nephrotoxicity. Monitor for signs of worsening renal function.

Pemetrexed: Meloxicam used with pemetrexed may increase myelosuppression, renal, and GI toxicities. In patients with creatinine clearance 45 to 79 mL/min, monitor for pemetrexedassociated toxicities.

OVERDOSE No data are available with regard to overdose of ZYNRELEF. Management of Local Anesthetic Overdose: At the first sign of change, oxygen should be administered. The first step for convulsions, underventilation, or apnea is immediate maintenance of a patent airway and assisted or controlled ventilation capable of immediate positive airway pressure. After assuring airway and ventilation, evaluate and establish adequate circulation as indicated. Drugs that treat convulsions may depress the circulation. If convulsions persist despite adequate respiration, and if the circulation permits, small increments of an ultra-short acting barbiturate or a benzodiazepine may be administered intravenously. Supportive treatment of circulatory depression may require intravenous fluids and, when appropriate, a vasopressor. If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs, and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if maintenance of a patent airway is inadequate or if prolonged ventilatory support is indicated.

CLINICAL PHARMACOLOGY ZYNRELEF contains bupivacaine, an amide local anesthetic, and meloxicam, an NSAID. The contribution of each active ingredient in ZYNRELEF has been studied in clinical studies in herniorrhaphy or bunionectomy, utilizing ZYNRELEF and formulations of meloxicam alone or bupivacaine alone in the ZYNRELEF vehicle. Meloxicam alone provided negligible local analgesia and bupivacaine alone provided greater analgesia compared with placebo through 24 hours post surgery, despite exposure to bupivacaine for approximately 72 hours. Compared with bupivacaine alone in both studies, ZYNRELEF demonstrated greater and longer analgesia through 24, 48, and 72 hours. The instillation of ZYNRELEF into the surgical site results in significant systemic plasma levels of bupivacaine and meloxicam through 96 hours. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy.

PATIENT COUNSELING Inform patients of the risks and mitigations for: CV thrombotic events; GI bleeding, ulceration, and perforation, including the increased risk of GI toxicity with use of NSAIDs in the postoperative period; anaphylactic reactions; serious skin reactions, including DRESS; methemoglobinemia; fetal toxicity; and temporary loss of sensation near the surgical site.

This information is not comprehensive. Visit www.zynrelef.com to obtain the full Prescribing Information, including Boxed Warning.

Manufactured and marketed by: Heron Therapeutics, Inc., 4242 Campus Point Court, Suite 200, San Diego, CA, 92121, USA. Copyright© 2021 Heron Therapeutics, Inc. All rights reserved.

ZYNRELEF® is a registered trademark of Heron Therapeutics, Inc. PP-HTX011-0102 12/21

Up Front

Pharmacy Practice News • May 2022

5

From Our Readers Handling COVID-19 Therapeutics: Hospitals, Yes; Chain Pharmacies, Not So Much?

Re: “AMA, Pharmacists Face Off Over Test-to-Treat” (bit.ly/3vyvF0u): As a practicing pharmacist with experience in hospital and retail settings, I would agree that, under President Joe Biden’s “test-to-treat” initiative governing COVID-19 therapeutics, a hospital pharmacist would be qualified to prescribe these drugs because they have total control of what the patient takes, based on access to medication histories and other key information in the electronic health record.

As for retail chain drugstores, they often are so poorly staffed that if they had to obtain two or three drug

histories, their staff would explode.

Yesterday I went to a chain pharmacy where I used to work to find almost all the staff had left in the 18 months since I had been there. The staff consisted of two pharmacists (one who was at lunch) and one pharmacy technician who was certified to give the COVID-19 vaccine booster shot my wife, and I had made appointments for.

The pharmacist (manager) was on a weekly conference call and trying to check prescriptions or run the register at the same time. The technician was also getting prescriptions ready to check, answering the phone and getting our shots ready.

When things finally quieted down and the other pharmacist came back from lunch, she was able to give us our shots and did a great job. Now imagine a patient comes in who wants a test that turns out positive; the pharmacist then would have to obtain a complete drug history and check for interactions while the panicky patient waits furiously.

Right now in California (and probably other states), there is an overabundance of pharmacists, which has led to new

Advantages of an IV-Workflow Management System

graduates getting $10 or more of a salary cut per hour from previous years—and still the chains lower the staff.

So, I have to agree with the AMA’s [American Medical Association’s] position that pharmacists—or more specifically, chain pharmacists—are not capable of handling the clinical requirements of the test-to-treat program. Maybe in the future, people will have insurance cards with all their drug histories built in. Under such a scenario, the technician swipes the card and it gives the pharmacist a COMPLETE list of Rx drugs. At that point, maybe this could be done in the retail setting.

—DanSusanK

‘Flawed’ 340B Program: How Do You Really Feel?

Re: “340Bs Push Back On Abuses Cited In COA Report” (bit.ly/3Eu0G9U): The 340B program is a flawed system that perpetuates and further promotes the radical and insane distortions in drug pricing and reimbursement. It does nothing to rein in Big Pharma’s unfettered price gouging but instead

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REIMBURSEMENT Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

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SPECIALTY PHARMACY JoAnn Stubbings, BSPharm, MHCA, Chicago, IL

Sarah Rezvani, Account Manager srezvani@mcmahonmed.com

Elaine Strauss, PharmD, MS, Atlanta, GA

STERILE COMPOUNDING Kristina N. Bryowsky, PharmD, MBA, BCPS, Fenton, MO

Joe Malichio, Director, Medical Education jmalichio@mcmahonmed.com

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

TECHNOLOGY Thomas Van Hassel, RPh, Yuma, AZ

Craig Wilson, Advertising Manager, Classified Sales cwilson@mcmahonmed.com

INFECTIOUS DISEASES Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH David P. Nicolau, PharmD, Hartford, CT Jason Pogue, PharmD, Detroit, MI LEADERSHIP Ernest R. Anderson Jr., MS, RPh, Boston, MA

Michele McMahon Velle, MAX Graphics/Creative Director

Marty Barbieri, Associate Director of Production NUTRITION Beverly Holcombe, PharmD, BCNSP, FASHP, FASPEN Chapel Hill, NC Vanessa Kumpf, PharmD, BCNSP, Nashville, TN

David S. Craig, PharmD, BCPS, Tampa, FL

Re: “Pharmacists Have a Role to Play in Deprescribing” (bit.ly/3Me7ElX): This article underscores the fact that there needs to be a mechanism for pharmacists to be reimbursed as licensed providers; this is the only way to move pharmacy outside of the “retail” model and mindset. It’s counterintuitive to deprescribe when your salary and reimbursement is tied to dispensing. I know we turn away prescriptions all the time, and we also scrutinize the controlled-substance prescription that comes through with great detail, yet we are never reimbursed for the review and oversight and counseling we provide to the patient, not to mention the coordination with the primary care provider and pain physician. When we practice as a healthcare provider, we aren’t recognized and aren’t paid.

—jteague@pmhd.org

For late-breaking session coverage, plus videos, visit pharmacypracticenews.com/ ConferenceNews!

ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

AMBULATORY CARE Meghan D. Swarthout, PharmD, MBA, BCPS, Sallston, MD

Pharmacists Need To Become Licensed Providers

Missed a pharmacy meeting but still want news highlights?

In this episode of “One Burning Question,” Keith Streckenbach asks Ann Cabri, PharmD, of UC Davis Medical Center: How do IVWMS improve efficiencies while compounding? Listen at https://bit.ly/36X1V55-PPN.

EDITORIAL BOARD

Indu Lew, PharmD, Livingston, NJ

exaggerates it with subsequent winners and losers.

—rayerik@gmail.com

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6 Clinical

Pharmacy Practice News • May 2022

Nutrition

Hot Trends at ASPEN, NHIA All articles by David Wild and Marcus Banks

Ongoing shortages of critical nutrition components, a push for legislation that could significantly expand access to affordable nutrition care and the value of data-mining for optimizing nutrition therapy were just a few of the hot practice trends highlighted during two recent nutrition conferences.

No Sign of Relief for PN Component Shortages Seattle—With no indication that the protracted period of shortages of parenteral nutrition (PN) components is ending, one expert at the American Society for Parenteral and Enteral Nutrition (ASPEN) 2022 Nutrition Science and Practice Conference told attendees to keep perfecting the art of rationing these critical products.

“Over the last decade or so we’ve had more active shortages, they’ve been lasting longer and are more intense—meaning the amount of product that’s in the market is very, very low,” said Beverly Holcombe, PharmD, a clinical practice specialist at ASPEN. Approximately 12% of the drug shortages reported by the University of Utah Drug Information Service in 2021 were for fluids and electrolytes, some of which are used in PN formulations.

Some of these currently in short supply include calcium gluconate, magnesium sulfate, potassium acetate, potassium chloride, sodium acetate, sodium chloride and sodium phosphate as well as sterile water, Dr. Holcombe said.

These scarcities are not a recent phenomenon, she reiterated. “Parenteral multivitamins for adults and pediatrics, as well as concentrated sodium chloride, have been on shortage for more than 10 years, which has made it really challenging to provide parenteral nutrition.”

With no resolution in sight, pharmacists and PN providers need to continue implementing shortage management strategies for PN micronutrient components and products.

“A key strategy is to make sure PN components are part of the shortage management plan for your entire institution and that the same general shortage strategies we use for all shortage medications apply to PN components as well,” Dr. Holcombe said.

Once a shortage is confirmed, providers should immediately implement strategies such as those recommended by organizations like ASPEN, which lists current nutrition component shortages on its website. “Assess the need for PN in each patient; switch to an oral formulation if possible; reserve the supply you have for vulnerable patient populations and save the age-specific products for those designated populations,” she said.

Dr. Holcombe recommended looking for other sizes or concentrations of a product in short supply to find replacements that might fill the gap in the short term.

For those who turn to imported products during a shortage, she recommended using them “with caution and care and following the manufacturers’ instructions.” (Ms. Holcombe added that such efforts would involve contacting vendors, because institutions can’t import directly themselves.)

One important contribution that clinicians can make during a shortage is to report related adverse events or suboptimal patient outcomes to the Institute for Safe Medication Practices, so the impact of the shortage can be tracked and documented. In 2013, for example, three cholestatic extremely premature infants developed zinc deficiency dermatitis in light of a nationwide shortage of injectable zinc (MMWR Morb Mortal Wkly Rep 2013;62[7]:136-137).

Dr. Holcombe stressed that once a PN component shortage is over, it is important to stop rationing or conserving products, even if it is done out of fear of a recurring shortage. “Once a product is available through your normal supplier channels, you need to buy enough product to give patients their full daily dose,” she said.

For those who are weary of off-again, on-again PN component availability, Dr. Holcombe issued a note of encouragement. “You have to have some trust and also remember that our commitment is to take care of our patients and make sure they get adequate micronutrients,” she said. “Partial dosing of micronutrients over long periods of time may lead to deficiencies, particularly in long-term PN patients.” (JPEN J Parenter Enteral Nutr 2019;43 Suppl 1:S5-S23. doi: 10.1002/jpen.1525.)

ASPEN Advocate Urges Passage of NutritionRelated Legislation Seattle—Congress is faced with several bills that can immediately expand access to affordable, effective and safe nutrition care if passed, an advocate for the American Society for Parenteral and Enteral Nutrition (ASPEN) told attendees of the organization’s 2022 Nutrition Science and Practice Conference.

One important piece of legislation, which ASPEN is pushing Congress to pass, is an expansion to the Medical Nutrition Therapy (MNT) Act. According to Jay Mirtallo, MS, RPh, a clinical practice specialist at ASPEN and professor emeritus, The Ohio State University in Delaware, the MNT Act was initially passed in 2000 and provides individualized nutrition assessment and therapy as well as support for behavioral and lifestyle changes to Medicare Part B recipients with renal disease or diabetes.

However, the bill “is a good example of what happens when you pass a bill that’s overly restrictive,” Mr. Mirtallo said. “MNT services are not utilized to any great degree because under the MNT Act, they can only be provided to Medicare beneficiaries with diabetes and renal failure, only by a registered dietitian who needs to meet very specific criteria, and only through physician referral.”

He added that the expansion is being spearheaded by the Academy of Nutrition and Dietetics.

With only two patient groups receiving MNT, registered dietitians may not have access to the volume of patients needed to make the application process to become a certified MNT provider worthwhile, Mr. Mirtallo noted. To that end, the legislative expansion would expand patient eligibility to include patients with prediabetes, obesity, cancer, high blood pressure, high cholesterol, malnutrition, eating disorders, celiac disease, HIV/AIDS, cardiovascular disease and, more broadly, any condition or disease that causes unintentional weight loss.

In addition, it would allow nurse practitioners, physician assistants, clinical nurse specialists and psychologists to refer patients to a registered dietitian for nutrition services, improving access to MNT services, Mr. Mirtallo said.

Another legislative priority that ASPEN is pursuing is gaining reimbursement for nutrition therapy, which is a challenge. “CMS [Centers for Medicare & Medicaid Services] currently does not distinguish between a usual diet and food and enteral medical nutrition products or oral supplements,”

Mr. Mirtallo said. The enteral products and oral supplements, he noted, are used by patients to meet a specific disease-related dietary need because they are unable to maintain nutritional health without them.

To create that legal distinction, ASPEN is encouraging legislators to pass the Patient Access to Medical Foods Act, an amendment to the Orphan Drug Act that would recognize enterally administered foods as medical foods but would require a practitioner prescription. “If this is passed, it would give enteral foods an NDC [National Drug Code] number, which is a first step towards gaining reimbursement,” Mr. Mirtallo said.

Other laws that are under congressional consideration and that ASPEN is advocating for include the Medical Nutrition Equity Act, which would provide coverage for medically necessary foods, vitamins and individual amino acids for patients with digestive and inherited metabolic disorders under federal health programs and private health insurance, and the Preserving Patient Access to Home Infusion Act, which would reimburse some home infusion payment components, even if a healthcare professional is not present to administer the infusion.

While ASPEN is advocating on the Hill and in capitals across the country, Mr. Mirtallo urged attendees to contact their representatives and help advance the cause of better nutrition care. “The best and most direct way for us to accomplish our advocacy efforts is to have our members and patients speak up,” he said. “Our legislators need to hear how difficult it is as a clinician to provide good care for patients and how patients can suffer as a result of barriers, and that legislation can address these barriers. Every voice counts.”

Tweaking Dextrose Reduces PN-Related Hyperglycemia Seattle—Conservative rates of dextrose infusion can mitigate the risk for hyperglycemia in hospitalized adults with obesity who are receiving parenteral nutrition (PN), as shown in see HOT TRENDS, page 8

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PROTECTING THOSE WHO CARE FOR US: USP <800> Guidelines for Safe Handling of a Hazardous Drug

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The pandemic showed us that the most valuable resources in the healthcare industry are the healthcare workers themselves. They are the ones that worked tirelessly to bring us out of a state of fear and uncertainty when the rest of us felt powerless. From that experience, we learned that we need to work to protect the Healthcare workers as much as they do us every day. There are hundreds of ways that healthcare facilities try to protect their employees. One that is particularly regulated, and for good reason, is the handling of chemotherapy and hazardous drugs (HDs). Since USP <797> was implemented in 2004, pharmacies and facilities across the US have been adhering to the requirements to help safeguard the drugs and patients that receive them.

With the implementation of USP <800>, procedures for healthcare personnel who receive, compound, transport, administer, dispose of, or otherwise come into contact ZLWK KD]DUGRXV GUXJV DV GHŰQHG LQ WKH UHJXODWLRQV DUH FDOOHG RXW VSHFLŰFDOO\ LQ order to protect our healthcare workers.

By walking through the lifecycle of the hazardous drugs within the healthcare continuum, we can better understand the needs of the healthcare worker and the requirements of USP <800> in order to better protect the people who receive, handle, compound, administer, cleanup and dispose of these critical hazardous drugs.

RECEIVING The safe handling of chemotherapy or hazardous drugs during the entire life cycle of the drug within a healthcare setting is more complicated than one might otherwise think. It starts when a facility takes possession of the drug in the receiving department. This may be in a truck loading dock or other secure delivery area of the healthcare facility. While the hazardous drug may come in multiple levels of packaging, there is always a risk of it being dropped, improperly packaged or even broken upon arrival. In addition, due to the nature of the product, the packaging, VSHFLŰFDOO\ WKH FDUGERDUG VKLSSLQJ ER[ SRWHQWLDOO\ could be contaminated at the manufacturing facility.1 Ideally, the receiving department personnel should be properly trained to safely handle hazardous drugs including proper use of required PPE such as eye protection, disposable protective gowns or coveralls, shoe covers and respirator masks and access to spill kits and training on proper spill cleanup.

STORAGE Once the HDs are received, they must be placed in a negative pressure storage area until ready to be prepared. This may be part of a central drug storage room or in the storage room of the cleanroom or compounding facility room to be ready to be taken in for compounding. Before

LIFECYCLE OF A HAZARDOUS DRUG

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Emergency Spill Clean-up the chemotherapy or HDs are brought into WKH FOHDQURRP WKH\ DUH ŰUVW WDNHQ RXW RI WKH corrugated box or secondary packaging to limit the particulate or contamination in the cleanroom.

This step also requires the staff member to be wearing gloves and PPE to limit any potential hazardous drug exposure. Because the drug is now being taken out of the protective shipping packaging, there is more potential breakage to occur with the packaging of the hazardous drug. Due to the hazardous nature of the drug and to USP <800> requirements, any hazardous drug spill must be cleaned up immediately with a hazardous drug spill kit with any involved personnel using the correct PPE and clean-up procedures. In addition, the spill incident must be reported to the correct facility department within 24 hours.

COMPOUNDING From the storage room, the hazardous drug is taken into the pharmacy cleanroom for compounding. During the compounding phase of the hazardous drug lifecycle, proper USP <800> PPE must be used to protect the hospital personnel from low dose and long-term potential exposure to the HD. This includes non-permeable, coated, chemotherapy or hazardous drug rated sterile gowns or coveralls, bouffant caps, shoe covers and double gloving with sterile HD rated gloves along with eye protection with side shields and N95 masks or respirators. As each facility has different requirements for PPE, your facility may have slightly different requirements/procedures and protocols for the compounding pharmacy but the principles of personnel protection are the same. All are a requirement to limit the exposure of the healthcare worker to the hazardous drugs.

