Pharmacy Practice News - July 2022

The Best-Read Pharmacist’s News Source

pharmacypracticenews.com

Paxlovid Useful For COVID-19, But Know Risks

OPERATIONS & MGMT

By Tom Rosenthal

C Aiming low not a good strategy for USP success ...............................5 CLINICAL

New Rx options for early breast cancer .........

TJC expects big things from pharmacist surveyor ....

8

14

linicians should not avoid prescribing nirmatrelvir-ritonavir (Paxlovid, Pfizer) to treat mild to moderate COVID-19 out of fear of potential drug–drug interactions, Infectious Diseases Society of America (IDSA) experts said in a media briefing to promote the organization’s recently updated COVID-19 treatment guidelines on the drug’s usage.

In developing the guidelines, the IDSA panel examined the possible interactions of the top 100 medications prescribed in the United States with nirmatrelvir-ritonavir.

Two experts at the briefing noted that they had anecdotally heard of clinicians refusing to prescribe nirmatrelvir-ritonavir out of uncertainty, confusion or fear of potential drug–drug interactions.

TECHNOLOGY

9 tips for adding automation to IV compounding sites .....

Real-world research tool helps boost specialty drug adherence ............ 28 REVIEW ARTICLE

CDC taking steps to limit confusion for use in children

Waste, Mix-Ups From COVID-19 Vax Labeling Possible

By Marie Rosenthal

D New and Emerging Options for Hypercholesterolemia See page 16.

In pediatrics:

PGx Testing for Complex Cases Beats Trial and Error

By Gina Shaw

P

harmacogenomic testingg in children with complex x medical histories can help predict and prevent adverse drug reactions, improve adherence and salvage drugs with high toxicity.

The tests yield actionable results in most cases, acording to Shannon Manzi, PharmD, BCCPS, the former director of the clinical pharmacoge-nomics service at Boston Children’s Hospital ospital (BCH). “More than 92% of patients tested ested by the BCH service” received such results, ults, she said.

Cystic fibrosis (CF) is a condition that at is particularly amenable to pharmacoge-nomic testing, and is one of several disorders for which the testing is mandatory, Dr. Manzi noted. She cited ivacaftor

Continued on page 22

26

iscrepancies on the packaging for both of the COVID-19 messenger RNA (mRNA) vaccines to immunize younger children could lead to missed opportunities to vaccinate, as well as the waste of expensive vaccine products, according to experts. However, they said the inconsistencies should not be a safety concern.

Getting shots in arms is the primary goal for public health officials, Continued on page 23

Volume 49 • Number 7 • July 2022

Continued on page 12

Pharmacists Help to Increase Access to OUD Medications

By David Wild

W

ith drug overdose deaths surging, it is imperative for pharmacists to help patients obtain opioid use disorder (OUD) treatment, and a number of programs are showing they can do just that.

“We’re experiencing the highest rates of fatal opioid overdoses ever recorded, and current levels of buprenorphine access simply do not meet the needs of people with OUD,” said Terri Jorgensen, RPh, a national program manager for clinical pharmacy practice integration and model advancement at the Veterans Health Administration (VA), in Washington, D.C. In 2021, the number of fatal drug overdoses in the United States reached approximately

NEW COLUMN! Tech Trends: What’s hot in the digital space?

See page 29.

110,000, with many cases involving either illicit or prescribed opioids, she noted.

“Thankfully, there are novel models of care out there that reduce barriers to access by using clinical pharmacists, and they are showing great promise in saving lives,” said Ms. Jorgensen, who moderated a session on the topic at the ASHP 2021 Midyear Clinical Meeting and Exhibition, held virtually.

Lowering Barriers Hildi Hagedorn, PhD, the director of the implementation core at the Minneapolis VA Health Care System’s Center for Care Delivery and Outcomes Research, is part of a team of investigators looking at one such model.

Continued on page 20

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 | 02/22

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

Operations & Management 5

Pharmacy Practice News • July 2022

Compounding

Don’t settle for minimum compliance

Aiming Low Not A Good Strategy For USP Success

By Karen Blum

Phoenix—As the pharmacy community awaits impending updates to USP General Chapters <795> and <797>, it would be wise to start adjusting compounding policies and procedures accordingly and to be aware of state requirements, speakers said at the 2022 ASHP Summer Meetings and Exhibition.

Revisions to chapters <795> and <797> were proposed in 2021 and are still being reviewed, said Patricia Kienle, RPh, MPA, BCSCP, the director of accreditation and medication safety at Cardinal Health. This means the 2014 version of <795> and the 2008 version of <797> are official. Chapter <800>, published in 2016, and <825> for radiopharmaceuticals (sidebar, page 7), published

in 2019, also are current. “Remember that these standards as written by USP are minimum standards,” Ms. Kienle noted. “The best practices that come out of what we all do drives improvement.”