In addition, since the drugs will be taken out of the vials or ampuls etc. during compounding, a chemotherapy prep mat can be used along with a Closed System Transfer Device (CSTD) to reduce the potential for a spill and the spread of any spill within the compounding area. In the case of a spill inside the cleanroom/compounding area, a VSLOO NLW ZLWK FOHDQURRP FHUWLŰHG ORZ OLQW ZLSHV and cleaning supplies must be stored and used for proper clean up.

TRANSPORTATION After the compounding of the chemotherapy or HD, it may be transported to various locations

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within and outside the acute care hospital or compounding facility. Inside the hospital, it may be transported to a room or other administration area where nurses or other hospital personnel administer the chemotherapy or other hazardous drug. It may also be transported to a variety of other settings such as an Oncology clinic, long-term care facility or a home health organization that will then administer the drug in an outpatient setting such as a clinic, a patient’s home or other assisted living area. It might even go to a veterinary clinic. In each of these cases, it is important to not only provide a way to deactivate, decontaminate, clean and disinfect any hazardous drug spills, but also train the healthcare workers, who will be handling and transporting the HDs, on the proper procedures to handle, clean up and mitigate exposure to the drug. No matter the location of the patient administration, all personnel transporting the drugs should follow their facilities protocol for the use of proper personal protective apparel. This may include using PPE such as chemotherapy/ HD gowns, shoe covers, eye protection, N95 masks and proper gloves while transporting the chemotherapy or HDs to the administration area. In addition, the HD’s should be in an appropriately labeled chemotherapy/HD bag. If traveling any distance from the compounding facility, the transporter must have access to a spill kit in case of an accidental spill.

ADMINISTRATION The administration area is where the chemotherapy or hazardous drug is administered to the patients. As mentioned, it is not just done in the Acute Care setting anymore. During administration there are as many opportunities for exposure as in the compounding environment. While absorbent chemotherapy mats are not necessarily PPE for healthcare personnel, they can be useful environmental controls in preventing spills that may occur during administration of the drug. ,Q DGGLWLRQ LI DQ\ VSLOO RI D ERGLO\ űXLG UHVXOWV during the administration of the drug, the bodily űXLG PXVW EH WUHDWHG OLNH D FKHPRWKHUDS\ RU hazardous drug spill with the proper cleanup and mitigation procedures outlined in the USP <800> regulations. Proper PPE must be on hand to protect the nurse or healthcare worker who is administering the HD’s including double nitrile

chemotherapy/HD gloves, a coated chemotherapy gown, N95 mask, shoe covers and goggles or other protective eyewear.

DISPOSAL From this point, any remnants of the drug or possible spills must be disposed of in accordance with your facility’s protocols and following all state and local bulk and trace chemotherapy/HD waste disposal guidelines. Generally, the empty (or almost empty) package must be properly handled to reduce the possibility that the drug remnants create an exposure hazard. Sharps containers, hazardous drug disposal containers and hazardous spill waste bags are all examples of appropriate waste containers for hazardous drugs and packaging. All packaging, tubing, PPE, mats, cleanup supplies or other materials that have come in contact with the hazardous drug are included in this disposal requirement.

TRAINING Training in each of these areas on the proper handling technique is not only required by USP <800> regulations, but also is important to properly protect our healthcare workers for years to come. Many of the hazardous drugs have longlasting negative effects over a long time period even if the exposure was minimal each time.2 Protecting and properly training the people who care for us in what may be our most vulnerable time is something in which we all must take part.

A Hospeco Brands Group Company For more information on personal protective equipment for USP <797> and <800>, go to www.pharma-choice.com.

1 Luci A. Power, et al.,” Hazardous Drug Residue on Exterior Vial Surfaces: Evaluation of a Commercial Manufacturing Process,” Hosp Pharm, 2014 Apr; 49(4): 355–362. Published online 2014 Apr 15. DOI: 10.1310/hpj4904-355 2

The Pharmaceutical Journal, PJ, March 2017, Vol 298, No 7899;298(7899):DOI:10.1211/ PJ.2017.20202440

8 Clinical

Pharmacy Practice News • May 2022

Nutrition

HOT TRENDS continued from page 6

findings presented at the ASPEN 2022 Nutrition Science and Practice Conference. Moreover, obesity alone does not predict the likelihood of hyperglycemia during PN administration.

“Hyperglycemia is a well-described metabolic complication of parenteral nutrition in any patient, but obese adult hospitalized patients may be at an elevated risk, given the higher prevalence of insulin resistance and glucose intolerance in these individuals,” said Angela Bingham, PharmD, the vice chair and an associate professor of clinical pharmacy at Philadelphia College of Pharmacy.

To determine the effect of obesity on glycemic control in patients on PN, Dr. Bingham and her colleagues retrospectively studied 646 adult patients hospitalized from 2013 to 2021, who received at least two consecutive days of PN. The group included 205 obese patients with a body mass index (BMI) of at least 30 kg/m2; the median BMI for obese and nonobese patients was 35.55 and 23.85 kg/m2, respectively. The researchers defined a hyperglycemic episode as a blood glucose level above 200 mg/dL. Obese patients were younger than nonobese patients (median age, 58 vs.

62 years), more likely to have critical illness (42% vs. 29.7%) and diabetes (35.6% vs. 18.1%), and had higher serum creatinine levels (median, 0.84 vs. 0.76 mg/dL) (P<0.05 for all). Nearly all patients received PN through a central line. Dextrose infusion rates for obese patients were lower than for nonobese patients, at 1.66 and 1.92 mg/kg per minute, on day 1 of PN (P<0.0001) and 2.62 and 2.79 mg/kg per minute on day 2 (P=0.0003).

Dr. Bingham told meeting attendees that hyperglycemic episodes were infrequent in both groups on days 1 and 2 of PN, but occurred significantly more commonly in obese patients (0.89 vs. 0.52; P<0.05).

However, multivariate analyses that adjusted for potential confounders, including age, critical illness, Charlson Comorbidity Index score, cerebrovascular disease, diabetes mellitus, serum creatinine, creatinine clearance, serum osmolarity, baseline hyperglycemia and macronutrient provision found that obesity was not an independent predictor of hyperglycemic episodes (odds ratio [OR] on day 1, 1.047; 95% CI, 0.639-1.717; P=0.8551 and OR on day 2, 0.964; 95% CI,

0.611-1.521; P=0.8758).

“Our experience shows that conservative dextrose infusion rates may minimize the risk of hyperglycemia in adult hospitalized patients with obesity receiving parenteral nutrition, and that obesity is not an independent predictor of hyperglycemic episodes during the first two days of parenteral nutrition initiation,” Dr. Bingham said.

She added that her institution’s guidelines of “vigilant” blood glucose concentration monitoring every four to six hours in PN recipients may have also contributed to the low rates of hyperglycemia.

Data Mining May Help Boost Use of Alternative Lipid Formulation Nashville—A study presented at the National Home Infusion Association’s (NHIA) 2022 Annual Conference underscored the value of tracking prescribing and dosing of nutrition products for patterns that may affect outcomes.

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Lisa Kinder, RD, CNSC, a nutrition support dietitian for Optum’s home infusion pharmacy, in Huntington Beach, Calif., and her colleagues examined the uptake of a parenteral nutrition (PN) formulation that contains 80% olive oil/20% soybean oil (Clinolipid, Baxter). The lipid formulation, introduced to the market in 2019, is designed specifically to help patients absorb fats while experiencing less inflammation, a side effect that has been tied to infusion products with a higher soybean content, Ms. Kinder noted.

However, putting something on the market does not mean physicians will prescribe it, which spurred Ms. Kinder and her colleagues to investigate the uptake of the olive oil–soybean combination after the 2019 introduction.

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10 Clinical

Pharmacy Practice News • May 2022

COVID-19 Pandemic

Anakinra Spares CRS Rx continued from page 1

and potentially fatal complication after CAR T-cell therapy, noted lead author Ailin Kim, PharmD, a PGY-2 hematology/ oncology pharmacy resident at Stanford Health Care, in California. Tocilizumab (Actemra, Genentech), either with or without corticosteroids, is the primary agent used as first-line treatment for the condition, she noted. Tocilizumab typically is administered every eight hours

for up to four doses. Given the potential role of this IL-6 receptor agonist in treating severe COVID-19 symptoms, many institutions have adopted strategies for conserving tocilizumab over the past two years, she said.

In the study, Dr. Kim and her colleagues conducted a retrospective review of adult patients who received CAR T-cell therapy from Jan. 1, 2019, to Sept. 30, 2021. Two groups were included in the study: patients (n=13) who received anakinra after an initial dose of tocilizumab, and patients who were given two or more doses of tocilizumab (n=21).

The primary outcome, median duration of CRS, was identical in both groups at seven days (P=0.93), Dr. Kim reported, adding, “ICANs [immune effector cell–associated neurotoxicity syndrome]–related outcomes, infection rate, overall survival and overall response to CAR T-cell therapy were similar in both groups.”

Overall survival at 30 days was 92% for anakinra and 100% for tocilizumab (P=0.20), and at 100 days, 92% for anakinra and 95% for tocilizumab (P=0.72), she added.

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There was significantly greater total corticosteroid use in the anakinra cohort, with an average total dose of 268 mg compared with 114 mg for the tocilizumab group (P=0.01). “This was likely due to a higher proportion of grade 3 or higher CRS in that group,” Dr. Kim said (23% for anakinra vs.

5% for tocilizumab). “Although the small sample size may have limited our ability to detect a difference in CRS outcomes and control for variables, such as histology, tumor burden and CAR-T product, this study suggests that anakinra is an acceptable alternative to tocilizumab for the treatment of CRS after initial management with tocilizumab.”

The results lend credence to changes that already had been made to CRS protocols at Stanford as part of its tocilizumab rationing efforts. In April 2020, Dr. Kim noted, the facility added anakinra to its institutional CRS management guidelines to conserve tocilizumab during national shortages. According to the updated guidelines, patients with recurrent/refractory grade 2 CRS after an initial dose of tocilizumab are treated with anakinra and dexamethasone; patients with grade 3 to 4 CRS are treated with all three agents concurrently.

The results also are encouraging

Clinical

Pharmacy Practice News • May 2022

11

COVID-19 Pandemic ‘Although it’s a small sample size, 13 patients is actually pretty good in this situation, and the findings reaffirm what we have seen and add confidence that anakinra can be used as an alternative [CRS treatment].’

—Mary McGann, PharmD is refractory to tocilizumab or steroids, they’re in a tough spot, probably in the ICU, on vasopressors and potentially

intubated. You want any treatment to improve symptoms, and anakinra is not only effective but it doesn’t have a huge

Cytokine release syndrome results from the rapid production of inflammatory cytokines, an important immune signaling molecule. Severe cases can result in multiorgan failure and death.

Source: The Jackson Laboratory.

based on data suggesting tocilizumab still is in short supply. As of March 31, ASHP still had tocilizumab on its drug shortages list.

MUSC’s Approach The pharmacy and therapeutics (P&T) committee at Hollings Cancer Center at the Medical University of South Carolina (MUSC) just added anakinra to its formulary for this indication within the last month, according to Mary McGann, PharmD, a clinical pharmacy specialist in blood and marrow transplantation & cellular therapy.

“With the tocilizumab shortage, we have been trying to use it with our refractory patients and have had some success with three or four patients, but each time we had to jump through hoops to get it approved because it was not on the formulary,” Dr. McGann told Pharmacy Practice News. “There has been a lot of anecdotal experience with anakinra in refractory CRS and ICANS, but not a lot of hard evidence, so this study is good to have. Although it’s a small sample size, 13 patients is actually pretty good in this situation, and the findings reaffirm what we have seen and add confidence that anakinra can be used as an alternative.”

The MUSC formulary allows anakinra to be used in patients with grade 2 or higher CRS who remain refractory after two or more doses of tocilizumab; in patients with grade 3 or higher ICANS if there has been no improvement after 24 hours of steroid use; or in patients with any grade of ICANS if there is an increase in severity after the initial dose of steroids.

“We’ve been reserving our tocilizumab stock and haven’t had as much of an issue with supplies recently, but ASHP is still reporting shortages and we’re still having COVID patients eligible for tocilizumab, so it is good to have alternatives,” Dr. McGann said. “Once a patient

Fast susceptibilities save lives.

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“Accelerate Diagnostics” and diamond shaped logos and marks are registered trademarks of Accelerate Diagnostics, Inc. Any trade, product or service name referenced in this document using the name “Accelerate” is a trademark and/or property of Accelerate Diagnostics, Inc. All other company and product names may be trademarks, registered trademarks, or service marks of the companies with which they are associated

price tag. Having more literature to support its use in these indications helps everyone that is doing CAR T around the country.”

Dr. Kim reported no relevant financial disclosures. Co-authors reported financial disclosures as follows: Theresa Latchford, RN, MS: speakers bureau for Bristol Myers Squibb and advisory board for Bristol Myers Squibb and Kite-Gilead. Matthew Frank, MD, PhD: advisory board for Kite-Gilead; researcher for Adaptive Biotechnologies and Allogene Therapeutics. Dr. McGann reported no relevant financial disclosures.

12 Clinical

Pharmacy Practice News • May 2022

Oncology

Highlights From the 2022 HOPA Annual Conference All articles by Gina Shaw and Dave Doolittle

Remote Clinical Oncology Pharmacists Boost Outcomes

R

emote clinical oncology pharmacists can provide financial and patient care support to communitybased oncology practices that have been affected by staffing shortages or where telepharmacy might be necessary, new research shows.

Melissa Carroll, PharmD, a senior clinical pharmacist at McKesson and the U.S. Oncology Network, outlined a review program that employed three remote clinical pharmacist services at four community oncology practices in the United States.

The U.S. Oncology Network designed the program, called ClinReview, to determine the value of remote oncology clinical pharmacists to community practices, which often have only one clinical pharmacist on staff or none at all, Dr. Carroll said.

“The majority of [community practice] pharmacists … tend to wear many hats: They troubleshoot patient-specific needs of a practice, they manage inventory and drug-shortage control, and they often support the medically integrated dispensaries,” she said. “These are many of the reasons that prompted the creation of the ClinReview program.”

Throughout the 10-month study period, ClinReview’s remote oncologytrained clinical pharmacists provided electronic medical record cycle 1 day 1 (C1D1) regimen reviews at the level of a 0.5 full-time equivalent pharmacist with the goal of reviewing clinical components and reducing waste while tracking interventions and workload, Dr. Carroll said.

At the start of the program, ClinReview pharmacists gathered basic

information from each practice, including a review of day-to-day operations, contact lists for providers and key clinic staff, and existing medication and pharmacy policies, she said. They also participated in practice meetings and visited each site, if possible.

“Integration into the practice was key, knowing that there are often roadblocks and delays to treatment,” Dr. Carroll said. “Our goal was to implement ClinReview within 24 to 48 hours after an order was placed to reduce errors, prevent delays and help the process flow smoothly, minimizing the potential for rework.”

Throughout the study, ClinReview’s remote pharmacists reviewed C1D1 regimens to evaluate clinical efficacy, while also checking guidelines, verifying doses, reviewing relevant pathology and biomarker testing, and identifying therapeutic alternatives based on payor drug coverage, Dr. Carroll said.

They also were able to revise policies— with physician consultation—if needed, such as auto-substitutions of preferred biosimilars and dose-rounding of chemotherapy and monoclonal antibody medications.

At the end of the study, ClinReview pharmacists had documented more than 4,300 reviews among the four practices, over half of which required modifications by the pharmacist, she said. Of those modifications, 36% were for dose rounding, 35% were therapeutic interventions and 27% for product selections.

ClinReview also had a significant financial effect on the four clinics, improving their total margins by more than $1.1 million, while costing approximately $218,000 total—a return on investment of approximately 480%, Dr. Carroll said. “The ClinReview pharmacists, through intervention, more than paid for themselves,” she said.

“Based on the data we collected while implementing the ClinReview program, we [found] that clinical oncology

pharmacists are a cost-effective and invaluable member of the care team, demonstrating financial impacts on small-scale budgets in community oncology,” Dr. Carroll said.

“Future directions for remote clinical oncology pharmacists include expanding clinical services provided, such as day of treatment reviews—including dosage adjustments, identifying opportunities for patient enrollment in research trials and possibly expansion of reviewing regimens in the oral chemotherapy space.”

Extending Letermovir May Cut CMV Reactivation in HSCT

E

xtended-duration prophylactic therapy with letermovir (Prevymis, Merck) may reduce cytomegalovirus (CMV) reactivation in allogeneic hematopoietic stem cell transplant (HSCT) patients, according to researchers at Houston Methodist Hospital.

Despite advances in diagnosis and treatment, CMV reactivation remains a common complication, and the most common clinically significant infection, among HSCT recipients (J Med Virol 2021;93[11]:6292-6300).

Letermovir was approved for CMV prophylaxis in HSCT patients in November 2017, following the results of a phase 3 trial demonstrating that it resulted in a significantly lower risk for clinically significant CMV infection than placebo, without significant toxicities (N Engl J Med 2017;377[25]:2433-2444).

“That trial also found a notable incidence of CMV reactivation in high-risk patients post-prophylaxis,” said Breanna Hinman, PharmD, a PGY-2 oncology pharmacy resident at Houston Methodist Hospital and lead author of the new study. “We see that there is an unmet need for patients who have late CMV reactivation,” she said. “The only published data available is a retrospective study looking at CMV-seropositive patients who had graft-versus-host disease [GVHD]; they gave extended-duration letermovir and found that there was a reduced incidence of clinically significant CMV infections.

So, currently, we don’t know what the optimal duration of letermovir prophylaxis should be.”

Dr. Hinman and her colleagues conducted a retrospective chart review of patients who received letermovir between November 2017 and July 2021 to compare the rates of CMV

reactivation in HSCT recipients who stopped letermovir prophylaxis at day 100 post-transplant with those who continued letermovir prophylaxis. Of the 82 patients included in their analysis, 24 received standard-duration letermovir and 58 received extended-duration prophylaxis. The primary end point was rate of CMV reactivation between the two groups, with secondary end points including 200-day mortality and clinically significant infections.

The investigators found that CMV reactivation after day 100 occurred in 46% of the standard-duration patients, compared with 36% of those in the extended-duration group. “It is worth noting that 52% of the patients in the extended-duration group who had CMV reactivation reactivated after discontinuing letermovir,” she said. “The most common cause for mortality in both

groups was sepsis or relapsed disease.

No patients in the extended-duration group experienced CMV tissue disease, and one patient in the standard-duration group experienced CMV pneumonia, which was fatal.”