Sterile-to-sterile compounding will undergo some nomenclature changes in the proposed revisions, to represent the areas where materials are prepared rather than ingredients. Low risk will be Category 1, for materials prepared in the segregated compounding area. Medium risk will be Category 2, for those prepared in cleanroom suites. A proposed Category 3 will cover materials prepared in the cleanroom suites using extended beyond-use dates (BUDs), and will add some significant personnel and facility monitoring and testing requirements.

‘You have to remember that these standards as written by USP are minimum standards. The best practices that come out of what we all do drives improvement.’

—Patricia Kienle, RPh, MPA, BCSCP Common questions arise regarding repackaging, Ms. Kienle said. This area of practice is not covered in <795> but rather, in an FDA guidance document, “Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities,” she noted (bit. ly/3xAzTpe). Even so, the requirements listed are enforceable by regulations

Training a Key Component of USP Compliance PHOENIX—Training and competency are the linchpin of safe sterile compounding—and a key to USP compliance, according to Patricia Kienle, RPh, MPA, BCSCP, the director of accreditation and medication safety at Cardinal Health.

“We can have all the greatest facilities; we can have all the greatest policies and procedures; but if we don’t have folks who are adequately trained and competent in what they’re doing, that’s a problem,” Ms. Kienle said. “They need to know not only what they need to do, but where things are starting to look suspicious and that need to be escalated.

This is absolutely the most important part” of training, she noted.

General Chapters <795>, <797> and <800> use the term “designated person” as the individual to oversee training competence and compliance with policies and procedures.

The proposed revisions also describe an “assigned trainer,” or someone responsible to the designated person to

oversee training. Compounding facilities may want to begin incorporating that component, Ms. Kienle said, encouraging pharmacy leaders to look at the proposed revisions.

Training also comes into play when ensuring compliance with USP revisions that include a list of necessary core skills, including proper hand hygiene, garbing, measuring and mixing, and the cleaning process, Ms. Kienle noted. Inspectors from state boards of pharmacy or surveyors from accrediting organizations that come in may ask for this information, she said. So, it’s a good idea to keep a continuing checklist of how you train pharmacy staff in these skills. If your organization does anything in an unusual manner, be prepared to explain it, she added, especially if it’s something that a surveyor or inspector might not have seen before.

Training needs to be conducted for everyone who enters the compounding area, Ms. Kienle stressed, not just for compounding staff. Consider what policies and procedures you’ll need for other pharmacists who may enter orders but are not involved with compounding; visiting inspectors and surveyors; students who observe; maintenance workers who may need to touch some surfaces or materials when making repairs; and environmental services personnel who clean the rooms.

As an example, Ms. Kienle mentioned an environmental services worker she observed at a facility, who rolled up a mat placed in front of a compounding preparation area and put it under the hood while cleaning the floor, unaware of the potential hazard.

—Karen Blum Ms. Kienle is an employee of Cardinal Health and a member of the USP Compounding Expert Committee. The comments in this article are her own.

in many states. Chapter <797> covers repackaging for drugs, diluents, containers and closures, while <800> covers repackaging regarding protections to workers from hazardous drug contamination.

When it comes to nonsterile compounding, Chapter <795> is the standard, but it should be recognized that every state board has regulations on compounding that can vary, Ms. Kienle said. She cited the following examples: • Avoid carpeting.

• Ensure no other activities are happening when compounding is occurring.

• If you have a containment ventilated enclosure, it needs to be certified at least once a year.

The proposed revision also states that training and documentation of competency should be done for personnel doing the compounding. Additionally, whereas gloves are required for nonsterile compounding, Ms. Kienle also recommended using face masks and hair covers. The sources of your components should be known, too. If there are chemicals or other components in your cabinets that are undated or have been there for years, they should be discarded appropriately. Water used should be purified or better. Many pharmacies use sterile water for irrigation, which is fine; however, she said, accreditors may question bottles of sterile water because they are intended for single use. From a best-practice perspective, consider adding a sticker that indicates the bottle is for nonsterile compounding only and establish a policy including when it must be discarded. see USP SUCCESS, page 6

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6 Operations & Management

Pharmacy Practice News • July 2022

Compounding

USP SUCCESS continued from page 5

The proposed revisions of <795> and <797> discuss activities related to water use because of a risk for microbial contamination. Managers should review the revisions for the types of dosage forms considered aqueous or not for a guideline of what to consider in their preparations, Ms. Kienle advised.

Compounding allergenic extracts is covered in Chapter <797> because they are sterile preparations. They can be

prepared in a cleanroom or segregated compounding area. Do not prepare them in the regular IV room, Ms. Kienle said, because that could introduce contaminants such as dander or mold. Chapter <797> revisions also state they can be prepared in an allergenic extracts compounding area, which is a designated space with a visible perimeter. It should be ascertained whether the allergenic extracts are being prepared for specific patients or not, she said, as that affects how the materials need to be handled.