Dr. Hinman added that although the study wasn’t designed to look at safety, letermovir “appeared to be very well tolerated, with few reports of significant toxicities.” The most common reason for discontinuation of the drug was cost, she noted. Mortality at 200 days was similar between the two groups.

“Adequate recovery of these patients’ adaptive immune systems can take months to years after transplant, leaving them vulnerable to a lot of viral infections,” Dr. Hinman said. “Previous studies have shown that even after prophylaxis, they are still experiencing a lot of CMV reactivation, which our study found as well. For patients who may have multiple risk factors for reactivation, such as unrelated/mismatched donors, myeloablative conditioning regimens, alemtuzumab therapy and chronic GVHD, our study suggests that they may benefit from continuing letermovir prophylaxis. We hope to confirm these findings in a prospective study.”

Clinical

Pharmacy Practice News • May 2022

13

Oncology Double ABx Coverage Does Not Improve Febrile Neutropenia

E

arly empirical double coverage with an aminoglycoside added to cefepime for the initial management of febrile neutropenia offers no significant difference in outcomes compared with monotherapy, new data suggest.

Guidelines for high-risk febrile neutropenia management, including those from the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN), recommend monotherapy with an antipseudomonal beta-lactam in patients with febrile neutropenia—but with some caveats, said Amber Clemmons, PharmD, BCOP, a professor of pharmacy at the University of Georgia (UGA) College of Pharmacy, in Athens.

“IDSA says that combination therapy can be considered for patients with suspected or proven resistance or management complications, such as hypotension or pneumonia, while NCCN also says that it can be considered where antimicrobial resistance is suspected,” she noted.

“The European guidelines offer more of an escalation/de-escalation approach, and also state that if patients are seriously ill or resistance is likely per local susceptibilities or colonization, you can consider dual therapy with an aminoglycoside. But none of the guidelines delineate a specific threshold for issues with susceptibility.”

Prior literature does not settle the question, Dr. Clemmons noted. She cited a 2012 study from Critical Care Medicine that found combination antimicrobial therapy with an aminoglycoside was an independent predictor of lower mortality, but that study was conducted specifically in medical ICU patients with sepsis/ shock (Crit Care Med 2012;40[1]:43-49).

“You can’t extrapolate [those findings] to all comers,” she said.

On the other hand, a 2014 Cochrane review of randomized controlled trials found no difference in mortality, but the infection-related mortality data favored monotherapy. The authors concluded that the addition of an aminoglycoside to beta-lactams for sepsis should be discouraged (Cochrane Database Syst Rev 2014;2014[1]:CD003344).

UGA’s 2018 antibiogram identified resistance to cefepime, with susceptibility only at about 85%, Dr. Clemmons said. After discussions between the hematology-oncology and infectious diseases teams, the institution decided to institute a protocol of dual therapy with cefepime plus tobramycin for the first 48 hours of therapy in adults with febrile neutropenia.

The study was a retrospective chart review with a primary outcome of adherence rate to the dual therapy,

and multiple secondary outcomes including: • incidence of gram-negative bacilli growth; • incidence of gram-negative bacilli resistant to cefepime; • percentage of patients with escalation/change of antibiotic therapy; • incidence of acute kidney injury; • hospital and ICU length of stay; • percentage of patients transferred to ICU; and • in-hospital mortality.

“We knew that we weren’t always following the protocol, so we wanted to compare patients who were on versus off protocol for differences in efficacy and safety outcomes,” Dr. Clemmons said.

In fact, adherence to the protocol was low; among 350 adults with febrile neutropenia treated between January 2019 and July 2020, 185 (53%) received monotherapy and 165 (47%) received dual therapy. (A small subset of that group, 19 patients, received delayed dual therapy, beginning after 48 hours from diagnosis with a median time to start of 77.4 hours.)

All fever demographic data significantly favored the monotherapy group: • Median duration of fever: 9.75 hours in monotherapy versus 20 hours in the early dual-therapy group.

• Recurrent fever: 34.6% for monotherapy versus 65.8% for dual therapy.

• Patients febrile within 72 hours of initial antibiotic: 20.5% for monotherapy, 47.9% for dual therapy.

• Febrile at least once every 24 hours for at least 72 hours after starting therapy: 20.5% for monotherapy versus 47.9% for dual therapy.

• Subsequent fevers after defervescence: 18.4% for monotherapy versus 34.2% for dual therapy.

Gram-Negative Bacteria Overall, the incidence of gram-negative bacteria was 10.6%, and among those patients, resistance to cefepime was 13%.

“There was no significant difference in many end points, including the incidence of gram-negative bacteria with resistance, gram-negative bacilli on any culture and the incidence of gram-negative bacteria on any culture with resistance to cefepime, as well as escalation or change in antibiotics, ICU admission and acute kidney injury,” Dr. Clemmons said.

Hospital length of stay also was shorter for monotherapy versus either dual-treatment cohort (six, 15 and 22 days, respectively; P<0.001).

“We saw no significant difference in resistance rates or mortality overall,” she added. “A higher in-hospital mortality

rate observed in the delayed dual-therapy group—2.7% versus 15.8%—was likely due to differences in that population, which had more malignant hematology and stem cell transplant patients than solid tumor and benign hematology. That could have produced differences in mortality unrelated to febrile neutropenia.”

As a result of the study, Dr. Clemmons said, the pharmacy and therapeutics committee already has revised the institutional protocol for febrile neutropenia back to empirical cefepime monotherapy. “While a history of resistance or other patient-specific factors could trigger an individual evaluation for the addition of tobramycin when necessary, we no longer treat all comers with double coverage.”

Oxaliplatin Sequencing May Lessen AEs In FOLFIRINOX Regimen

P

atients who were given oxaliplatin as the first agent in the FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) chemotherapy regimen for pancreatic or colorectal cancer experienced an eightfold higher rate of adverse events than those receiving irinotecan first, according to new research by investigators at the University of Rochester Medical Center (URMC), in New York.

There is conflicting evidence in the literature regarding the optimal sequencing order for irinotecan and oxaliplatin, said lead author Kara Kubli, PharmD, BCOP, a clinical specialist in the bone marrow transplant program at URMC. “Some studies suggest that there is no difference based on safety or efficacy [Am J Clin Oncol 2004;27(3):294-298; J Hematol Oncol Pharm 2011;1(1):17-25], while other evidence suggests that irinotecan should be administered first to limit cholinergic side effects [J Natl Cancer Inst 1998;90(2):160; BioDrugs 2018;32(6):585-606]. There’s also the idea, based on in vitro studies, that oxaliplatin should be administered first to reach maximal cytotoxic efficacy.”

(An audience survey during the session found that the majority of participants either reported that oxaliplatin was administered first at their institution, or that they were unsure of the sequencing order.)

After a change to URMC’s institutional protocol for FOLFIRINOX, going from no preferred sequencing to oxaliplatin administered first, providers had noticed an increase in infusion reactions, including dysarthria, dysphagia, numbness and gastrointestinal discomfort. “We wondered if the sequencing could be impacting these reactions,” Dr. Kubli said.

The pharmacy conducted a retrospective study, reviewing the records for all adult patients with an active treatment plan for FOLFIRINOX or FOLFOXIRI (a modified version of the regimen; folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) who received both oxaliplatin and irinotecan between July 1, 2017, and Aug. 30, 2020.

Among the 84 patients included in the study, the overall infusion reaction rate was 14.4%. But among those who received oxaliplatin first (n=116), the infusion reaction rate was 18.4%, while those who received oxaliplatin second (n=54) had an infusion reaction rate of 2.8% (odds ratio [OR], 7.94).

Even when adjusted for age, sex and atropine in the bag, the OR for infusion reactions among those who received oxaliplatin first was 7.6.

The researchers then grouped the infusion reactions into two categories: dysarthria, dysphagia and numbness versus gastrointestinal. For the first group of reactions, the overall infusion reaction rate was 3.3%, but it was 3.7% in the oxaliplatin-first group and 0.3% in the oxaliplatin-second group (OR, 12.2). When adjusted for age, sex and atropine in bag, the OR was still 11.5.

But the picture was different with gastrointestinal reactions: an overall reaction rate of 4.6%, with an OR for oxaliplatin first of only 2.02.

“Sequencing had a significant effect on the rates of reaction for dysarthria, dysphagia and numbness, but not for gastrointestinal reactions,” Dr. Kubli said.

“We have now changed our administration of these agents so that we are administering irinotecan first, and in future research, we plan to evaluate the impact of sequencing on efficacy.”

Dr. Kim reported no relevant financial disclosures. Two of her co-authors reported financial relationships with Adaptive Biotechnologies, Allogene Therapeutics, Bristol Myers Squibb and Kite-Gilead. The sources in the remaining briefs reported no relevant financial disclosures.

14 Clinical

Pharmacy Practice News • May 2022

Oncology

New Renal Dosing Guide continued from page 1

Pharmacy Practitioners, the Cancer and the Kidney International Network, and the National Cancer Institute’s Organ Dysfunction Working Group.

The final guideline is planned for publication in June.

Ben Sprangers, MD, a staff physician in the Department of Nephrology at the University Hospitals Leuven, in Belgium, underscored the risks posed by renal dysfunction in cancer patients. “Altered kidney function alters the pharmacodynamics of anticancer agents,” Dr. Sprangers said. “Renal insufficiency can result in overdoses of chemotherapy drugs and dose-dependent toxicities, associated with increased morbidity and mortality.

On the other hand, if renal insufficiency is diagnosed and dose adjustments are applied, because of the lack of good guidelines, sometimes dose adjustments can be too severe and suboptimal cancer treatment can occur, also associated with increased morbidity and mortality.”

Although a few other resources exist to aid clinicians with dose adjustments to cancer therapies for patients with renal disease, including those from Australia’s eviQ, Cancer Care Ontario, National Comprehensive Cancer Network in the United States, and the University College London Hospitals, the new guideline is aimed at providing more comprehensive and consistent guidance.

“There is a large variability in recommended dose adjustments in international guidelines and published studies,” noted Geeta Sandhu, BPh, PhD, a cancer pharmacist at the Cancer Institute NSW in New South Wales, Australia. “Cyclophosphamide, for example, has a wide variation of recommendations in how to approach dosing in these patients depending on which source you use. What’s a junior faculty member to do with all this information? This is the first attempt at a robust international guideline,

‘This is the first attempt at a robust international guideline [for renal drug dosing in cancer patients], developed with a standardized goal-setting process.’

—Geeta Sandhu, BPh, PhD developed with a standardized goalsetting process.”

Just Getting Started The guideline includes three primary recommendations (sidebar) and includes 59 anticancer drugs, but that list is expected to grow. It incorporates a stoplight system for dosing adjustment recommendations for each drug. “Green means that you are good to go with standardized dosing; yellow means to think about dose adjustments; and red means don’t use it, find an alternative regimen,” Dr. Sandhu said.

As an example, high-dose cytarabine has a red indicator for patients with an eGFR of 29 or lower, and a yellow

indicator for patients with an eGFR between 30 and 59. For patients in that zone, the guideline recommends choosing an alternative regimen or reducing dosage by 50%, while cautioning to avoid further dose reduction if an age-adjusted dose is used.

Going forward, Dr. Sprangers called for more studies of anticancer drug dosing to include people with kidney disease. “We do need specific trials to obtain more data to guide anticancer drug dosing, because the data in these populations are limited,” he said. “It’s problematic that, at this time, systematic exclusion of patients with advanced cancer and reduced kidney function from clinical trials prevents us from getting the information we need to do optimal chemotherapeutic dose adjustment in our patients.”

Another Oncology Pharmacist’s Perspective

3 Core Recommendations

T

he new International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction guideline includes three primary recommendations:

Calculate eGFR using the Chronic Kidney Disease – Epidemiology Collaboration equation to guide assessment of kidney function. “This is the most reliable way to estimate kidney function in the average stable patient. It’s more precise than other estimates, has been tested in diverse populations and is easily available at the point of care,” said Geeta Sandhu, BPh, PhD, a cancer pharmacist at the Cancer Institute NSW in New South Wales, Australia. She stressed, however, that “measured GFR remains the gold standard and should still be used in certain situations when clinically necessary—for example, in patients without stable kidney function at initiation of treatment, in extremes of body weight or exceptional dietary intake, and with specific anticancer drugs where a measured GFR is recommended at the first dose, such as carboplatin, cisplatin and methotrexate at greater than 500 mg/m2.”

For anticancer drugs where the dose depends on kidney function, eGFR should guide dosing in the absence of measured kidney function. Again, in some circumstances, measured GFR might be necessary, Dr. Sandhu noted.

KDIGO’s CKD categories should be used to guide stepwise dose reductions of anticancer drugs in kidney dysfunction. “Different resources measure kidney dysfunction differently, and it’s vital to standardize,” Dr. Sandhu said.

“KDIGO also matches with what the FDA is moving toward, and we hope this aligns with future clinical trials as well.”

—G.S.

Jim Siderov, a senior pharmacist in Cancer Services at the Olivia NewtonJohn Cancer & Wellness Centre at Austin Health, in Heidelberg, Australia, said the new guidelines were sorely needed.

Echoing Dr. Sandhu’s point, “there are inconsistencies in assessing and defining kidney function, large variations in international guidelines and published studies, and limited evidence for older medications,” he said in a video posted to the eVIQ website (bit.ly/3ODbB5N).

“We need new guidelines based on sound acceptable methodology.”

Traditionally, Mr. Siderov noted, “we have used the Cockcroft-Gault equation to assist in the determination of dosing strategies. This has helped us in the past, but is not used universally.”

He praised the new eVIQ anticancer dosing guidelines for taking the alternative approach of relying on “the internationally recognized” KDIGO criteria, along with other evidence-based renal dosing strategies. “Having a single reference of easily retrievable, consensusbased standardized practical information resourced from published references and the experience of practitioners in the field is essential,” he said.

“This valuable resource will assist all practitioners—not only pharmacists— to make appropriate decisions to dose patients with renal dysfunction.”

The sources reported no relevant financial disclosures.

Q&A

Pharmacy Practice News • May 2022

15

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16 Clinical

Pharmacy Practice News • May 2022

Critical Care

Guidance for ICU Kids continued from page 1

“Practice guidelines serve as a rigorous foundation for care improvement efforts and evidence gap recognition,” John W. Devlin, PharmD, a professor of pharmacy at Northeastern University, in Boston, told Pharmacy Practice News.

“Pediatric ICU clinicians from around the world will now be able to benchmark their current recognition, prevention and treatment practices regarding

pain, agitation and delirium against these new recommendations, and develop, implement and evaluate new daily care standards,” added Dr. Devlin, the chair of SCCM’s 2018 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU (Crit Care Med 2018;46[9]:e825-e873).

Produced by a multidisciplinary

task force representing more than 24 U.S. health systems, children’s hospitals and schools of medicine, nursing and pharmacy, the PANDEM document focuses on “seven domains” of critical care: pain, sedation/agitation, iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment and early mobility. It offers 44 recommendations, 14 of them strongly grounded in evidence and 30 listed as conditional, as well as five goodpractice statements (Pediatr Crit Care Med 2022;23[2]:e74-e110).

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The guidelines detail three areas requiring special attention: • the need to routinely monitor patients for pain, agitation, withdrawal and delirium using validated tools, including at least twice-daily assessments, from PICU admission to discharge; • greater use of sedation and analgesia protocols; and • recognition of the importance of nonpharmacologic interventions for enhancing the comfort of young patients and providing comprehensive care.

SCCM’s quest began in 2009 with its formation of a multidisciplinary group tasked with developing comprehensive, pediatric-specific critical care guidelines. The group’s early work was hampered, however, by a dearth of quality research on which to base its recommendations.

Over the past decade, this began to change. “The pediatric critical care literature devoted to pain, sedation and delirium exponentially expanded over the past few years,” Dr. Devlin said.

The emergence of fresh research reenergized SCCM’s pursuit, and in 2018, a newly formed task force mounted an extensive search for actionable studies from January 2012 to January 2020.

The results of that effort underpin the

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Clinical

Pharmacy Practice News • May 2022

‘[PICU patients] have less drug withdrawal when they are treated using a standardized protocol versus provider preference.’

—Peter N. Johnson, PharmD guideline’s recommendations, suggestions and good-practice statements.

Much of the work in PICU care is carried out by critical care physicians and nurses at the bedside. But pharmacists also have a key role to play, said Peter N. Johnson, PharmD, BCPPS, a professor at the University of Oklahoma, in Oklahoma City, and a member of the pediatric guidelines task force.

“Pharmacists can help to establish clinical practice protocols and standardize care based on the guidelines,” Dr. Johnson said, noting that the literature has shown that PICU patients “have less drug withdrawal when they are treated using a standardized protocol versus provider preference.”

Where there are gaps in the literature, “pharmacists can work with the team to identify how to approach those patients that the guidelines don’t specifically focus on,” added Dr. Johnson, whose practice setting is in the cardiac ICU at Oklahoma Children’s Hospital at OU Health, in Oklahoma City.

Can the steroid dose be reduced? Can nonopioid analgesics be introduced?

If the patient still requires continuous sedation, can dexmedetomidine be used rather than midazolam?”

One important difference between critically ill adults and children is the

risk for opioid and sedative withdrawal, Dr. Devlin said. “The prevalence seems to be much higher in kids than in adults.”

He noted that pediatric guidelines “recommend sedation and opioids be regularly titrated to keep patients at a light level of sedation and that daily interruption

Critical Care be avoided.” In adults either approach is recommended, he noted.

“Another important series of recommendations concern the importance of early initiation of nonopioid analgesics like ketamine, acetaminophen and nonsteroidal, using a multimodal strategy, to reduce PICU opioid use,” Dr. Devlin said.

“As in adults, stopping the use of opioids before hospital discharge, when possible, is an important care goal.”

The sources reported no relevant financial disclosures.

Peter N. Johnson, PharmD

Delirium Remains a Challenge One particular challenge for PICU clinicians relates to “the surprisingly high prevalence of delirium in critically ill children,” Dr. Devlin said. In the absence of screening tools and a history of deep sedation practices, “delirium has often gone under-recognized in this setting,” he said. However, “there are two easy-to-use, validated delirium assessment tools” for screening children at the PICU bedside (see box). The use of both is supported by strong, highlevel evidence, according to the guidelines, Dr. Devlin noted.

Dr. Devlin emphasized that delirium screening should be more than conducting and documenting the assessment.

“In a child with a positive delirium assessment,” he said, “bedside clinicians should evaluate patients for presence of fear, delusions and anxiety—symptoms not well captured on assessment tools— and bring a positive assessment back to the interprofessional PICU team for discussion regarding potential causes and the implementation of usually nonpharmacologic treatment strategies.”