For sterile best practices, consider

that BUDs in <797> are not defaults, Ms. Kienle said. Not all preparations can use the maximum BUDs; there may be stability issues that would require a shorter time. Furthermore, moving compounds from one storage temperature to another will change the BUD. Another area to watch is surface sampling, Ms. Kienle said. The current <797> chapter requires this action periodically, and it is usually done by a certifier. But the proposed revision requires monthly sampling, and it will affect all classified areas and pass-throughs

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opening into the classified areas. Make sure that’s included in your surface sampling plan, she said. Pharmacies will need instruction, media, an incubator and microbiology support.

Don’t Go It Alone Relying too heavily on one in-house “expert” for USP compliance is not a recipe for success, noted Caryn Belisle, RPh, MBA, the director of pharmacy regulatory compliance, quality and safety at Brigham and Women’s Hospital, in Boston. “Having dedicated staff focused on cleanroom compliance is imperative nowadays,” said Ms. Belisle, who was not part of the ASHP session. “You can’t expect your cleanroom manager to do it all. You need someone outside the cleanroom’s day-to-day operations who is focused on quality and compliance.

First, it’s just too much for one person to have to keep their eye on, and second, it’s always good to separate your quality from your operations when you are compounding significant amounts of product, either patient-specific or batch.”

Internal audits are also highly beneficial, Ms. Belisle added. “You can observe your trends in environmental monitoring, but you need to also get out of your chair and watch the staff gown and garb, and see how they’re behaving in the cleanroom. At Brigham, we perform monthly quality rounds” to ensure such quality control steps are being followed, she noted.

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Ms. Belisle reported no relevant financial disclosures. Ms. Kienle is an employee of Cardinal Health and a member of the USP Compounding Expert Committee. The comments in this article are her own.

Operations & Management 7

Pharmacy Practice News • July 2022

Compounding

Nuclear Pharmacy Demystified in USP <825> PHOENIX—Nuclear pharmacy can seem like a mysterious practice, but pharmacists who understand USP General Chapters <797> and <800> also can easily understand Chapter <825> concerning radiopharmaceuticals, presenters said at the 2022 ASHP Summer Meetings and Exhibition.

“This is still pharmacy,” Christopher deHoll, PharmD, the co-chair of the Pharmacy and Therapeutics Radiopharmaceutical Subcommittee at Moses H. Cone Memorial Hospital, in Greensboro, N.C., said. “A radiopharmaceutical is still a pharmaceutical. It’s everything you’ve studied and known. All we’re doing is adding a little radiation to it.”

Most hospitals use a centralized nuclear pharmacy contracted by the nuclear medicine department, Dr. deHoll said. Diagnostic imaging is the main use of radiopharmaceuticals, such as technetium-99m, which distributes to certain tissues and emits gamma radiation. This radioactivity enables visualization of perfusion, such as around the heart, or metabolism, helpful in monitoring cancer, he said, giving it an advantage over traditional imaging such as MRI or ultrasound.

About 90% of all radiopharmaceuticals are diagnostic, Dr. deHoll said.

The most commonly used products are Tc-99m sestamibi and Tc-99m tetrofosmin for myocardial perfusion, to indicate any areas of ischemia; Tc-99 medronate for skeletal imaging, to identify high metabolic activity from cancer, stress fractures, or other bone diseases or musculoskeletal traumas; and Tc-99m mebrofenin for gallbladder and other hepatobiliary imaging.

The remaining 10% of radiopharmaceuticals are used therapeutically, Dr. deHoll noted. These isotopes emit alpha or beta radiation and destroy areas of DNA and surrounding cells, such as sodium iodide I-131 for hyperthyroidism and some thyroid cancers.

The unique characteristics of radiopharmaceuticals make compliance with Chapter <797> “either difficult or impossible,” Dr. deHoll said. Although <797> addresses minimum standards and best practices for preparing compounded sterile preparations, 95% of radiopharmaceuticals are made aseptically as sterile products. Chapter <825> applies to all individuals who prepare and dispense radiopharmaceuticals, sterile or nonsterile.

The main difference between <797> and <825> is radiation safety, keeping radiation exposure as low as reasonably achievable (ALARA), Dr. deHoll noted. This precaution incorporates four principles: 1. time (minimizing handling time minimizes exposure); 2. distance (operators may use tongs or other remote handling tools); 3. shielding (using syringe shields or materials, such as lead and tungsten, to decrease radiation exposure); and 4. radiation contamination control, which incorporates use of vertical laminar airflow hoods to ensure

radioactive materials do not blow at the operators, and lead-lined barrels to dispose of used needles and other equipment.

There are some subtle differences in <825>, he said, including the following: • Materials must be prepared in a segregated radiopharmaceutical processing area, similar to a sterile compounding area but with a defined perimeter containing a primary engineering control (hood).

• All items must be wiped with

appropriate disinfectants except in instances that violate ALARA principles, such as wiping an unshielded source of radioactive material.

• Microbiological air and surface monitoring must be performed at the conclusion of processing, but before cleaning and disinfecting.

• Radiation safety procedures must be observed before cleaning and disinfecting.

Whenever a radiopharmaceutical is altered from the package insert into

another form, Dr. deHoll added, there must be a master formulation record listing the type of material, detailed procedure of what was done, and range of radioactivity, among other requirements.

Packaging and labeling also have some unique requirements, he said, including that materials must be in properly labeled shielding containers, and labels must show the radioactive hazard symbol.

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—Karen Blum Dr. deHoll reported no relevant financial disclosures.

8 Clinical

Pharmacy Practice News • July 2022

Oncology

New Options for Patients With Early-Stage Breast Ca

By Gina Shaw

Boston—Recent advances in the management of early-stage breast cancer include new options for aggressive forms of the disease and strategies for or sparing patients from at least some of the toxic effects of adjuvant chemotherr-apy, according to a wide-ranging update tee on these challenging patient populaations presented at the Hematology/ y/ Oncology Pharmacy Association 2022 2 annual meeting.

New Options for TripleNegative Disease Triple-negative breast cancer (TNBC), ), which is estrogen receptor–negative, e, progesterone receptor–negative and d HER2-negative, is considered particularr ly aggressive and, until recently, has had limited treatment options beyond traditional cytotoxic chemotherapy (Curr Treat Options Oncol 2019;20[11]:82).

But recent trials have demonstrated the potential for immunotherapy as an adjunct to chemotherapy in this population, noted Jeremy Pappacena, PharmD, BCOP, a clinical pharmacy specialist in hematology and oncology at Allegheny Health Network, in Pennsylvania.

In November 2020, the FDA approved pembrolizumab (Keytruda, Merck) for the treatment of unresectable locally advanced or metastatic TNBC that is programmed death ligand-1 (PD-L1)– positive. In July 2021, that approval was expanded to include high-risk (stage II-III) early-stage TNBC, whether or not the tumor is PD-L1–positive. The approval was based on the updated results of KEYNOTE-522, a phase 3 clinical trial comparing neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebo (Ann Oncol Oncol 2021;32[9]:1198-1200).

The pembrolizumab arm showed a statistically significant and clinically meaningful improvement in event-free survival (EFS), with a 36-month EFS rate of 84.5% (95% CI, 81.7%-86.9%) in the pembrolizumab group versus 76.8% (95% CI, 72.2%-80.7%) in the placebo group.

The EFS improvement was seen in both PD-L1–positive (hazard ratio [HR], 0.67) and PD-L1–negative (HR, 0.48) patients.

“The benefit was most pronounced in patients with node-positive disease,” Dr. Pappacena said. “There was also a favorable overall survival trend in the pembrolizumab group [HR, 0.72], but the data are still immature.”

The adverse event rate for nausea/ vomiting, diarrhea, peripheral neuropathy, febrile neutropenia and laboratory abnormalities was similar in both groups, but as expected, the pembrolizumab group had a significantly higher rate of

‘The data are very reassuring that seven years [of endocrine therapy in early-stage hormone-positive breast cancer] is a good target to aim for. For many patients, it doesn’t appear that there is much more to be gained by going beyond that duration.’

—Erica Mayer, MD, MPH immune-related adverse events than the (33.5% vs. 11 11.3%). placebo arm (33 5% vs 3%) “This regimen is now supported by NCCN [the National Comprehensive Cancer Network] and the American Society of Clinical Oncology [ASCO],” Dr. Pappacena said. He noted that there were two neoadjuvant chemotherapy regimen options: • paclitaxel 80 mg/m2 IV weekly plus carboplatin AUC (area under the free carboplatin plasma concentration vs. time curve) 5 mg IV every three weeks or AUC 1.5 mg IV weekly; or • doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 IV every three weeks plus cyclophosphamide 600 mg/m2 IV every three weeks.

“With the platinum-based regimen, clinicians should consider utilizing a weekly carboplatin schedule to reduce significant myelosuppression and maintain dose intensity and density,” he said.

Hormone-Positive Cancer A longstanding question in the management of early-stage hormone receptor–positive breast cancer has been which patients can safely be spared the toxic effects of adjuvant chemotherapy.

The use of gene expression assays has helped answer that question, and in February 2022, an interim analysis from the phase 3 RxPONDER trial provided more clarity. The study found that adding chemotherapy to endocrine therapy improved invasive disease–free survival (IDFS) among premenopausal—but not postmenopausal—women with hormone receptor–positive, node-positive breast cancer and a recurrence score of up to 25 on the Oncotype DX 21-gene assay (N Engl J Med 2021;385[25]:2336-2347).

Among premenopausal women, the HR for five-year IDFS with the addition of chemotherapy was 0.60, but much of this benefit was concentrated in the younger age group. Among women younger than 50 years, the HR for five-year IDFS was 0.48, but 0.98 in premenopausal women over 50. For postmenopausal women, by

contrast, co the HR for five-year IDFS with the ad addition off ch chemotherapy was ddi diti tion on o chem e ot othe hera rapy py w as 11.02.