For pharmacists, Dr. Devlin said, eliminating or reducing the use of medications known to cause delirium is paramount. “A lot of medications can potentiate delirium in the PICU setting, including high-dose steroids, opioids and benzodiazepines. If the patient has delirium today and not yesterday, what’s changed in their medications?

17

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

Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL.

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 infants and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion.

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

18 Policy

Pharmacy Practice News • May 2022

Advocacy

Some Key Barriers to Making Provider Status Work

By Karen Blum

Provider status legislation being considered by Congress would permit pharmacists to practice at the top of their license and improve patient outcomes, a panel said at the ASHP 2021 Midyear Clinical Meeting and Exhibition, held virtually.

However, some barriers to more widespread adoption still exist, as well as a need for automated tools to help with manual pharmacy tasks, the panelists said.

The Pharmacy and Medically Underserved Areas Enhancement Act (H.R. 2759/S. 1362)—bipartisan bills to amend Section 1861(s)(2) of the Social Security

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

FreseniusKabiNutrition.com.

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 infants 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 SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated.

Limitations of Use The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions.

DOSAGE AND ADMINISTRATION The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk Package for admixing only and is not for direct infusion. Prior to administration, transfer to a separate PN container. Protect the admixed PN solution from light.

CONTRAINDICATIONS Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL. WARNINGS AND PRECAUTIONS • Death in Preterm Infants: (see BLACK BOX WARNING) • Hypersensitivity Reactions: SMOFlipid contains soybean oil, fish oil, and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut oil. Signs or symptoms of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and undertake appropriate treatment and supportive measures.

• Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can support microbial growth and is an independent risk factor for the development of catheterrelated bloodstream infections. The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions or drugs.

• Fat Overload Syndrome: This is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, fatty liver infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma).

• Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop.

Fresenius Kabi USA, LLC Three Corporate Drive, Lake Zurich, IL 60047 Phone: 1.888.386.1300 www.fresenius-kabi.com/us

Act to include pharmacists on the list of recognized healthcare providers in medically underserved areas—would grant pharmacists provider status under Medicare Part B, to help address a shortage of primary care physicians. They would be reimbursed for services, such as medication therapy management, immunizations, point-of-care testing, cholesterol screening and chronic disease management.

• Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum. During prolonged PN administration in patients with renal impairment, the aluminum levels in the patient may reach toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, including preterm infants, who receive parenteral intakes of aluminum at greater than 4 to 5 mcg/kg/ day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products.

• Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction.

• Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome.

• Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended.

• Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream.

ADVERSE REACTIONS Most common adverse drug reactions >1% of patients who received SMOFlipid from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device-related infection.

Less common adverse reactions in ) 1% of patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis.

The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Infections and Infestations: infection.

Respiratory, Thoracic and Mediastinal Disorders: dyspnea.

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

DRUG INTERACTIONS Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters.

USE IN SPECIFIC POPULATIONS • Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women.

• Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients.

• Hepatic Impairment: Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure.

OVERDOSAGE In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid infusion until triglyceride levels have normalized. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum.

Fresenius Kabi USA Nutrition ©2021 Fresenius Kabi USA, LLC. | All Rights Reserved. | 2325-SMF-05-12/21

The bill, sponsored by Sen. Charles “Chuck” Grassley (R.-Iowa), is timely. Along with widespread clinician burnout, the United States may see a shortage of 139,000 physicians by 2033, said James Stevenson, PharmD, FASHP, FFIP, the chief clinical officer at Omnicell, citing statistics from the Association of American Medical Colleges. “To put that number in perspective, it’s one-seventh of today’s total physician population,” he said during the panel discussion, which was sponsored by Omnicell.

Exclusive Video: For more on the provider status legislation, go to bit.ly/3DwCYYm. For an exclusive Pharmacy Practice News video interview on provider status with Tom Kraus, MHS, JD, the vice president of government relations at ASHP, see bit.ly/3iO9ux4.

Primary Care ‘Deserts’ Particularly acute is the shortage of primary care physicians (PCPs), now estimated at 15,000 but predicted to increase to as much as 55,000 by 2033.

There are some primary care “deserts” with less than one primary care provider for every 3,500 people, Dr. Stevenson said. It’s estimated that 39%—or 1,200 of the 3,100 counties in this country—will have a primary care physician shortage, affecting 13% of the U.S. population, according to the Health Resources and Services Administration.

Granting pharmacists provider status would help narrow that PCP gap, and also offer significant financial incentives for pharmacists in health systems to devote more time to higher value, clinical and patient-focused tasks in outpatient clinical settings, said Jeff Little, PharmD, MPH, BCPS, the director of pharmacy at Saint Luke’s Hospital, in Kansas City, Mo. Furthermore, it would permit pharmacists to optimize their scope of practice, improve job satisfaction, be fairly compensated and further enhance patient outcomes, Dr. Little said.

Pharmacist productivity at his hospital currently is measured by hours worked divided by patient volumes, he said. “I don’t think that’s the best measure … because that doesn’t take into account what kind of patient care we’re doing.” Productivity based on billing for services provided would be more accurate and better for patients, he said.

Dr. Little cited another disconnect: tying pharmacy practice to drug products. For example, some hospitals initially justified having pharmacists on hospital floors for their ability to save money through formulary compliance or preventing adverse drug reactions, because they can’t be reimbursed for the clinical services they provide. Provider status would allow a shift away from this obstacle, he said.

Policy 19

Pharmacy Practice News • May 2022

Advocacy Under a pending provider status bill, pharmacists would be reimbursed for medication therapy management, immunizations, point-of-care testing, cholesterol screening, chronic disease management and other key clinical services.

Ways to Support Legislation

A paper he coauthored (Am J Health Syst Pharm 2021;78[7]:636-645) details how automation can help pharmacists shift into direct patient care roles.

Pharmacists can complete a free selfassessment and download a white paper at www.autonomouspharmacy.com.

Pharmacists can take several actions to help support efforts to pass the provider status bill, Dr. Little said, including writing letters and emails to their congressional representatives; scheduling meetings with their offices in their home state or in Washington, D.C.; and inviting them to visit their hospital to observe what pharmacists do. (Be sure to involve the hospital’s government relations staff in such efforts, he stressed.) Additionally, Dr. Little noted, insurance often is regulated at

the state level; therefore, it’s important to work toward getting states to pass provider status provisions. In some states, Medicaid and even state private insurers allow provider status to compensate pharmacists for some services.

Make sure to educate other pharmacists, healthcare providers and patients about the importance of provider status, he advised.

The sources reported no relevant financial disclosures other than their stated employment.

“By removing the financial barriers associated with the delivery of [broader] clinical pharmacy services, we can empower the pharmacist to become affiliated with patient outcomes, rather than simply the drug itself,” Dr. Little noted.

Roadblocks Remain Several challenges to implementing provider status remain, said Christopher Fortier, PharmD, the chief pharmacy officer for Massachusetts General Hospital, in Boston. Among them are labor and staffing constraints. Thinking about large clinics with many providers, “this is just not going to get done the right way with one or two pharmacists,” he said. “We need a lot more ambulatory care pharmacists to really affect patient care to the degree that we all agree is needed.”

Additionally, Dr. Fortier said, drug preparation and distribution systems continue to be too labor-intensive. Better automation and technology solutions are needed to relieve some of that burden so more pharmacists can assume direct patient care roles, he noted.

Data management is another potential roadblock. Clinical data needed to assess patients and make decisions often are stored in disparate databases, Dr. Fortier said. Additionally, there are limited data analytics available to riskstratify the sickest patients most in need of pharmacy services.

Artificial intelligence and automation may offer a solution, he noted, because the technology has the potential to help expand clinical services. Such programs could be used to help prevent highrisk patients from developing medication complications, optimize pharmacy workflows and digitally track pharmacists’ clinical interventions and patient outcomes. However, some of these solutions do not yet exist.

“Ultimately, this is a call to action, both for pharmacy and for automation technology vendors within the healthcare space,” said Dr. Fortier, who is a member of the Autonomous Pharmacy Advisory Board, a coalition of pharmacy leaders working to replace manual activities with automated processes.

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20 Policy

Pharmacy Practice News • May 2022

Compounding

Hazardous Drug Containment: How Much Is Enough?

By Marcus A. Banks

Nashville, Tenn.—It is impossible to eliminate all hazardous drug (HD) residue contamination in sterile compounding suites. In fact, exposure to very small amounts of HDs may not always present a health risk. That’s why adhering to the principle of “as low as reasonably achievable” (ALARA) with respect to hazardous residue removal, rather than complete elimination, is a

more attainable standard, a safe handling expert noted during a workshop at the National Home Infusion Association 2022 Annual Conference.

The outside of chemotherapy vials sometimes contains trace residues of HDs, with the residue adhering to technicians’ gloves as they transport the drugs within a facility. When this happens, the residues can wind up on surfaces without anyone knowing they are

there. Whereas obvious dangers such as spills have clear mitigation plans, the more subtle risks of trace contamination are harder to manage.

“People may think, ‘I didn’t drop a vial today. I didn’t squirt a syringe into the hood.’ So, things seem fine,” said workshop presenter Mark Wiencek, MS, PhD, the lead microbiologist for Contec Healthcare, in Spartanburg, S.C. Wipe sampling—a method that Dr. Wiencek

noted is recommended but not required in USP General Chapter <800>—can detect trace amounts of an HD. If a wipe sample detects the presence of an HD, the question immediately becomes, “How do I get rid of these residues?”

Dr. Wiencek said.

It turns out that the answer is complex.

The Difference Between Decontamination And Deactivation

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The most reliable response to HD residue is decontamination, Dr. Wiencek explained.

This involves removing the drug onto a wipe, pad or towel, and disposing of it in an HD/ hazardous waste/chemotherapy bag.

While this solves the immediate problem, decontamination doesn’t guarantee that every particle of the dangerous drug is removed.

That’s where deactivation comes in— to chemically neutralize a harmful compound or product. But Dr. Wiencek noted that with more than 200 drugs on the HD list maintained by the National Institute for Occupational Safety and Health (NIOSH), each with its own complex chemical structures, developing a chemical that can deactivate every one of these drugs is a tall order.

“Can’t we have a chemical that breaks down or degrades these hazardous drugs? Well, it turns out that this is more complicated than killing a germ. You’re basically doing a chemistry experiment,” Dr. Wiencek said, and often with unsatisfying results because the complex chemistries of HDs repel full neutralization, at least within a reasonable time frame. “Whatever’s going to happen has to happen quickly,” Dr. Wiencek said. Even if a chemical could perfectly neutralize a hazardous compound, he added, one still has to remove the neutralized residues.

Given the number of drugs on the NIOSH list, many different chemicals would need to be on hand to neutralize many different drugs—an unfeasible situation, in Dr. Wiencek’s view.

“That’s why USP <800> doesn’t depend on deactivation as the sole containment strategy,” Dr. Wiencek said.

Rather, the thrust of USP <800> is to keep the drugs contained (or “from escaping”) in the first place. This requires proper use of engineering and administrative controls, extensive training and the appropriate use of personal protective equipment.

Wipe sample tests are so sensitive that they can detect extremely trace

Policy 21

Pharmacy Practice News • May 2022

Compounding HD Containment in Action One Pennsylvania hospital’s goal is to minimize personnel exposure and workplace contamination to HDs through training, team member engagement and surface testing.

“We try to impart to our associates that one person’s deviation from procedures may ripple out in ways they did not anticipate, whether it is microbial or hazardous drug contamination,” said workshop presenter Christine Roussel, PharmD, BCOP, BCSCP, the senior executive director

amounts of an HD. “I’m talking fractions of a nanogram on a surface,” Dr. Wiencek said. “Potentially relatively small amounts, especially with repeated exposure, could make someone sick,” he added. But on the flip side, a one-time-only exposure to a trace level of an HD may have no health consequences. “That’s because we don’t know the threshold beyond which exposure to hazardous drugs is dangerous,” Dr. Wiencek said, and in any case, such thresholds vary by drug. Urine samples may be able to detect whether someone was exposed to some drugs, he noted, but this information doesn’t reveal whether a healthcare worker will face health consequences.

‘Going Rogue’ by Advocating ALARA In Dr. Wiencek’s view, USP <800>’s approach to risk mitigation does not consider these nuances. “USP <800> doesn’t mention ALARA/as low as reasonably achievable, so I’m going rogue by promoting it,” Dr. Wiencek said.

“Per <800>, any amount of contamination recovered from a wipe sample, no matter how small, would mean that a compounding facility has failed,” he said, adding that this could lead to costly and time-consuming cleaning procedures that delay the work of compounding drugs, or potentially some facilities not doing any wipe sampling. “There are a lot of musts in <800>, and wipe sampling is a should.”

Dr. Wiencek said he hopes that future revisions of USP <800> endorse the ALARA principle.

Asked to comment, a USP spokesperson confirmed that “the concept of ALARA is not described in USP <800>,” and the chapter “is not under revision.

However, USP welcomes suggestions for revisions via email to CompoundingSL@usp.org.”

of pharmacy, laboratory and medical research at Doylestown Hospital, near Philadelphia.

For the past nine years, nursing and pharmacy associates have received targeted training during orientation and annually on proper handling of HDs. The education includes research on contamination and exposure, as well as detailed information on classes of drug toxicity and proper handling techniques. “Despite our robust handling program with all its training and signage, nothing is perfect,” Dr. Roussel

said, which is why surface sampling is also part of the process.

“When I first started surface testing for hazardous drugs over 10 years ago, there was resistance and lack of funding,” Dr. Roussel said. “Now it is a part of our facility’s state of environmental control, where we focus on both microbial and hazardous drug contamination.”

Dr. Wiencek reported no relevant financial disclosures beyond his stated employment.

Dr. Roussel reported that she is a member of the Pennsylvania Board of Pharmacy.

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Indication EXPAREL® is indicated for single-dose infiltration in patients aged 6 years and older to produce postsurgical local analgesia and in adults as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Safety and efficacy have not been established in other nerve blocks.

Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia.

Adverse reactions reported in adults with an incidence greater than or equal to 10% following EXPAREL administration via infiltration were nausea, constipation, and vomiting; adverse reactions reported in adults with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation.

Adverse reactions with an incidence greater than or equal to 10% following EXPAREL administration via infiltration in pediatric patients six to less than 17 years of age were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritus, and tachycardia. If EXPAREL and other non-bupivacaine local anesthetics, including lidocaine, are administered at the same site, there may be an immediate release of bupivacaine from EXPAREL. Therefore, EXPAREL may be administered to the same site 20 minutes after injecting lidocaine.

EXPAREL is not recommended to be used in the following patient populations: patients <6 years old for infiltration, patients younger than 18 years old for interscalene brachial plexus nerve block, and/or pregnant patients.

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease.

Warnings and Precautions Specific to EXPAREL Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. ©2022 Pacira BioSciences, Inc. Parsippany, NJ 07054

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EXPAREL is not recommended for the following types or routes of administration: epidural, intrathecal, regional nerve blocks other than interscalene brachial plexus nerve block, or intravascular or intra-articular use.

The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days, as seen in clinical trials.

Warnings and Precautions for Bupivacaine-Containing Products Central Nervous System (CNS) Reactions: There have been reports of adverse neurologic reactions with the use of local anesthetics. These include persistent anesthesia and paresthesia. CNS reactions are characterized by excitation and/or depression.

Cardiovascular System Reactions: Toxic blood concentrations depress cardiac conductivity and excitability, which may lead to dysrhythmias, sometimes leading to death.

Allergic Reactions: Allergic-type reactions (eg, anaphylaxis and angioedema) are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients.

Chondrolysis: There have been reports of chondrolysis (mostly in the shoulder joint) following intra-articular infusion of local anesthetics, which is an unapproved use.

Methemoglobinemia: Cases of methemoglobinemia have been reported with local anesthetic use.

Please refer to brief summary of Prescribing Information on adjacent page.

For more information, please visit www.EXPAREL.com or call 1-855-793-9727.

Connect with us to learn more

22 Policy

Pharmacy Practice News • May 2022

FDA Watch

First Generic of Symbicort to Treat Asthma/COPD Approved

By PPN News Staff

T

he FDA approved budesonide and formoterol fumarate dihydrate (Breyna, Viatris/Kindeva) for the maintenance treatment of asthma and chronic obstructive pulmonary disease (COPD). The drug is the first approved generic version of Symbicort (AstraZeneca).

Breyna is approved for asthma patients who are 6 years of age and older. The

Brief Summary (For full prescribing information refer to package insert) INDICATIONS AND USAGE EXPAREL is indicated for single-dose infiltration in patients aged 6 years and older to produce postsurgical local analgesia and in adults as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia.

Limitation of Use: Safety and efficacy has not been established in other nerve blocks.

CONTRAINDICATIONS EXPAREL is contraindicated in obstetrical paracervical block anesthesia.

While EXPAREL has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death.

WARNINGS AND PRECAUTIONS Warnings and Precautions Specific for EXPAREL As there is a potential risk of severe life-threatening adverse effects associated with the administration of bupivacaine, EXPAREL should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity.

Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amidecontaining products.

Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration.

• epidural • intrathecal • regional nerve blocks other than interscalene brachial plexus nerve block • intravascular or intra-articular use EXPAREL has not been evaluated for use in the following patient population and, therefore, it is not recommended for administration to these groups.

• patients younger than 6 years old for infiltration • patients younger than 18 years old for interscalene brachial plexus nerve block • pregnant patients The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days as seen in clinical trials.

ADVERSE REACTIONS Clinical Trial Experience Adverse Reactions Reported in Local Infiltration Clinical Studies The safety of EXPAREL was evaluated in 10 randomized, double-blind, local administration into the surgical site clinical studies involving 823 patients undergoing various surgical procedures. Patients were administered a dose ranging from 66 to 532 mg of EXPAREL. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, constipation, and vomiting. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration were pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus, tachycardia, headache, insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain.

Adverse Reactions Reported in All Local Infiltration Clinical Studies in Pediatric Patients Aged 6 to Less Than 17 Years The safety of EXPAREL in 110 pediatric patients between the age of 6 and 17 years old undergoing various surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site. Patients were administered a weight-based dose of EXPAREL at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg). In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritus, and tachycardia.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration were bradycardia, muscle spasms, tachypnea, hypoesthesia oral, anemia postoperative, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment.