02 “ASCO has just updated their guidelines to strongly recommend Oncotype DX in all node-negative and the majority of node-positive early-stage breast cancer patients,” Dr. Pappacena said.

Erica Mayer, MD, MPH, the director of breast cancer clinical research and an institute physician at Dana-Farber Cancer Institute, in Boston, offerred some caveats. “Although RxPONDER confirms no benefit from chemo in postmenopausal patients with lower Oncotype, sparing a large portion of the breast cancer patient population exposure to chemotherapy, the results in premenopausal patients are controversial,” she said in a separate interview. “Although there appeared to be benefit from chemotherapy in these patients regardless of Oncotype score, some of the apparent ‘benefit’ seen with chemotherapy may have been due to chemotherapy-induced ovarian suppression, a strategy which can provide substantial benefit in reducing risk of cancer recurrence. Use of Oncotype should be encouraged in post-menopausal patients and can be considered in select premenopausal patients with node-positive disease to guide decisions around use of chemotherapy.”

Another perennial question in the management of early-stage hormonepositive breast cancer has been duration of endocrine therapy. “In this population, the most important systemic therapy to reduce the risk of cancer recurrence is adjuvant endocrine therapy,” Dr. Mayer said. “Years ago, the duration of adjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor was established at five years; however, risks of cancer recurrence can extend beyond those initial five years, and multiple recent trials have studied extended therapy durations ranging from seven to 10 years.”

The most recent of those trials is ABCSG-16/SALSA, which found no difference in disease-free survival (HR, 0.99) or overall survival (HR, 1.02)

between women given seven years of treatment and those who continued treatment for 10 years (N Engl J Med 2021;385:395-405). SALSA randomized postmenopausal women younger than 80 p yyears of age with early-stage hormonepositive breast cancer who had already p rreceived five years of adjuvant endocrine ttherapy to an additional two years or ffive years of aromatase inhibitor therapy.

IIn addition to the comparable survival outcomes, there was no difference in o tthe risk for a contralateral or secondary primary cancer between the two groups. p The risk for clinical bone fracture, by T ccontrast, was significantly increased in tthe group that received an additional five yyears (HR, 1.35).

“This is a very important study, and the data are very reassuring that seven years is a good target to aim for,” Dr. Mayer said. “For many patients, it doesn’t appear that there is much more to be gained by going beyond that duration.”

She noted, however, that patients in this study overall were in a lower-risk group, with approximately 73% tumor stage I and 67% having no lymph node involvement. “For patients with higherrisk breast cancer, who are tolerating therapy well and are interested in a longer duration of therapy, it may be reasonable to extend up to 10 years. We do need to continue to personalize therapy.”

People with high-risk hormone-positive breast cancer also have a new treatment option. In October 2021, the FDA approved abemaciclib (Verzenio, Eli Lilly) in combination with endocrine therapy for the treatment of these patients, provided that they score at least 20% on a companion assay for the proliferation marker Ki-67. This approval was based on the monarchE trial, in which patients who received abemaciclib plus endocrine therapy had significantly improved twoyear IDFS (92.2% vs. 88.7%; P=0.01) and two-year distant recurrence–free survival (93.6% vs. 90.3%; P=0.01) compared with standard endocrine therapy alone (J Clin Oncol 2020;38[34]:3987-3998).

“The primary added side effect was diarrhea, which occurred in 82.2% of the patients in the abemaciclib arm versus 7.1% those given standard endocrine therapy,” Dr. Pappacena said. “Dose adjustments occurred in 68.1% of patients, and 16.6% discontinued treatment, so it’s important to prepare patients for this side effect.”

He noted that neutropenia was also increased in the abemaciclib group (44.6% vs. 5%), but the increase in neutropenia did not increase rates of infection.

Dr. Mayer served as a consultant to AstraZeneca, Eli Lilly, Gilead and Novartis.

Dr. Pappacena reported no relevant financial disclosures.

Clinical

Pharmacy Practice News • July 2022

9

Oncology

Supportive Care Best Practices for Glioblastoma

By Gina Shaw

Boston—Given the challenges of treatment and overall poor prognosis for newly diagnosed glioblastoma, oncology pharmacists play an essential role in optimizing treatment and supportive care to maintain the best possible quality of life for these patients for as long as possible, said Sara Moran Smith, PharmD, BCOP, the oncology pharmacy manager with M Health Fairview in Minnesota, during a session at the 2022 Hematology/Oncology Pharmacy Association annual conference.

qualify. But the standard of care remains debulking surgery followed by daily radiation and oral temozolomide for 6.5 weeks, and then a six-month regimen of oral temozolomide five days per month.