Adverse Reactions Reported in Nerve Block Clinical Studies The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies involving 469 patients undergoing various surgical procedures. Patients were administered a dose of either 133 or 266 mg of EXPAREL. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, pyrexia, and constipation.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following EXPAREL administration as a nerve block were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, hypoesthesia oral, pruritus generalized, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, body temperature increased, edema peripheral, sensory loss, hepatic enzyme increased, hiccups, hypoxia, post-procedural hematoma.

medication should not be used to treat acute asthma attacks, the FDA said. The COPD indication includes chronic bronchitis or emphysema.

Two inhalations via a metered-dose inhaler twice daily—usually morning and night, about 12 hours apart—treat both diseases by preventing symptoms, such as wheezing, and by improving lung function. The inhaler is approved for two strengths (160/4.5 mcg per actuation and

Postmarketing Experience These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes (SOCs): Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin and Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).

DRUG INTERACTIONS The toxic effects of local anesthetics are additive and their coadministration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia:

Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic cyclophosphamide, flutamide, hydroxyurea, ifosfamide, agents rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Bupivacaine Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2.

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

Water and Hypotonic Agents Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no studies conducted with EXPAREL in pregnant women.

In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations Labor or Delivery Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has not been studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death.

Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function.

Data Animal Data Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/ kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryofetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity.

Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day buprenorphine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight)

80/4.5 mcg per actuation).

The most common documented side effects of the combination medication include nasopharyngitis, sinusitis and oral candidiasis, among others. “[This] approval of the first generic for one of the most commonly prescribed complex drug–device combination products to treat asthma and COPD is another step forward in our commitment to bring generic copies

from implantation through weaning (during pregnancy and lactation).

Lactation Risk Summary Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EXPAREL and any potential adverse effects on the breastfed infant from EXPAREL or from the underlying maternal condition.

Pediatric Use The safety and effectiveness of EXPAREL for single-dose infiltration to produce postsurgical local anesthesia have been established in pediatric patients aged 6 years and older. Use of EXPAREL for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 6 years and older.

Safety and effectiveness have not been established in pediatric patients aged less than 6 years old for local infiltration or less than 18 years old for interscalene brachial plexus nerve block.

Geriatric Use Of the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. Of the total number of patients in the EXPAREL nerve block clinical studies (N=531), 241 patients were greater than or equal to 65 years of age and 60 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical experience with EXPAREL has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease.

Renal Impairment Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. This should be considered when performing dose selection of EXPAREL. OVERDOSAGE Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution.

Signs and symptoms of overdose include CNS symptoms (perioral paresthesia, dizziness, dysarthria, confusion, mental obtundation, sensory and visual disturbances and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia and asystole).

Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,500 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL. Management of Local Anesthetic Overdose At the first sign of change, oxygen should be administered.

The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted.

Endotracheal intubation, employing drugs and techniques familiar to the clinician, maybe indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

DOSAGE AND ADMINISTRATION Important Dosage and Administration Information • EXPAREL is intended for single-dose administration only.

• Different formulations of bupivacaine are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL. • DO NOT dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles.

• Use suspensions of EXPAREL diluted with preservative-free normal (0.9%) saline for injection or lactated Ringer’s solution within 4 hours of preparation in a syringe.

• Do not administer EXPAREL if it is suspected that the vial has been frozen or exposed to high temperature (greater than 40°C or 104°F) for an extended period.

of complex drugs to the market, which can improve quality of life and help reduce the cost of treatment,” said Sally Choe, PhD, the director of the Office of Generic Drugs in the FDA Center for Drug Evaluation and Research. “This reflects the FDA’s continued efforts to increase competition and access to quality, safe, effective and affordable medicines for patients and consumers.”

• Inspect EXPAREL visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer EXPAREL if the product is discolored.

Recommended Dosing Local Analgesia via Infiltration Dosing in Adults The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266mg (20 mL), and is based on the following factors: • Size of the surgical site • Volume required to cover the area • Individual patient factors that may impact the safety of an amide local anesthetic As general guidance in selecting the proper dosing, two examples of infiltration dosing are provided: • In patients undergoing bunionectomy, a total of 106 mg (8 mL) of EXPAREL was administered with 7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue.

• In patients undergoing hemorrhoidectomy, a total of 266 mg (20 mL ) of EXPAREL was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block.

Local Analgesia via Infiltration Dosing in Pediatric Patients The recommended dose of EXPAREL for single-dose infiltration in pediatric patients, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), and is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery.

Regional Analgesia via Interscalene Brachial Plexus Nerve Block Dosing in Adults The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg (10 mL), and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair.

Compatibility Considerations Admixing EXPAREL with drugs other than bupivacaine HCl prior to administration is not recommended.

• Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more.

• Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2.

The toxic effects of these drugs are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity.

• When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, the site should be allowed to dry before EXPAREL is administered into the surgical site. EXPAREL should not be allowed to come into contact with antiseptics such as povidone iodine in solution.

Studies conducted with EXPAREL demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of EXPAREL any more than they are by saline. None of the materials studied had an adverse effect on EXPAREL. Non-Interchangeability with Other Formulations of Bupivacaine Different formulations of bupivacaine are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL and vice versa.

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute.

CLINICAL PHARMACOLOGY Pharmacokinetics Administration of EXPAREL results in significant systemic plasma levels of bupivacaine which can persist for 96 hours after local infiltration and 120 hours after interscalene brachial plexus nerve block. In general, peripheral nerve blocks have shown systemic plasma levels of bupivacaine for extended duration when compared to local infiltration.

Systemic plasma levels of bupivacaine following administration of EXPAREL are not correlated with local efficacy.

PATIENT COUNSELING Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly.

Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Pacira Pharmaceuticals, Inc. San Diego, CA 92121 USA Patent Numbers: 6,132,766 5,891,467

5,766,627

8,182,835

Trademark of Pacira Pharmaceuticals, Inc. For additional information call 1-855-RX-EXPAREL (1-855-793-9727) Rx only

March 2021

Policy 23

Pharmacy Practice News • May 2022

Reimbursement Matters

It’s Spring, and Payment Trends Are Blooming COVID-19 benefit extension, drug savings plans among key developments

O

n April 12, urged by hospital groups and other stakeholders, the Department of Health and Human Services renewed the COVID-19 public health emergency declaration for another 90 days, effective April 16. This decision helps health systems continue to work with COVID-19 patients. In addition to the array of 2023 rules and regulations being released in the next few weeks, other significant developments are affecting your hospital system pharmacy practice. Here are a few to keep an eye on.

The FDA’s accelerated approval program. This program brings primarily high-cost oncology and orphan drugs to market before randomized clinical trials are finished, with the expectation that confirmatory studies will be completed for full approval. However, manufacturer and FDA follow-up are inconsistent. With the FDA Prescription Drug User Fee Act up for renewal, changes are possible, perhaps lowering reimbursement until these medications gain full approval, according to a report in AIS Health Daily. (For more details on these pathways, see an FDA guidance at bit.ly/3OzclbT.) Insulin drug pricing. U.S. Senate– proposed legislation would place a $35 monthly cap on what patients have to pay for insulin, accompanying a separate bipartisan effort to curb the drug’s price in a more comprehensive way, including having the uninsured protected. Another source of relief for the high cost of diabetes medications comes from Civica Rx and development partner GeneSys Biologics, which plan to manufacture and distribute three generics: aspart, glargine and lispro, available to consumers for $30 or less per vial or $55 for a box of five prefilled pens, according to a report in Fierce Healthcare (bit.ly/37uWKcLZ). The program has a start date of 2024, pending FDA approval of the generics. Collaboration partners include Blue Cross Blue Shield Association, Intermountain Healthcare, Kaiser Permanente, Providence, Trinity Health and others.

which officially launched on Jan. 19, 2022, announced it will introduce 27 drugs that will be discounted by $100 or more per prescription (bit.ly/3xDVWNe-SPC).

Here are a few examples: generic imatinib (Gleevec, Novartis) for $17.10 per month, compared with $2,502.80 at retail; generic memantine (Namenda XR, Allergan) for $12.90 per month, compared with $359.42 at retail; and

generic esomeprazole (Nexium, Pfizer) for just $6, compared with $216.66.

MCCPDC employs a cash-only model and directs customers with questions to call Truepill, MCCPDC’s fulfillment partner. “Because the company refuses to pay spread prices to third-party PBMs [pharmacy benefit managers] … to process insurance claims, the online pharmacy will be a cash-pay venture,” 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

company’s launch statement said. Touting transparency, “every product is priced see PAYMENT TRENDS, page 25

THE MORE YOU DETECT THE BETTER YOU PROTECT Improve care for more patients with ePlex® Blood Culture Identification Panels, the only BCID panels that can detect >95% of organisms that cause sepsis Sepsis is a common complication of COVID-19 and rapid diagnosis is key to effective treatment. ePlex BCID Panels rapidly detect more of the organisms that cause sepsis. Armed with this critical information, you can prescribe the right treatment within hours – rather than days – improving patient care.

The ePlex BCID Panels can identify >95% of the pathogens that cause sepsis. Combine this with order-to-report integration and templated comments and you’re ready to fast-track treatment intervention, enabling earlier escalation for resistant organisms or de-escalation of empirical antimicrobials.

Pharmacy Disruptors A billionaire’s bid for lower drug prices. As reported in Specialty Pharmacy Continuum, venture capitalist Mark Cuban’s generic drug company, Mark Cuban Cost Plus Drug Co. (MCCPDC),

To learn more, scan or visit GenMarkDX.com/DetectMore

24 Policy

Pharmacy Practice News • May 2022

FDA Watch

CMS Issues Final Aducanumab Coverage Decision

By Gina Shaw

T

he Centers for Medicare & Medicaid Services (CMS) finalized its Medicare coverage policy for the controversial Alzheimer’s disease drug aducanumab (Aduhelm, Biogen) on April 7, 2022. As in the initial plan released in March, aducanumab will be covered for Medicare recipients under the “coverage with evidence development” (CED) guidance, meaning the drug will only be covered in the setting of a clinical trial.

However, the final proposal contains several key changes from the original draft.

Coverage is expanded beyond the original proposal, which included only CMSapproved randomized controlled trials.

Instead, Medicare will cover the drug for participants in any trial approved by the FDA or the National Institutes of Health.

“The final decision allows for flexibility in a less rigorous study design for antiamyloid mAbs [monoclonal antibodies] that

other populations who were excluded from eligibility for CED coverage in the original proposal will be eligible for trial participation and coverage under the final policy. The trials also must comply with a Medicare requirement to recruit a racially and ethnically diverse group of participants; most participants in the original EMERGE and ENGAGE trials of aducanumab were white.

Finally, any future FDA-approved mAbs targeting amyloid will not automatically be subject to the same CED policy, as proposed in the draft policy.

For drugs that follow the FDA’s traditional approval pathway, patients will not need to be enrolled in a randomized trial to have the drug covered by Medicare, according to CMS; instead, they can be in a registry-based study, which does not require a placebo arm. (Drugs that go through the same accelerated approval pathway as aducanumab will be subject to the same clinical trial requirements.)

‘While [aducanumab] is known to reduce amyloid plaques in the brain, there is no [currently available] evidence that this leads to clinical benefit in the form of improved cognitive function.

have been approved by FDA through the traditional approval process for the treatment of AD,” CMS noted in a statement.

These trials are not restricted to hospital-based outpatient facilities, as in the original proposal, and can be conducted in other sites such as freestanding outpatient infusion centers and physician practices. The coverage decision does require that “any clinical study protocol submitted for CMS-approval include a description of the multidisciplinary dementia team and optimal medical management, and the study sites with clinical expertise and infrastructure to provide treatments consistent with the safety monitoring outlined in the FDA-approved label.”

People with Down syndrome and

“CMS wants to support the development of and access to innovative therapies that provide reasonable and necessary treatments to Medicare patients,” said Tamara Syrek Jensen, JD, Director of the Coverage and Analysis Group in the Centers for Clinical Standards and Quality at CMS, in a public call with stakeholders on April 11, 2022, explaining the rationale behind the two coverage pathways. “The second pathway allows for a wider array of studies for drugs that receive traditional approval, such as data collection in a registry.”

Ms. Jensen added that the approach was “tailored to drugs in this class” and would not affect CMS’ decisionmaking about other drugs approved via the FDA’s accelerated approval pathway.

“This is an evolving area and we intend to be nimble and flexible as new evidence is developed,” she said. “We can reconsider our coverage with evidence development decisions, and have done so in the past when appropriate.”

“This unprecedented CMS decision effectively denies all Medicare benefi-

importance of remembering the original scope of aducanumab’s approval. The drug “was approved for mild cognitive impairment, meaning that it is directed at patients who are recently healthy and may not have outward signs of dementia,” he said during the stakeholder call.

“There may be potential for promise

‘Under extraordinary pressure from many different sides, they have made an evidence-based decision that doesn’t abandon the notion that we need to understand if drugs are safe and effective before they’re used and covered.’

—Caleb Alexander, MD ciaries access to Aduhelm,” Biogen said in a statement. “These coverage restrictions, including the distinction between accelerated approval and traditional approval, have never been applied to FDA-approved medicines for other disease areas.”

‘Evidence-Based Decision’ Caleb Alexander, MD, a professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health and the co-director of the Johns Hopkins Center for Drug Safety and Effectiveness, in Baltimore, told Pharmacy Practice News that CMS had threaded the needle fairly well under difficult circumstances.

“Under extraordinary pressure from many different sides, they have made an evidencebased decision that doesn’t abandon the notion that we need to understand if drugs are safe and effective before they’re used and covered, and that’s exactly what we need for a question that is as important as this one to get right,” said Dr. Alexander, who serves on the FDA’s Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee, which recommended in November 2020 that the agency not approve aducanumab. “They will evaluate the next products on their own merits, which will obviously require more work on the part of CMS, but it’s the right decision. There may be important differences in how these products work, as well as in the totality of evidence regarding their safety and effectiveness. This approval was highly atypical in many ways, and I think the FDA is unlikely to approve another product based on evidence that is as flimsy as this was.”

Lee Fleisher, MD, the chief medical officer and director of CMS’ Center for Standards and Quality, underscored the

with this treatment; however, while it is known to reduce amyloid plaques in the brain, there is not currently evidence that this leads to clinical benefit in the form of improved cognitive function. Meanwhile, the known risks include potentially fatal brain bleeds. Taken together, there is not yet sufficient evidence to support coverage of this drug for people with Medicare until the statutory ‘reasonable and necessary’ standard is met.”

A History of Concern Although patient advocacy groups have been lobbying for a more favorable aducanumab coverage determination, several managed care and provider stakeholders have long been on record urging far more restraint.

In July 2021, for example, at least three major hospital systems—Cleveland Clinic in Ohio, Mount Sinai Health System in New York, and Providence Health in Washington state—announced they will not provide aducanumab, although affiliated physicians could, at least in theory, prescribe it for their patients to receive it elsewhere. At the time, the Neurology Center, a leading independent neurology group with seven locations in Washington, D.C., and Maryland, also announced that it would not be providing aducanumab.

Pushback also has come from several commercial plans, with several announcing that they will not cover aducanumab, including Blue Cross Blue Shield affiliates in Florida, Kansas, New York, Michigan, North Carolina and Pennsylvania. Policies posted online indicated that these payors were denying coverage because they considered the drug “investigational” or “experimental” or because “a clinical benefit has not been established.”

The sources reported no relevant financial disclosures.

Policy 25

Pharmacy Practice News • May 2022

Reimbursement Matters

PAYMENT TRENDS continued from page 23

exactly the same way: our cost plus 15%, plus pharmacy fee, if any” and a $5 shipping cost per prescription.

GoodRx + VitaCare prescription services. This plan doesn’t provide pharmacy services; instead, it acts as a comparison-shopping service, collecting the best prices, coupons and discounts to help consumers find the lowest-cost pharmacy for their prescriptions—both brand-name and generic drugs—along with its prescription discount card and coupons.

Amazon Pharmacy. This mail-order pharmacy dispensing service partners with Prime Therapeutics and Blue Plans in five states. Pharmacists who are on call 24/7 offer either out-of-pocket payment options or insurance payments.

The Amazon Prime Rx prescription drug benefit, with 40% to 80% discounts off cash prices of generic and brandname drugs at pharmacies, including CVS, Rite Aid, Walgreens and Walmart, is included. Specialty drugs, Schedule II controlled substances or Risk Evaluation and Mitigation Strategies medications and suspensions are not included.

Wholesale offerings. In a virtual satellite symposium at the 2021 ASHP Midyear Clinical Meeting and Exhibition, AmerisourceBergen described four ways to achieve financial sustainability, including prescription internalization and value-based contract outcomes (bit.ly/ 3vsrPG2). Cardinal Health offered its own take on innovative payment strategies with several programs. The company’s Reimbursement Solution program helps reduce patients’ rejected claims and helps connect patients to available financial assistance. Cardinal Health Specialty group purchasing organizations (GPOs) help qualifying health-system outpatient facilities access the most cost-effective pricing available for qualifying specialty, brand-name and biosimilar limited distribution drugs. The new Cardinal Health Traverse GPO provides qualified, non-340B outpatient facilities access to health-system class-of-trade pricing across oncology, urology, rheumatology, nephrology, ophthalmology, gastroenterology, neurology, allergy and asthma.

PBMs: old and new. Rising list prices are being linked to rising rebates from PBMs, with three major PBMs—CVS Caremark, Express Scripts and OptumRx—controlling nearly 80% of U.S. prescription benefit transactions. PBMs have been criticized for profiting from rebates and discounts and failing to pass on an estimated $120 billion back to consumers, as noted in an amicus brief advocating for more state regulation of PBMs posted on the Community Oncology Alliance website (bit.ly/3uTQJza).

New entrants into the PBM space

promise to take a different approach, including EmsanaRx, a nonprofit venture owned by the Purchaser Business Group on Health; CostPlus PBM, a startup funded by Mr. Cuban; Prescryptive Health, a blockchain-powered prescription data platform; and CapitalRx, which claims that it is “on a mission to change the way prescriptions are priced and administered to create enduring social change.”

Specialty Pharmacy Savings Hospitals and physician offices charged patients significantly higher

amounts for drugs than specialty pharmacies, according to a new study by AHIP, a national association representing health insurance providers (bit. ly/3Mk7CZG). Researchers analyzed costs of 10 drugs between 2018 and 2020 that healthcare settings—including hospitals—purchased, stored and administered, and examined how specialty pharmacies could safely and securely deliver those medications for provider administration. Medications administered by hospitals cost an average of $7,000 more than those delivered by

specialty pharmacies—on average double the price. Drugs dispensed in physician offices cost an average of $1,400 more than specialty pharmacy-derived medications, for an average increase of 22%. Why the upcharge? Both hospitals and physician offices charge additional fees to administer the drugs, according to the researchers.

Another key development: The pandemic pause on sequestration’s -2% payment cuts has ended! On April 1, 2022, the cuts resumed at -1%, and on July 1, they will resume at -2%.

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26 Operations & Management

Pharmacy Practice News • May 2022

Medication Safety

A Patient Safety Defeat continued from page 1

strong safety culture within our healthcare organizations, and this verdict represents a real setback. Right after the verdict, I received a number of emails from our nursing leadership expressing concern about the impact that this [guilty verdict] would have on the nursing profession.”

Michael R. Cohen, RPh, MS, the president emeritus and founder of the Institute for Safe Medication Practices (ISMP), also criticized the verdict.

“When RaDonda Vaught was convicted, the entire healthcare community lost as well,” he said. “Her conviction, which made a scapegoat of one individual instead of focusing on fixing larger, preventable systemic issues, will have serious consequences for patient safety. It could hinder the reporting of errors so that we are not able to learn from them and prevent future mistakes.”

He added that the verdict also could “exacerbate the current shortage of healthcare providers by driving them away from clinical practice. If nurses believe that society, their community,

and the judicial system holds them to a standard of perfection, why would they want to work in healthcare?”

On March 25, 2022, Ms. Vaught was convicted of negligent homicide in the 2017 death of 75-year-old Charlene Murphey, and is set to be sentenced on May 13. She faces up to eight years in prison. The circumstances that led to Ms. Murphey’s death sounded hauntingly familiar to many nurses, pharmacists and others involved in patient safety.

Ms. Murphey was being transferred from the neuro-ICU to a step-down unit after being diagnosed with an intraparenchymal hemorrhage. Her physician had ordered a PET scan, and Ms. Murphey asked for something to help her relax during the scan, as she was claustrophobic. The physician ordered a one-time 1-mg dose of 1 mg IV midazolam, writing the order for the brand name Versed. (Although practitioners still commonly use that name, ISMP noted that the Versed brand has been discontinued in the United States for some time). Both the patient’s

6 Paralytic Error Prevention Strategies

T

he Institute for Safe Medication Practices (ISMP) recommended several systems-based approaches to reduce the risk for medication errors involving sedation and paralytics in the wake of the RaDonda Vaught case. Here, we highlight 6 of the strategies. (For more details, access an ISMP article on the strategies at bit.ly/3EOH8Nn.)

1

Establish a standard process for patients who require sedation before radiology procedures that starts with an oral antianxiety medication and includes patient monitoring requirements.

2

Include IV moderate sedation agents such as IV midazolam on high-alert medication lists, with specified monitoring requirements, including a means of evaluating the adequacy of ventilation.

3

Eliminate storage of neuromuscular blockers outside of areas where they are not routinely needed. Outside perioperative areas (e.g., critical care or the emergency department), store these agents in a sealed box or rapid sequence intubation kit. If vials must be stored in automated dispensing cabinets (ADCs), place them in locked-lidded pockets with auxiliary warning labels stating, for example, “WARNING: CAUSES RESPIRATORY ARREST—PATIENT MUST BE VENTILATED.” Warnings should be visible when ADC pockets, drawers or lids are open.

4

Require a witness upon removal of certain medications on override.

5

Implement barcode scanning verification in all areas.

6

Teach practitioners how to toggle between brandname and generic search functions if they are separate, and to verify the drug search criteria if initially unable to find the desired medication, rather than triggering an override.

Source: ISMP. Safety Enhancements Every Hospital Must Consider in Wake of Another Tragic Neuromuscular Blocker Event. Jan. 17, 2019. https://bit.ly/3EOH8Nn

primary nurse and a radiology nurse were unavailable to administer the medication, so Ms. Vaught, a “help-all” (floater) nurse, was summoned.

At the neuro-ICU’s automated dispensing cabinet (ADC), Ms. Vaught entered the first two letters of the drug’s brand name, “VE,” into the search field but received no results, because the ADC’s default setting was generic drug names.

She then initiated an override setting, searched for VE again and selected the first medication in the results, the neuromuscular blocker vecuronium. A red box warning noted that the medication should be associated with a STAT order, but the ADC nonetheless opened and allowed the nurse to retrieve the medication.

Ms. Vaught missed several red flags, including the drug name on the front of the vial label, the fact that Versed is only available as an injectable liquid while the vecuronium she drew up was a powder requiring reconstitution, and the warning label on the red vecuronium vial ferrule that said, “WARNING: PARALYZING AGENT.” (That label has been overlooked or misunderstood in other paralyzing agent errors, ISMP reported.)

After administering what she thought to be Versed, Ms. Vaught left Ms. Murphey in the radiology holding area and went to the emergency department; she had been on her way there to conduct a swallowing study before being called in for this task. When the patient was found unresponsive by a transport technician about 30 minutes later, a code blue was called.

Although she was resuscitated, her condition worsened and she died the next day after being withdrawn from life support.

Ms. Vaught immediately responded when the code team was called, reporting to the physicians her belief that she had administered IV Versed. She gave the bag containing the empty vial and syringes with leftover drug to the patient’s primary nurse, who discovered the error.

It was disclosed to the patient’s family—with whom Vanderbilt later reached a confidential settlement—but neither reported to state/federal officials nor the Joint Commission until an anonymous “tipster” registered a complaint with a state agency in October 2018.

At Ms. Vaught’s trial, Tennessee Bureau of Investigation officer Ramona Smith, who was testifying for the prosecution, stated that her criminal investigation focused only on Ms. Vaught’s error and not on Vanderbilt’s actions or systems. “The investigation and prosecution put everything on RaDonda, that she didn’t do this and she didn’t do that,” Mr. Cohen said. “But that ameliorates the hospital’s role in setting their systems up so that something like this won’t happen.” (Vanderbilt declined a request for comment from Pharmacy Practice News.)

“Many state health profession boards are ill-equipped to deal with the science

At RaDonda Vaught’s trial, the prosecution emphasized her failure to heed the warning label on top of the vial that clearly stated the drug was a paralytic.

But medication safety experts note that these vial-cap warnings are not fail-safe, since the caps are not seen or are quickly removed and discarded when a “stat” drug is being prepared for administration.

of safety and the concept of human-based errors,” agreed Dan Degnan, PharmD, associate director, professional skills laboratory and senior project manager of the Purdue Center for Medication Safety Advancement, in West Lafayette, Ind. “Instead of holding a healthcare organization to rigorous system improvement methods, there is a focus on the human performance within flawed systems.”

Overrides Are Common As for specific systems improvement lessons that can be learned from the Vaught case, one obvious starting point is to probe how overrides are managed. In a July 2021 hearing that ultimately led to the revocation of her license, Ms. Vaught testified before the Tennessee Board of Nursing that overrides such as the one she performed were common at the institution, and that a 2017 upgrade to the hospital’s electronic health record had caused such frequent delays that nurses were instructed to use overrides to circumvent those delays. Another nurse corroborated that testimony at the trial.

“The reason why overrides exist is that there are certain medications for which the time for a pharmacist to review an order may take longer than the time that is needed to get the medication to a patient, such that the delay itself can cause a safety risk,” the University of Chicago Medicine’s Dr. Hope said.

“It’s standard practice in all hospitals to maintain an override list, but these lists can sometimes get very long or become abused. One of the things that ISMP, the Joint Commission and other

Operations & Management 27

Pharmacy Practice News • May 2022

Medication Safety agencies have stressed with pharmacy departments over the years is to evaluate that list carefully. Does this medication truly warrant being on the list? Is this an antidote? Is it for a critical patient?

Will there be a physician at the bedside?

There need to be criteria such as these to decide if a drug goes on override or not.”

That said, a paralytic agent would legitimately be on the override list, Dr. Hope noted. “If you have a patient crashing at the bedside and the anesthesiologist needs to administer the paralytic to intubate and put the patient onto a respirator, you want that done fairly quickly.

But to avoid errors such as the one that happened here, we have added an alert for paralytics that specifically asks if the patient is intubated or about to be intubated. That’s not just a pop-up warning— you have to answer it with a yes or no.”

Labeling of Paralytics At Ms. Vaught’s trial, there was much emphasis on her failure to note the label on top of the vial that clearly stated the drug was a paralytic. But Dr. Hope observed that this ignores how most healthcare providers work with such vials. “The first thing we do is pop the cap,” she said.

“That’s the first thing that gets removed and is in the garbage. No one is reading the cap. Labeling needs to be designed on these products such that they help to mitigate those errors that occur because we are human, we are rushing and we are distracted—all those things that can happen in a complex healthcare system.”

One possible solution, she observed, might be shrink-wrapping around the entire vial for paralytic agents, possibly with a bright yellow color and stripe that says “PARALYTIC.” “That might take a little extra effort to open, but that’s the point: to slow you down for a second to realize what this is,” she said.

“At our institution, after this incident happened, we went and reviewed our Omnicell data to run reports on how often paralytics are being pulled out on override and who is doing it, and providing that feedback as part of our surveillance of safety practices.”

ISMP agrees that shrink-wrapping could be a potential fix—but with a caveat. “Be aware that the use of a shrink wrap sleeve … on different neuromuscular blockers can make them look similar and contribute to mix-ups.

Limiting the variety of neuromuscular blockers available in ADCs can help reduce similar appearance,” ISMP reported in a 2019 article on strategies for preventing errors with neuromuscular blocking agents (sidebar).

The 2-Letter Shortcut Stocking and dispensing from ADCs have become much more systematized and safety-focused over the past several years, Mr. Cohen said, but the potential

for errors remains. “In this case, we saw that you can type in two letters and get a drug that could kill someone, if used incorrectly. And if you don’t have a way to barcode scan that vial against what is on the patient’s list of medications, or you are doing this on override, then you are in jeopardy of possibly preparing and giving the wrong thing,” he noted.

“We have asked Pyxis and Omnicell, the two vendors used by most institutions, if they can make software modifications available so that if you’re removing something on override, you need to

type in at least five letters rather than just two. If that solution had been in place here, she never would have gotten vecuronium on the list. I know that at least Omnicell has made that modification available, and understand that BD Pyxis will be doing this as well.”

While awaiting the verdict, Ms. Vaught told the Tennessean that she had “zero regrets about telling the truth.” But Mr. Cohen predicted that the “just culture” model may well take a hit. “Mistakes that did not lead to a serious outcome, near misses—those are the kinds

of things I do think may not get reported as they have been in the past, because people don’t want to put themselves in a position of getting punished by internal management, nursing boards, or as in this case, something criminal. But we implore people to continue to report, because the learning has to be there and our hospital organizations have to understand how important it is to truly follow the just culture model.”

The sources reported no relevant financial disclosures.

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INDICATIONS AND USAGE CLINOLIPID is indicated in adults for providing a source of calories and essential fatty acids for parenteral nutrition 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 • When admixing CLINOLIPID, protect the admixed parenteral nutrition solution from light. Use only a 1.2 micron in-line filter to administer CLINOLIPID and admixtures containing CLINOLIPID. • 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.

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• Monitor for signs or symptoms of hypersensitivity reactions.

1. Granato D, et al. JPEN J Parenter Enteral Nutr, 2000;24:113-8 2. Buenestado, et al. JPEN J Parenter Enteral Nutr 2006;30:286-296.

3. Olthof ED, et al. Clin Nutr. 2013;32(4):643-649.

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28 Operations & Management

Pharmacy Practice News • May 2022

Collaborative Care

Pharmacists Can Be OUD Experts and Combat Abuse

By Dave Doolittle and Bob Kronemyer

H

ealth-system pharmacists should continue to play a major role in the treatment of people with opioid use disorder (OUD), particularly patients on long-term buprenorphine therapy.

That’s why ASHP was involved recently in a joint venture of several health societies that developed recommendations on how to boost use of the

opioid partial agonist after surgery and before discharge for patients with OUD. The recommendations, published in Regional Anesthesia & Pain Medicine (2021;46[10]:840-859), are intended to be an educational resource for anesthesiologists and pain physicians but can be used by anyone on the care team, according to its developers.

The American Society of Regional Anesthesia and Pain Medicine (ASRA) led

100,000 deaths have been attributed to opioid use over the past

12 months

Baxter is a registered trademark of Baxter International Inc. US-CN00-220010 V1.0 04/2022

the venture along with ASHP, American Society of Anesthesiologists, American Academy of Pain Medicine and American Society of Addiction Medicine.

“ASHP advocates for a collaborative approach to pain management and ensuring access to care across all care settings and for patients across the continuum of opioid prescribing, including prevention, treatment and supportive therapy,” Sophia Chhay, PharmD, an assistant

director off th ASHP Center, direc ctor o ct thee AS SHP HP IInnovation nnov nn ovat ovat atiio atio on Ce C en ntter ter er, Bethesda, Md., Pharmacy Practice in Bet ethe et the hesd sd da, M d.., told d told to d Ph P Phar harma arma ar acyy P raccttic ra tic ice News.

ASHP New ws. “Moreover, “M Mor o eo oveer, r, A SH SHP HP ad aadvocates dvoc voccaate vo tess fo ffor or a sh shared model that puts har ared ed decision dec e isio issio i n m mo od deel tth hat at p utts th tthe he patient decisions.” patie een n ntt at a tthe he ccenter ente en ter of of ccare aarrree de d ecis ciissiion ons.” s.” s.

A Challenge Ch hal a leng le eng ge F Fr From ro om mF Former orm or rme mer Surgeon Surg geo on Ge G General en ne era er ral al Jerome Jero ro rome ome m Adams, Ada dams ms, MD M MD, D, MP M MPH, PH, H, ssparked parrk pa keed d tthe he he review off th during rre view ew w o tthe he re rrecommendations ecco comm mmen enda dati tio on ns d du urriin ngg ASRA 2019 meeting, where tthee A th SRA RA A sspring priin pr pri ng 20 2 019 19 m eeti ee eeti ting ngg,, w wh h her eerre he, surgeon was h e, a former form meerr U.S. U.S .S.. su urge rggeo eon general, geeneera ral,l, w aass Adams, course, spoke a speaker. speeaker.. “Dr.. Ad Adam dam ams, s, of of co cou ursee, sp ur pok ke opioid crisis and his aabout boutt the o pioid d cri isi siss an nd hi h is in is iinitiatives,” nittiaati tivvees, s” R. Vi Viscusi, MD, the senior ssaid aid Eugene R iscusi iscu cu ussii MD M D th he se eni nio orr author of the recommendations and an immediate past president of ASRA. “We started talking about the specific role of anesthesiologists and pain physicians in addressing the opioid crisis.”

Dr. Viscusi and his colleagues shared some of their clinical initiatives and research in this area with Dr. Adams.

“Dr. Adams essentially challenged me to produce some sort of initiative that would spur anesthesiologists to embrace their role in treating patients with OUD and to help initiate buprenorphine, specifically in these patients, when they enter the perioperative arena,” said Dr. Viscusi, the chief of pain medicine and a professor of anesthesiology at Sidney Kimmel Medical College of Thomas Jefferson University, in Philadelphia.

In the case of a patient admitted to the hospital with a complication from addiction, such as infection, the recommendations support transitioning the patient from the use of standard opioids to buprenorphine after surgery and before discharge. The recommendations detail an approach that can be relatively easily accomplished without causing opioid withdrawal, assuming the patient is interested in treatment.

For example, starting buprenorphine can be considered “for postoperative analgesia in patients with suspected OUD, using available social work or ancillary services to help facilitate linkage to outpatient buprenorphine prescribers when possible,” the recommendations state.

Additionally, “in circumstances in which a warm hand-off has not been definitely established, the amount of buprenorphine prescribed can be consistent with appropriate postoperative discharge standards; however, a longer course of treatment could be provided, depending on the prescribing physician’s comfort level.”

The other scenario is patients in drug addiction recovery currently on buprenorphine, for whom the recommendations advocate continuing the medicine during hospitalization and after discharge without interruption.

Operations & Management 29

Pharmacy Practice News • May 2022

Collaborative Care

100,000 deaths have been attributed to opioid use over the past

12 months

The recommendations state that in preoperative planning for patients on long-term buprenorphine therapy, the drug should not be discontinued before surgery. In addition, for postoperative pain management in patients on long-term buprenorphine therapy, multimodal analgesia, including adjunctive nonopioid medications and regional anesthesia, should be instituted.

“Supporting patient access to buprenorphine perioperatively, as the paper outlines, is a pragmatic and efficient way to initiate and maintain therapy,” Dr. Chhay said.

Pharmacists’ Expertise Called Crucial ASHP was involved in the joint venture as part of its commitment to advocating for pharmacists’ role in increasing patient access to OUD medications, which in general are severely underused, Dr. Chhay said.

“While not specific to the perioperative setting, it is estimated that as low as 10% of the population with an indication for a medication treatment of opioid use disorder, like buprenorphine, receive it or have access to it,” said Dr. Chhay, who pointed to an American Medical Association article on OUD treatment (JAMA Netw Open 2022;5[3]:e223821).

Pharmacists play a crucial role on the interprofessional care team as medication experts and patient care providers, Dr. Chhay said. For example, pharmacists can provide health professionals with details specific to buprenorphine, such as indications, dosing, mechanism of action and side effects, she said. For patients, pharmacists can offer counseling, prescription assistance information and education regarding a specific pain management plan, she added.

publication to Pharmacy Practice News.

In determining optimal pain management for these patients, he urged clinicians to take a multi-pronged approach.

“Opioids are not fully effective for this population because of the patient’s chronic opioid exposure and tolerance,” he said. “Therefore, to increase the analgesic efficacy, you must use an aggressive multimodal approach, with regional anesthesia if you can, and likely ketamine and other nonopioid analgesics.”

As for any challenges in implementing

the OUD recommendations, they usually are caused by the healthcare system itself, Dr. Viscusi noted. To avoid problems, “you need to have a prescriber at the other end of this process,” he said.

“You cannot just simply start patients on buprenorphine. Patients have to be plugged into a system, so once they leave the hospital, they have the appropriate follow-up.”

Having said that, buprenorphine still will play a key role, in part due to the 100,000 deaths attributed to opioid use over the past 12 months. “If anything,

The sources reported no relevant financial disclosures.

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Multidisciplinary Approach Although the new recommendations are specific to anesthesiology, they are relevant to any clinician involved in the inpatient setting and OUD, noted Dr. Viscusi, who is a member of the editorial advisory board of Anesthesiology News, a sister

the number of these patients is spiraling out of control,” Dr. Viscusi said.