Typically, patients are started on a five-day dosing schedule of 150 mg/m2 of temozolomide during the first cycle of treatment, said Mallika P. Patel, PharmD, an oncology clinical pharmacist at the Preston Robert Tisch Brain Tumor Center at Duke Cancer Institute, in Durham, N.C., in a separate interview with Pharmacy Practice News. “We will

to standard therapy. In a 2019 trial, lomustine appeared to confer improved median OS (48.1 vs. 31.4 months; P=0.0492) compared with standard therapy alone, but it came at the cost of significantly increased toxicities, primarily myelosuppression and nausea (Lancet 2019;393[10172]:678-688).

“There were also a lot of shortcomings in this trial and the sample size was small, so the use of lomustine remains only a NCCN [National Comprehensive Cancer Network] category 2B recommendation for patients with good

skin irritation, as well as a quality-oflife burden because it has to be worn 18 hours a day.”

The Biggest Challenges “Some of the biggest challenges we see in supportive care for our patients with glioblastoma include neurocognitive issues, myelosuppression, nausea management and cerebral edema from the tumor itself and its sequelae, including headaches and seizures,” Dr. Patel said.

Among older patients and others with poor performance status who cannot tolerate the combined side effects of chemotherapy and radiation, Dr. Smith noted that several trials have supported the benefits of temozolomide alone for improved quality of life. As an example, she cited the ANOCEF (Association des Neuro-Oncologues d’Expression Francaise) trial of temozolomide alone in patients aged 70 years or older with a Karnofsky Performance Status (KPS) score less than 70. “With temozolomide alone, 33% of these patients improved their KPS by 10 or more points, while 26% became capable of self-care, which is really what we’re getting at,” she said (J Clin Oncol 2011;29[22]:3050-3055). “In the Nordic trial [Lancet Oncol 2012;13(9):916-926], overall survival was better with temozolomide and hypofractionated radiotherapy compared with standard radiotherapy in patients over 70 years old.

And the NOA-8 trial [Lancet Oncol 2012;13(7):707-715] teased out the importance of MGMT methylation, especially if the patient can only tolerate one type of treatment.”

Another Combination The addition of tumor-treating fields (TTFields) to standard therapy has been shown to extend survival for patients with newly diagnosed glioblastoma.

Source: Jove.

Such a management strategy requires a dynamic approach, despite the fact that treatments for glioblastoma have not changed significantly since 2005, when radiation therapy plus temozolomide (Temodar, Merck) chemotherapy replaced radiation therapy alone, Dr. Smith noted. “That’s not for lack of trying,” she said, citing nearly a dozen agents that have been studied in combination with standard treatment for glioblastoma over the last seven years alone.

“None of these resulted in progressionfree survival or overall survival [OS] improvements, and that list doesn’t include a number of other drugs abandoned earlier in clinical development.”

Because of the poor outcomes associated with glioblastoma, clinical trials are preferred for most patients who

monitor for both hematologic and nonhematologic toxicities, and if patients tolerate that first cycle well, increasing with subsequent cycles to 200 mg/m2 is common standard-of-care practice. This gets more drug to the tumor site, but many toxicities are dose-dependent.”

The DNA repair enzyme O(6)methylguanine-DNA methyltransferase (MGMT) plays a key role in drug metabolism. As a result, MGMT promoter methylation is arguably the most important molecular marker in glioblastoma, Dr. Smith noted. “This marker confers a survival advantage, because [MGMT-methylated patients] are more sensitive to alkylating agents,” she explained. For such patients, there is the option of adding one such agent, lomustine (Gleostine, NextSource),

performance status and methylated MGMT,” she said.

The addition of tumor-treating fields (TTFields) to standard therapy also has been shown to extend survival for patients with newly diagnosed glioblastoma, and was approved by the FDA for this indication in 2015. The clinical trial that led to the device’s approval found that median OS was 20.9 months in the TTFields-temozolomide group versus 16.0 months in the temozolomide-alone group (hazard ratio, 0.63; P<0.001) (JAMA 2017;318[23]:2306-2316).

“This is a wearable device attached to an electric field generator and battery pack that the patient carries around,” Dr. Smith said. “It disrupts mitosis and leads to tumor cell death. The only notable adverse effect is mild to moderate

Another treatment option for newly diagnosed glioblastoma patients with significant neurologic toxicities is the combination of temozolomide and bevacizumab (Avastin, Genentech).

“This is not for improvement of outcomes, but for quality of life,” Dr. Smith said. “Another ANOCEF trial focused on this combination found that 33% of patients became transiently capable of self-care; and cognition and quality of life, as measured by the Karnofsky score, significantly improved over time during treatment. So, for example, when you have a patient with significant neurologic symptoms, daily trips to the clinic for radiation are not a good thing, which is an argument for either temozolomide alone or temozolomide with bevacizumab in these patients” (Oncologist 2018;23[5]:524-e44).