“We are going to have to get used to dealing with these patients and do everything we can to get them through the system. Foremost, it is an ethical issue, and secondarily, it is going to bankrupt the healthcare system.

Buprenorphine is an important component to treating opioid addiction and keeping patients out of trouble.”

Head of Pulmonary and Critical Care Medicine MedStar Washington Hospital Center Professor of Medicine Georgetown University Washington, DC

David P. Nicolau, PharmD, FCCP, FIDSA Distributed by Infectious Disease Special Edition, Pharmacy Practice News, and cmezone.com

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30 Operations & Management

Pharmacy Practice News • May 2022

Practice Pearl

Ensuring Medication Access Amid Chaos How an outpatient pharmacy served its patients during George Floyd protests Anitha Nagelli, MPH-HPA, MEd

N

obody expects civil disorder to break out in the streets near their hospital, but that’s exactly what happened to us in May 2020, when vio-

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to medications for patients who were affected by pharmacy closures during the turmoil.

The front-line pharmacy team was able to absorb the influx of patients, address immediate medication needs, and identify and tag patients for followup. A central team was able to participate and provide longitudinal patient access to the rest of the medications.

As a result of these efforts, our team, working in the University of Illinois (UI) Health outpatient pharmacies in the Outpatient Care Center (OCC), provided care to many patients whose medications needs may not otherwise have been met during the unrest. Here are some notes from the field on how our front-line pharmacies and a central remote team used a collaborative workflow to meet the needs of our providers and patients.

Background Access to pharmacy services and medication therapy can be a barrier to disease treatment, leading to poor patient outcomes. The inability to access medications can lead to nonadherence, resulting in increased hospital admission rates as high as 69%. Various reasons may lead to nonadherence, such as affordability, transportation, or pharmacy deserts.1 During the summer of 2020, the pandemic had caused a high degree of strain on patients and pharmacies due to sickness, quarantine, and social distancing. Pharmacy teams were frantically evolving and adapting their workflow and services to continue to provide much-needed pharmacy care in a safe manner. From May 28 to June 1, 2020, the City of Chicago experienced mass lootings and destruction of businesses as a result of civil unrest related to the George Floyd incident.

Many pharmacies were closed due to the danger presented to employees.2 According to an estimate from the Illinois Pharmacists Association, about 60 Chicago pharmacies were damaged or

Operations & Management 31

Pharmacy Practice News • May 2022

Practice Pearl

140

Number of Claims

120

Send Us Your Practice Pearls!

133 117

Be sure to include:

111 95

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• The clinical/operational challenge you successfully managed • Tips (“tricks of the trade”) for how you succeeded, particularly if via an innovative system or strategy

74

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Nov

Dec

Figure 2. Medication needs met per month. closed during this period. The pharmacies were mainly located in the Loop and South Side.3 The closure of these pharmacies led to a frantic flood of patients trying to gain access to their medications at UI Health outpatient pharmacies. Working at the UI Health OCC pharmacy, we were able to engage and provide care for patients who were affected by these closures. Absorbing this influx of patients with unique challenges to access to medication in the midst of a pandemic required some workflow and staffing interventions. To support the OCC pharmacy front-line team and expand their capacity to care for these patients longitudinally, a collaborative model of workflow was created to promote coordination between the frontline pharmacy team and a centralized remote team (Table).

Role of the Front-Line Team The UI Health OCC pharmacy frontline team responded to patients who walked up to or called the pharmacy to access their medications. The team gathered information regarding the patients’ immediate medication needs and the pharmacies where the prescriptions were housed. An attempt was made to contact each pharmacy; however, the closed pharmacies had automated phone messages and did not provide options for transfer of medications. As a second step, the UI Health OCC pharmacy front-line team contacted the prescribers to initiate a new prescription to create medication access. The front-line team encountered refill-too-soon rejections from payors and made calls to get overrides. Once the immediate need medications were filled, patients were flagged for follow-up so we could meet the continued needs for medications in the event that the pharmacies did not reopen in a timely manner or remained closed indefinitely (Figure 1).

Role of the Central Remote Team The centralized remote team consisted of 1 pharmacist and 2 pharmacy

student externs. The pharmacy externs completed medication reconciliation on patients to tabulate their medication needs. Once reconciliation was complete, a data collection sheet was created to house data related to patient identifiers; patient contact information; list of medications; and the name, address, and contact number of the pharmacy where the prescriptions were housed.

A list of prescriptions that needed to be transferred was created.

Pharmacy externs were trained on how to transfer medications. A transfer data sheet was created to guide, establish scope, and document the transfer information for all the prescriptions that were to be transferred for each patient. Several virtual phone lines were created to allow for telephonic patient engagement. Each patient was engaged telephonically to review ongoing medication needs, obtain consent to transfer medications, or acquire new prescriptions, if needed.

Patients also were asked whether they were able to come to the pharmacy to pick up the medications or needed the medications to be delivered to their homes. The initial patient engagement calls, as well as calls to the pharmacy for transfer of prescriptions, were made by the pharmacist and subsequently by pharmacy student externs. A time study revealed that pharmacists spent a total of approximately 36 hours engaging patients and transferring their prescriptions. The student externs spent approximately 8 hours in medication reconciliation, prepping the transfer forms, and entering the prescriptions.

Results Sixty patients had an initial encounter with our front-line team. All 60 patients were referred to the central team for triage and further assistance with prescription access and longitudinal pharmacy care. Eventually, 40 patients chose to continue to receive their pharmacy care from the UI Health OCC pharmacy, and 20 patients returned to their original pharmacies. A total of 692 medication needs

were met from June to December 2020 (Figure 2). The top categories of medications included antihypertensive agents, diabetic agents, and statin therapies.

Conclusion Creating a remote centralized team and process to support a front-line pharmacy team allowed the UI Health OCC pharmacy to provide access to medications to patients who were affected by pharmacy closures due to the Chicago riots. A centralized remote team and workflow allowed for increased capacity, efficiency, social distancing, and off-loading of work burden from the front lines during

the pandemic. It also allowed for the creation of remote telephonic patient engagement capabilities.

References 1. CDC. Overcoming barriers to medication adherence for chronic diseases. Accessed March 3, 2022. bit.ly/3CpJfGx 2. Fields HE, Shaw TE. Looting during a time of civil unrest affects pharmacies on the South Side of Chicago. J Am Pharm Assoc (2003).

2020;60(6):e39-e40.

3. Schencker L. ‘It’s catastrophic’: Chicago-area patients struggle to get medications as pharmacies close amid George Floyd unrest. Chicago Tribune. June 3, 2020. Accessed March 3, 2022. bit.ly/3tl9idu Ms Nagelli reported no relevant financial disclosures.

32 Operations & Management

Pharmacy Practice News • May 2022

Pharmacy Education

Students Get Hands-on Supply Chain Experience

By Jillian Mock

T

his spring, four students from the College of Pharmacy of Xavier University of Louisiana, a historically Black university, started an unusual new supply chain elective course. The class is the result of a collaboration with AmerisourceBergen, which pro-

paths in the pharmaceutical industry, and empowering young, Black pharmacists to step into leadership roles.

AmerisourceBergen plans to continue offering rotations each year depending on XULA’s schedule and needs.

“It’s the supply chain … as a pharmacist you don’t typically think about [that

In the final week, the students give an oral presentation on an assigned topic, in which they demonstrate the skills they learned over the course of the rotation. In the final presentation, students are expected to demonstrate skills such as problem solving, effective communication and leadership.

Linking the Supply Chain To Patient Care The primary goal of the new course is “to give students an understanding of supply chain and how it links to [patient care delivery],” said Minh Duong, PharmD, the vice president of commercial solutions, client strategies and services at AmerisourceBergen and one of the course preceptors. “We really strive to expose learners to the wholesale business, distribution business, as well as the process—the interconnectivity between all the different stakeholders in this ecosystem.”

The course focus is unique in pharmacy education, said Milena Murray, PharmD, MS, an associate professor of pharmacy practice at Midwestern University College of Pharmacy, in Downers Grove, Ill., who is not involved with the project. Pharmacy students learn about distribution and supply chains during their didactic education, but this course provides hands-on experience with drug distribution. “I don’t think many pharmacy students are able to do that on a regular basis with their APPEs,” she said.

As a result of the traditional approach to pharmacy education, many students who end up working in a retail or hospital pharmacy don’t have a good idea of what happens to get all the drugs to their shelves every day, according to Kara Poole, the vice president of specialty distribution and community health at AmerisourceBergen, and the

Table. Tentative Rotation Schedule

vides the students with a closer look at the life of medications before they hit pharmacy shelves.

The new six-week class (bit. ly/3uuOke8) is an Advanced Pharmacy Practice Experience (APPE) Pharmacy Distribution Leadership Rotation for fourth-year pharmacy students. In its first iteration, the class was entirely virtual, although the course creators hope to include in-person site visits in the future. The students are exposed to multiple business areas within AmerisourceBergen, including business operations, financials, customer service, consultative selling, and value-added services and solutions to support AmerisourceBergen customers.

The class grew out of an existing sales course that XULA and AmerisourceBergen created together. Goals of the class include expanding students’ understanding of the drug supply chain, exposing them to alternative career

part of pharmacy practice],” said Rashad Haynes, a XULA pharmacy student who participated in the course in a video promotion about the class. “As a pharmacy student, you definitely don’t see ... how many hands are involved in the process of getting medication to the patients” (vimeo.com/684405627/e375614b2f).

In the first week of the course, the students receive an overview of AmerisourceBergen distribution centers and replenishment operations. In the second and third weeks, the students rotate with account services, learning about health-system and services solutions and community and specialty pharmacy. In the final three weeks of the program, the students learn about working with many different types of clients, including community and regional hospitals, physician distribution (oncology and nononcology) and children’s hospitals. Students also learn about account services, specialty distribution and transportation.

Time

Experience

Preceptor

Week 1

Welcome/orientation, distribution services • Learning management system training modules • Distribution center overview • Replenishment operations

Various copreceptors

Weeks 2&3

Account services • Health system and specialty services • Community and specialty pharmacy • Presentation topic assigned

Various copreceptors

Weeks 4-6

Client strategies, including but not limited to the following: • Group purchasing organization • National and strategic accounts • Regional and community health systems • Physician distribution: oncology supply • AmerisourceBergen specialty distribution • Pharmacy solutions • Marketing/legal • American Health Packaging • Global emerging therapies and channel strategy—branded products • Global generic pharmaceuticals • Coffee chats with AmeriSourceBergen leaders • Consignment • Solution development and commercialization • Supplier diversity • Topic presentation (week 6)

Various copreceptors will be assigned throughout the course of the rotation

Source: AmerisourceBergen.

Operations & Mgmt 33

Pharmacy Practice News • May 2022

Pharmacy Education other course preceptor.

Kathleen B. Kennedy, PharmD, the dean of XULA’s College of Pharmacy, said this was the case with her own education. She received primarily clinical pharmacy experience and instruction on how to work with patients during her initial training at the University of California, San Francisco. But early in her career, Dr. Kennedy was thrust into a role as the director of pharmaceutical services at a large teaching hospital.

“From inventory control to managing personnel, all of those things—it was learning on the spot, learning while you’re doing,” Dr. Kennedy said.

conversation, she said. “If we’re talking about the supply chain or distribution, again, being knowledgeable about what your role could be in making an impact is really important.”

The partnership with XULA is a component of AmerisourceBergen’s global diversity, equity and inclusion (DEI) strategy, according to a company press release about the project. “We are always trying to do more and be a part of diversity and inclusion,” Ms. Poole said.

“It’s one thing to say you are …[but] this has allowed us to be more actionable.”

Although the COVID-19 pandemic forced the team to adapt the course

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‘In the college of pharmacy, we train our students to make an impact, particularly in underserved communities to eliminate health disparities.’

—Kathleen B. Kennedy, PharmD Another course goal is to “showcase all the different nontraditional roles that the pharmacist has available to them within this industry,” Dr. Duong said, adding that many young pharmacists are not aware of these other career paths.

“Knowing that with my background I can use both my degrees and my experiences in a company, I didn’t know that was an opportunity,” Linda Nguyen, a XULA pharmacy student who enrolled in the course, said in the video about the class.

Empowering Black Students For Leadership In addition to providing practical skills, the class aligns with XULA’s mission to empower Black pharmacy students to be future leaders in the pharmaceutical industry, Dr. Kennedy said.

“Xavier’s overall mission is to promote a more just and humane society,” she noted. “In the college of pharmacy, we train our students to make an impact, particularly in underserved communities to eliminate health disparities.”

Black and other minority students have been excluded so often from opportunities that they can make a difference just by being a part of the

to be entirely virtual, there have been some advantages to that approach, Ms. Poole said. Virtual tours and meetings have made it possible to integrate multiple AmerisourceBergen business units and teams that work at different sites and offices into the course, she said. The preceptors plan to keep the course mostly virtual in the future, but ideally will add some in-person meetings, such as a distribution site visit.

Having a course like this one developed with a wholesaler like AmerisourceBergen allows a unique level of access, Dr. Murray said. “The students get to see behind the scenes what actually happens before the drug hits the shelf. I would imagine it’s a more complicated process than any of us imagine.”

Dr. Duong and Ms. Poole said they are not aware of another partnership and course like this one in the United States. “I’ve been in academia for a while,” Dr. Duong said, “and I have not seen a specific rotation experience structured with a distribution partner to give a level of exposure to this industry as we’ve created.”

The sources reported no relevant financial disclosures.

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If you are involved in pharmacy education, send us your innovative teaching and experiential learning strategies for a feature in a future issue.

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34 Operations & Management

Pharmacy Practice News • May 2022

Distribution

COVID-19 and the Cold Chain Lessons from the front lines of the vaccine rollout

By Gina Shaw

E

nsuring the safe handling, delivery and administration of more than a half-billion COVID-19 vaccines in the United States in less than two years was an unprecedented logistical feat. But distributing the two approved mRNA vaccines from Pfizer-BioNTech and Moderna has been a particular challenge, given the vaccines’ extreme temperature control requirements, according to a recent webinar on the topic and interviews with several experts in vaccine and drug distribution.

The good news is some of the

resources invested in COVID-19 vaccine cold chain supply management will still be available in the future.

“A tremendous amount of investment has been made in strengthening temperature management at all levels of the supply chain, and even end-user institutions have devices to be able to handle these products, as well as realworld experience with them,” said Eric Tichy, PharmD, the vice chair of pharmacy formulary for the Mayo Clinic Health System. “It’s a lot easier to replace things once you have them than to do an initial mobilization. We’re not

going to have to reinvent the wheel in the same way again.”

Some providers fared better than others, based on existing capabilities and infrastructure. “At Mayo, we were well positioned because we had a strong inventory of ultra-cold temperature freezers for other uses, such as cellular and gene therapies, but we have already made additional investments in these devices and distributed them further throughout our institution,” Dr. Tichy said. “We’ve seen that the future of vaccines and these types of treatment advances will require more

‘While a standard [for ultra-cold chain shipping] could be developed in this space, it wouldn’t be for the majority of the industry’s use, so how valuable would it be? It’s probably not something we at USP would consider at this time.’

—Desmond Hunt, PhD

The Long Haul: Making Best Practices More Sustainable

W

ith the initial “crisis mode” distribution of COVID19 vaccines in the rear-view mirror, what has been learned about temperature control management in this process that can be applied on an ongoing basis—and in potential future crisis situations? There are several key lessons, experts say.

Preparedness. “I believe we did a fairly good job coordinating between vaccine manufacturers, the government, the distribution network, and organizations like ours,” said Ranjeet Banerjee, CEO of thermal packaging solutions supplier Cold Chain Technologies in an interview with Pharmacy Practice News. “But in the future we may have even less time to respond to a surge, and the importance of the last mile is critical. We need to look at proactively building and maintaining supplies and capacity for potential future surges.”

Mr. Banerjee recommended the development of a cooperative “early warning system” among government and industry. “As soon as we start to see that there is something the CDC is picking up, the group should jump on it,” he said.

“We can keep some strategic inventory capacity aside for such a situation, using ‘first in first out’ to ensure that everything is refreshed.”

Improved digital capabilities. “The life sciences industry needs to enable our digital capabilities to become much

more predictive, in order to better ensure patient safety,” Mr. Banerjee said. In mid-2021, Cold Chain Technologies launched a digital platform that has improved its ability to do real-time location and condition monitoring for any drug or API that is shipped. “We’re now adding more functionality to enable it to be more predictive in outcomes for the last mile,” he said. “This takes things to a whole new level. For example, if your product has a shipping delay and is stuck at an airport, the platform can automatically predict if that delay will cause an excursion, if that delay will be relevant, and if relevant, what are our options for an intervention. This is something we did not have when COVID started.”

New product designs. Cold Chain Technologies is now in the process of rolling out new lines of temperaturecontrolled packing solutions aimed at the cellular and gene therapy market, incorporating experiences from the COVID-19 vaccine rollout in their design. “We were very pleased with the high level of performance of some of the products that we developed specifically for the vaccines, and we realized that we could tweak some of those designs to be useful in other areas where the payload is also so precious and so fragile.”

—G.S.

and more of these capabilities.”

As for the early days of COVID-19 vaccine distribution, many of those capabilities had to be developed on the fly, a panel of experts noted at a recent webinar hosted by the ELPRO Leading Minds Network. Adapting and streamlining the contractual process was a key starting point, noted Geoffrey Glauser, a former Pfizer/ Merck supply chain executive. “We did not have a suitable template or boilerplate language for the contractual operations with multiple manufacturers that we dealt with through Operation Warp Speed,” he said. “That was something we had to address, to coordinate the manufacturers for COVID-19 operations such that they could standardize what they proposed to the government for response time, supply chain questions, production quality and regulatory requirements.”

The proposal and quotation process also had to become much more efficient, responsive and flexible, said Rich Nelson, the senior manager of global logistics for packaging coordinators at the consulting firm PCI Pharma Services. “We had to figure out how to do something that typically took six weeks and condense it into a much shorter time period,” he said. Before COVID-19, PCI employed a cyclical, back-and-forth quotation process that involved multiple departments. During the pandemic, in contrast, the company created a streamlined process by obtaining vaccine sponsors' assessment on all packaging options very early on. “They could see right away everything we had available and how long it was going to take. As soon as they were ready to go, we were ready to start.”

Even so, sometimes contracts needed to be signed with limited information available about volume of vaccine, what distribution center would be shipping, and the destination country. “It’s hard to choose the right supplier if you don’t know the origin and destination of your

Operations & Management 35

Pharmacy Practice News • May 2022

Distribution product,” said Victoria Wilmore, the director of the temperature control support center for Johnson & Johnson.

“We had to take into account the global footprint of our suppliers and make the best decisions we could at the time with the information we had.”

Vendors quickly came to understand that just-in-time inventory wasn’t going to work for COVID-19 vaccine temperature control packing supplies.

Instead, PCI kept sufficient supplies and packaging components in stock and found standardized solutions for requirements, such as labeling, so special orders were not required.

“As soon as the contract was executed, we could keep momentum moving into operations because we didn’t have to go order or look for things,” Mr. Nelson said.

Given the high stakes, PCI also agreed to make contractual changes as easy as possible for customers, and flexibly adjusted bills of quantities and cost estimates as circumstances changed, he noted.

Traditional logistics plans didn’t really work under these unusual circumstances, the experts agreed. Once the countries and sites for clinical trials were established and temperature conditions were determined by the manufacturers, PCI reached out to all of its couriers. “We typically have just one of four different specialty courier companies carry everything for a particular clinical trial,” Mr. Nelson said. “In this case, we organized everything by shipping lane and scattered it all around among all the couriers we work with.

I would tell them all, ‘These are the countries we need to go to and these are the temperature conditions. Give me your availability, schedules and all the material you can on moving shipments through that particular lane.’

When couriers could not serve a particular lane, PCI requested cargo flights and chartered private planes, he noted.

Apprehension on The Cold Chain Trail With the initial temperature requirements for the mRNA vaccines—Pfizer’s, for example, had to be shipped at temperatures between -80° C and -60° C (-112° F and -76° F) and could only be kept in a normal freezer at -20° C (-4° F) for two weeks—there was a lot of apprehension about potential transport losses, but to a great extent that did not happen, said Mr. Glauser, the former Pfizer/Merck supply chain executive who also is a consultant to the Biomedical Advancement Research Development Authority (BARDA) in the Office of the Assistant Secretary for Preparedness and Response (ASPR) within Health and Human Services (HHS). “Pfizer had qualified a unique

shipments went to their destination without a hitch.”

PCI was well prepared to ship at those temperatures, Mr. Nelson said. “I would say that 90% of the shipments we make daily at some level of temperature control, we even ship on liquid nitrogen,” he noted. “We have designed multifunctional shipping containers with our partners such that the same box prequalified to hold 2 °C to 8 °C for 120 hours can hold -20 °C for a hundred hours or -80 °C for 120 hours. All we have to do is change the way we manage the phase-change materials, and then we can use the same containers.”

The government was prepared to intervene if manufacturers encountered significant capacity restrictions with carriers such as FedEx, UPS or DHL, but that was largely unnecessary, Mr. Glauser said. “We did make sure that the major carriers had forecasts from each of the manufacturers so that they had a pretty good idea of what kind of volume they would be facing and the timing.”

Is More Guidance and Regulation Coming?

Ranjeet Banerjee, CEO of thermal packaging solutions supplier Cold Chain Technologies, praised the way hundreds of organizations came together to make the COVID-19 vaccine rollout succeed. “This goes beyond business,” he said. “It brought out the best in our company and in others, with people working nights and weekends, coming together passionately to meet an enormous public need.”

‘At Mayo, we were well positioned because we had a strong inventory of ultra-cold temperature freezers for other uses, such as cellular and gene therapies, but we have already made additional investments in these devices and distributed them further throughout our institution.’

—Eric Tichy, PharmD container constructed for this vaccine, and went with a universal shipment qualification program for their large trays of 495 vials, relying heavily on the use of dry ice,” he said.

Early on in the vaccine program, there were speculations about potential shortages of dry ice, but that never materialized, he noted. “This demand represented only about 3% of the dry ice used in the U.S., so a comparatively

small percentage. Pfizer worked with suppliers to ensure they had daily deliveries.”

For the Moderna vaccine, they used gel packs pre-frozen at -35° C such that they would equilibrate once pulled out of the freezer to -20° C, Mr. Glauser added. With the Pfizer and Moderna vaccines, “we had a very good level of success, without much in the way of transport losses. Above 99.5% of our

Whether federal or state officials are ready to intervene in such a way is unclear, the experts noted. They also expressed some doubts as to whether standard-setting organizations are ready to add new sections to their relevant chapters or guidelines regarding ultra-cold chain shipping requirements. “When we have these discussions about where we are today with new technologies, the impact on standards is an obvious next question, and that’s valid, but we always have to think of standards as the minimum requirement, the floor,” said Desmond Hunt, PhD, USP’s senior principal scientist. “The packout for these ultracold products is so far on one end of the spectrum. While a standard could be developed in this space, it wouldn’t be for the majority of the industry’s use, so how valuable would it be? It’s probably not something we at USP would consider at this time.”

Ranjeet Banerjee, CEO of thermal packaging solutions supplier Cold Chain Technologies, praised the way hundreds of organizations, both private and public, came together to make the vaccine rollout succeed. “Sometimes the best comes out in a crisis, and leaders lead,” he said. “This goes beyond business. It brought out the best in our company and in others, with people working nights and weekends, coming together passionately to meet an enormous public need.”

The sources reported no relevant financial relationships other than their stated employment.

36 Technology

Pharmacy Practice News • May 2022

Informatics

Analytics Speeds Drug Diversion Detection

By Dave Doolittle

M

achine learning and analytics software detected drug diversion at 10 U.S. inpatient hospitals an average of 160 days faster than existing, nonmachine learning methods, according to a new study (Am J Health Syst Pharm 2022 Feb 8. doi:10.1093/ajhp/zxac035).

The retrospective data underscore the value of artificial intelligence (AI) in investigating and preventing drug

theft, according to the researchers.

“For healthcare systems that don’t yet utilize a drug prevention and detection program leveraging machine learning and advanced analytics tools, the research speaks for itself,” Don Tyson, one of the study authors and the director of pharmacy at Piedmont Athens Regional Medical Center, in Athens, Ga., said in a statement. “Advanced analytics and machine learning technology

can improve the accuracy, efficiency and effectiveness of any drug diversion prevention program and goes far beyond what can be addressed manually, especially when dealing with large amounts of data.”

About 10% of U.S. healthcare workers will divert opioids and other medications from patients and facilities at some point in their careers, according to the Healthcare Diversion Network.

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EXPIRATION DATE: DECEMBER 31, 2022

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The software detected

22 confirmed cases between seven and 529 days faster than existing detection methods.

However, drug theft often goes unnoticed or unreported because of the clandestine nature of diversion and/or the work culture at many healthcare facilities, the study authors wrote.

To prevent diversion, facilities traditionally used chain-of-custody policies, such as requiring two clinicians to sign off on waste destruction or regular reports from automated dispensing cabinets (ADCs), the researchers wrote.

Investigations typically rely on manually comparing records from ADCs with those from electronic medical record (EMR) systems and interviewing suspects and their supervisors.

To determine whether AI could automate those methods—thus saving pharmacists and other healthcare professionals time and hassle—researchers studied 10 acute care inpatient hospitals that had identified and confirmed 22 drug diversion cases using traditional methods.

Specifically, researchers extracted two data sets from each facility’s health technology systems. The data comprised 27.9 million medication movement transactions by 19,037 nursing, 1,047 pharmacy and 712 anesthesia clinicians.

“Supervised machine learning methods were iteratively used on the initial sample dataset to train algorithms to classify medication movement transactions as involving a low or high risk of diversion,” researchers stated in the study’s abstract. “Thereafter, the resulting machine learning model classified the risk of diversion in a historical dataset capturing 8 to 24 months of history.”

The software detected the 22 confirmed cases between seven and 529 days faster than existing detection methods (mean, 160 days; median, 74).

“Additionally, the machine learning model demonstrated 96.3% accuracy, 95.9% specificity and 96.6% sensitivity detecting transactions at high risk of diversion in the dataset,” the researchers said. Moreover, “auditing ADC and EMR records required only 10 to 30 minutes with the consolidated dataset; in comparison, auditing required four to 20 hours of manual reconciliation using existing methods.”

The sources reported no relevant financial relationships.

Access today at www.cmezone.com/SY212

Technology

Pharmacy Practice News • May 2022

37

Oncology

Using AI to Predict VTE Risk in Cancer Pts

By Gina Shaw

Boston—Artificial intelligence and machine learning could improve the ability to predict venous thromboembolism (VTE) in cancer patients over the current gold-standard approaches, according to a research grant award presentation at the 2022 Hematology/Oncology Pharmacy Association (HOPA) annual conference.

VTE, including both deep vein thrombosis and pulmonary embolism, represents a major source of morbidity and mortality for cancer patients, with an incidence ranging from 1% to 8% and a one-year mortality rate of more than 64% (Thromb J 2021;19[1]:21).

“VTE is the third leading cause of death in cancer patients behind relapse and infection, and drastically changes the clinical trajectory of our patients,” Benjamin Andrick, PharmD, BCOP, a hematology/oncology clinical pharmacist at Geisinger Health System, in Danville, Pa., told HOPA attendees.

“But identifying the risk factors for VTE is no small feat.”

In addition to the tumor’s direct impact, including release of procoagulants and prothrombotic manipulation of the tumor microenvironment, many other factors play a role in VTE formation, such as type of cancer, type of chemotherapy, surgery, comorbidities, infection and immobility, as well as other unknown heterogeneous risk factors, he noted.

Because of that heterogenicity, universal VTE prophylaxis is not the answer, Dr. Andrick stressed: Such an approach exposes patients to an increased risk for bleeding. Instead, “we need the ability to better predict who is at greater risk for VTE,” said Dr. Andrick, who is also an assistant professor of clinical research in the Center for Pharmacy Innovation and Outcomes at Geisinger. “There are several current clinical models, perhaps the most famous of which is the Khorana model, developed in 2005 and widely adopted in practice. But subsequent prospective trials show that the performance of this and other models falls over time.”

A 1.0 concordance index, or “c-index,” which measures a model’s ability to discriminate between binary outcomes, would be a perfect score for a predictive model. A 2017 review found the c-index at 180 days for Khorana and three other VTE predictive models to

range between 0.5 and 0.57 (Haematologica 2017;102[9]:1494-1501). “That’s almost random chance,” Dr. Andrick said. “VTE prediction becomes even more challenging, not only because of the complexities with heterogeneous disease and hundreds of risk factors at the outset but also even more heterogenicity and change over time.”

His group is using machine learning to develop a better predictive model, first by creating a high-fidelity cancer VTE data set by retrospectively querying Geisinger’s institutional electronic health record (EHR). “Ultimately, we were able to develop a data set of 9,498 cancer patients, 90% of whom did not develop VTE and 10% of whom did.

We found that 40% to 50% of the VTEs developed within six to eight months after diagnosis and starting chemotherapy.”

The team used that data set to test the machine learning model that they have built and are still refining. “With these models, it’s difficult to understand exactly how the prediction is made. It’s a black box,” Dr. Andrick said. “Certain features may be more or less important to the model.”

The Khorana score’s accuracy was 0.62 at three months after diagnosis and treatment (remember that performance tends to decline over time), compared with 0.67 for the machine learning model. At six months, the Khorana score declined to 0.6 and the machine learning model declined to 0.64.

The model uncovered several additional trends. At three months, some of the most important features associated with VTE risk were brain cancer, type 2 diabetes, Khorana site of cancer, and use of docetaxel, etoposide, gemcitabine, methotrexate and paclitaxel.

At six months, the single most important feature associated with VTE risk was oxaliplatin use, followed by brain cancer, lymphoma, cancer metastasis, minor surgery, Khorana site of cancer, and etoposide and methotrexate use.

“Our hope is that, ultimately,

clinicians can tell the model that they are planning to start a particular therapy with a particular patient, and receive a prediction window for VTE over time. The goal is also portability, [bringing] the model into the EHR, so a clinician could be sitting with a patient in real time, run the algorithm and discuss with them their risk of VTE over the next several months,” Dr. Andrick said.

“But first, the gold standard would be to create a reciprocal data set at another institution with a different set of patients, so we can test the model on a different group of patients than those it was created and derived from.

“We also want to set up a prospective study in which we model predicted VTE at the patient’s first visit, and then at an as-yet undecided interval, do a refresh in the background and feed the data back into the model. That would create a true real-world application and make it dynamic,” he said.

Dr. Andrick reported that he and his research team had no relevant financial disclosures.

38 Technology

Pharmacy Practice News • May 2022

Collaborative Care

Pharms, GI Docs Collaborate on IBD Biologics Use A

collaboration between pharmacists and gastroenterologists to establish a standardized protocol for use of biologics in inflammatory bowel disease (IBD)—guided in part by telemedicine and data-mining electronic health records (EHRs)—has changed routine practice in a multicenter system and improved several quality-of-care benchmarks.

“A pharmacist-gastroenterologist co-management program for use of biologics in IBD patients is superior to a traditional gastroenterologistonly model with regard to laboratory screening prior to treatment and monitoring after drug initiation,” said coinvestigator Jennifer T. Chan, MD, of the Department of Gastroenterology, Kaiser Permanente Medical Center, in San Leandro, Calif.

IBD pharmacists were first introduced at Kaiser Permanente Northern California more than five years ago, and provide support for IBD management to more than 100 gastroenterologists across several affiliated Kaiser Permanente facilities. The concept of specialized pharmacists is not novel, according to Dr. Chan, but has not been applied in the field of IBD or in a nonacademic setting.

Since its inception, 42,000 patients have benefited from the pharmacist-run clinic, according to Karen Tokunaga, PharmD, the interim vice president of Pharmacy Strategy and Operation for Kaiser Permanente Northern California in Sacramento.

“There are four full-time pharmacists and 150 gastroenterologists who are part of the IBD clinic,” Dr. Tokunaga reported. The pharmacists collaborate “to ensure proper lab work is completed, titrate dosing and drive therapeutic drug monitoring,” she said.

“We are proud of this connected team of clinical experts who collaborate seamlessly across departments and specialties to provide the highest quality care to our patients,” she added.

Multisite Collaboration Relative to other IBD clinics that employ pharmacists, the collaboration at Kaiser Permanente is also unique in its implementation across multiple geographic sites, Dr. Tokunaga noted.

Gastroenterologists are encouraged but not required to refer patients to the pharmacy specialists.

When patients are referred, pharmacists screen for tuberculosis and hepatitis B, participate in selecting an agent, and educate patients about biologics, including potential side effects and costs. After the biologic is initiated, pharmacists monitor patients for

symptomatic response through testing of C-reactive protein (CRP) and fecal calprotectin (FCP), and oversee therapeutic drug monitoring (TDM) when requested by the gastroenterologist.

“The pharmacists provide follow-up to gastroenterologists through the EMR [electronic medical record] system,” said Abhik Roy, MD, who, along with Fernando Velayos, MD, were collaborators on this study. Both Drs. Roy and Velayos are gastroenterologists working at centers in Kaiser Permanente Northern California. Dr. Roy presented these results at the 2021 annual meeting of the American College of Gastroenterology (abstract 70), in Las Vegas.

The protocol was evaluated by comparing patients who were managed by pharmacy specialists versus those managed in traditional gastroenterologistled care. The end points were screening before biologic therapy and TDM after biologic initiation.

The 2,533 IBD patients included in the analysis initiated biologic therapy from 2016 through 2019. The baseline characteristics, such as age (~43 years), sex (~50% male), race (~65% white) and type of IBD (approximately evenly divided between Crohn’s disease and ulcerative colitis) did not differ significantly between groups. The proportions of patients experienced with steroids or immunomodulators also were similar.

Fewer than 7% were smokers.

Screening for hepatitis B (74.0% vs. 62.1%) and tuberculosis (77.1% vs.

65.5%) were both higher among the 938 patients who received collaborative care from a gastroenterologist and a pharmacy specialist relative to those in traditional gastroenterologistled care. After initiating the biologic, the rates of patients undergoing TDM (70.9% vs. 41.7%), CRP evaluation (73.2% vs. 52.2%) and FCP testing (48.9% vs. 15.5%) were higher when a pharmacy specialist was involved.

On multivariate analysis that adjusted for age, sex, ethnicity and Charlson Comorbidity Index, the odds of prebiologic testing were increased nearly twofold (odds ratio [OR], ~1.8), monitoring for CRP was increased more than twofold (OR, 2.51), and TDM (OR, 3.38) and monitoring for FCP (OR, 3.13) were increased by more than threefold in the collaborative care group.

The study was not designed to evaluate symptom follow-up or disease outcomes, which Dr. Roy acknowledged limits this evaluation, but he emphasized that the pharmacist–gastroenterologist collaboration increased the proportion of patients meeting process benchmarks of quality of care.

“Assessing patient response to

100 Collaborative care group Traditional GI care

Tasks performed, %

By Ted Bosworth

75

74.0

73.2 70.9

62.1

52.2 48.9

50

41.7

25 15.5 0 CRP evaluation

FCP testing

Patients undergoing TDM

Screening for hepatitis B

Figure. The benefits of pharmacist– gastroenterologist collaboration.

CRP, C-reactive protein; FCP, fecal calprotectin; GI, gastroenterology; TDM, therapeutic drug monitoring

symptoms, drug monitoring and inflammatory testing after starting biologic therapy may identify important variations and additional opportunities for a protocolized IBD pharmacist–GI partnership,” he said.

The study also shows the feasibility of a pharmacist–gastroenterologist partnership across a large regional system, demonstrating that such an approach “does not require colocation of the pharmacist and the gastroenterologist,” Dr. Roy said.

Strength in Numbers As a pharmacist experienced in collaborating with gastroenterologists in the management of IBD at Cleveland Clinic, Shubha Bhat, PharmD, can corroborate the advantages identified in the Kaiser Permanente study. “It is not just the knowledge about medication management, including the use of biologics and biosimilars, that puts pharmacists in a

suitable position to help manage patients on IBD medicines,” Dr. Bhat said. She explained that pharmacists also can typically follow up with patients more frequently than a clinical gastroenterologist.

“A clinical pharmacist is well equipped to help ensure completion of labs before starting a biologic and with screening and follow-up of patients once treatment is initiated in order to obtain markers of treatment response,” she said.

Dr. Bhat noted that the IBD pharmacist model has been well received at other IBD centers, and praised the Kaiser study for the support it provides to using telemedicine as a means of communication for the clinical team. Such strategies, she noted, allow pharmacists to follow up with patients more frequently than is generally practical for gastroenterologists.

The sources reported no relevant financial disclosures.

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