“We know that bevacizumab can significantly and rapidly reduce patients’ cerebral edema caused by tumor see GLIOBLASTOMA, page 10

10 Clinical

Pharmacy Practice News • July 2022

Oncology

Neutropenic Fever Declines Amid COVID-19

By Gina Shaw

Orlando, Fla.—During the height of the COVID-19 pandemic, the seven hospitals affiliated with the University of Wisconsin (UW) Health experienced a significant decline in admissions for neutropenic fever (NF) among cancer patients.

UW Health pharmacists have found a reason for the fever falloff: a series of pandemic-related public health measures such as the use of barrier masks, quarantines and social distancing, public awareness campaigns, and access to rapid laboratory testing, they reported in a poster at the MAD-ID (Making a Difference in Infectious Diseases) 2022 annual conference.

Under normal conditions, NF is a frequent complicating condition in cancer patients, noted Courtney Baus, PharmD, a PGY-2 clinical pharmacy infectious diseases resident at UW Health and lead author of the poster. Neutropenic fever “occurs in up to 30% of patients with a solid tumor diagnosis receiving chemotherapy, and NF-associated admissions make up 5.2% of all cancer-associated hospitalizations,” Dr. Baus said.

After oncologists at UW Health noted that they had anecdotally observed less NF admissions during the pandemic period, Dr. Baus and her colleagues initiated a study consisting of the pre-pandemic period (September 2018-February

GLIOBLASTOMA continued from page 9

growth,” Dr. Patel agreed. “We have found that adding it for certain patients can really decrease symptom burden and improve their quality of life.”

Patients on temozolomide in combination with radiation are at high risk for infection. “Prophylaxis for Pneumocystis jiroveci pneumonia [PJP] is particularly important in this setting,” Dr. Smith said. Without prophylaxis, there is an increased risk for PJP, with an incidence of about 1% and a mortality rate of more than 50% (J Neurooncol 2003;63[3]:263-270). “Trimethoprimsulfamethoxazole DS [Bactrim, Roche] is recommended three times weekly, or pentamidine [Pentam, Fresenius Kabi] for those with Bactrim allergy. Even if your patient is on a single agent, you should monitor lymphocyte count, because significant lymphopenia can still result.”

Thrombocytopenia is the primary side effect that results in dose reductions and treatment discontinuation for patients on temozolomide and radiation, Dr. Smith warned. “Phase 3 clinical

2020) and pandemic period (March 2020-August 2021). All patients with a solid tumor diagnosis receiving chemotherapy regimens expected to cause neutropenia were included in the study’s “at risk of NF” population. Although the absolute number of patients with a solid tumor diagnosis receiving chemotherapy regimens associated with neutropenia was similar in both study periods (3,966 pre-pandemic vs. 4,317 during the pandemic), NF-associated admissions declined significantly: from 60 patients (1.5%) pre-pandemic to 28 during the pandemic (0.65%) (P<0.001).

Days on Rx Also Assessed The investigators also examined trends in antibiotic use over the same periods. Overall antimicrobial days on therapy (DOT) per 1,000 patient-days was similar between the study periods, although there was a 46% spike in DOT at the start of the pandemic. “That finding highlights the fact that we really didn’t know what we were dealing with at first,” Dr. Baus said. “Throughout the pandemic period, DOT have trended back to our standard baseline of antibiotic use.”

Patients undergoing cancer therapies “should continue to utilize nonpharmaceutical interventions such as masking and isolating to prevent NF admission, and that is certainly what

‘[Patients undergoing cancer therapies] should continue to utilize non-pharmaceutical interventions such as masking and isolating to prevent NF admission, and that is certainly what will be maintained at our institution.’

—Courtney Baus, PharmD will be maintained at our institution,” Dr. Baus said. The group also plans a subgroup analysis to determine whether there are any differences among cancer types or treatment regimens.

“One of our transplant providers would also like to investigate this

subject as well, as she feels that she has been seeing less rejection among her patients that could be attributable to these precautions.”

Dr. Baus reported no relevant financial disclosures.

‘Some of the biggest challenges we see in supportive care for our patients with glioblastoma include neurocognitive issues, myelosuppression, nausea management and cerebral edema from the tumor itself and its sequelae, including headaches and seizures.’

—Mallika P. Patel, PharmD trials have reported between 6% and 19% of patients with grade 3 or 4 thrombocytopenia, with a median onset of approximately 52 days and a median duration of approximately 32 days,” she said (Neurooncol 2007;9[1]:47-52). “In patients who can’t recover platelet counts, the phase 2 open-label PLATUM trial found that subcutaneous romiplostim [Nplate, Amgen] allowed 60% of patients to complete all six cycles of adjuvant temozolomide, so that’s a tool we can use to help them get through treatment” (Neurology 2019;93[19]:e1799-e1806).

Address Nausea Early It’s important to have good anti-nausea medications on board from the beginning of therapy, Dr. Smith noted. “We use ondansetron [Zofran, GSK]. Temozolomide must be taken on an empty

stomach, so we counsel our patients to take it at bedtime at least two hours after dinner, with the ondansetron 30 to 60 minutes prior. That can help them sleep through the worst of the nausea.

Constipation is another significant toxicity, especially during the chemoradiation phase. It’s not a matter of if but when, so you need to start the bowel regimen on the first day.”

Dr. Smith recommended one to two tablets of senna glycoside (available under a number of brand names) twice daily combined with docusate sodium, and one to two capfuls of polyethylene glycol 3350 (Miralax, Bayer) as needed with the goal of one soft bowel movement per day.

Seizure management also is essential, Dr. Patel said. “The medications we use are typically similar to those used in

patients with epilepsy, but the enzymeinducing antiepileptics tend to have a lot of interactions with other medications that our patients may be on, so we try to avoid that group and instead preferentially use something like levetiracetam [Keppra, UCB], which has fewer drug–drug interactions.”

The prognosis with glioblastoma remains poor, but there are a number of options for patients with poor performance status, Dr. Smith concluded. “It’s important for pharmacists to be closely involved with management of these patients and ensure that proper supportive care medications are on board before toxicities spiral out of control.”

Dr. Patel reported no relevant financial disclosures. Dr. Smith reported that she is on the speakers bureau of Karyopharm.

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12 Clinical

Pharmacy Practice News • July 2022

Pediatrics

PGx Tests a Boon in Kids continued from page 1

(Kalydeco, Vertex), which can only be prescribed in CF patients with CF transmembrane conductance regulator variants.

“It is also now highly encouraged that all investigational new drug applications to the FDA include pharmacogenomics information that can advise the labeling going forward,” Dr. Manzi said.

The BCH clinical pharmacogenomics

service, a collaboration between the Division of Genetics & Genomics and the Department of Pharmacy at BCH, averages about six clinic visits and 10 singlegene sequencing tests sent per week as well as five inpatient consults per month, she said. “Most of our patients have a complex history involving significant failure to respond to medications or a laundry list of adverse drug reactions

with the trial-and-error method,” Dr. Manzi said at ASHP’s 2021 Midyear Clinical Meeting and Exhibition.

Approximately 57% of patients have a significant finding from pharmacogenomic testing, according to internal data Dr. Manzi presented. “Another 36% of patients have no significant findings relative to the original question, but when we look at the entire panel, most of those patients have significant incidental results,” she said. “When you add it all up, over 92% of patients we see have an actionable result.”

Common Drug–Gene Pairs In addition to ivacaftor, there are multiple common drug–gene pairs that can influence medication selection in pediatric patients, Dr. Manzi noted. “For example, no one at BCH starts abacavir without HLA testing, because a severe Stevens-Johnson syndrome–type reaction can occur,” Dr. Manzi said.

As for which drugs are good candidates for pharmacogenomic testing prior to initiation, “they should have a narrow therapeutic index, with toxicity and effective dose closely related,” Dr. Manzi said. “For example, amoxicillin can have a very wide range of dosing and is not likely to result in toxicity, so testing wouldn’t be useful.

But for warfarin or phenytoin, the toxic and efficacious doses are very close and metabolism can make a difference.

There should also be published dosing and a validated, reliable assay.”

She cautioned that unlike a test such as a radiograph, pharmacogenomic results are revisable over time, meaning that pharmacists may have to reach out to a patient they haven’t seen in years as new information becomes available. “Guidelines can change, pharmacogenomic clinical activity definitions can change, and as a result, you may have to change what you’re telling your patients—for example, if a variant status has a new guideline based on emerging information.”

What Comes After Testing?

A

COMPANY

Pharmacogenomic testing sometimes can have broader familial implications that extend beyond the patient currently being assessed, said Cyrine-Eliana Haidar, PharmD, BCPS, a clinical pharmacogenomics coordinator at St. Jude Children’s Research Hospital, in Memphis, Tenn. “Most pharmacogenes have codominant inheritance patterns that don’t have implications for the patient’s family members, but some findings do have implications for full biological relatives,” Dr. Haidar said. Among the pharmacogenes that have dominant expressions, she noted, are HLA, which predisposes patients to skin reactions with certain medications; and mt-RNR1, which predisposes to immunoglycosideinduced autotoxicity. Then there are other genes that have X-linked inheritance, such as G6PD, she noted.

Dr. Haidar also discussed CACNA1S/ RYR1 and malignant hyperthermia, a potentially fatal hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine. “Because it has an autosomal dominant inheritance pattern, when we see this high-risk variant as a pharmacogenomic result, this means the person with the high-risk genotype inherited the allele from one of their parents,” she

Clinical

Pharmacy Practice News • July 2022

13

Pediatrics in a phenotypically male patient shows two G6PD alleles, it could suggest that the person has Klinefelter syndrome, a sex chromosome disorder in which a person has a total of 47 chromosomes instead of the normal 46. They are phenotypically male, because they have a Y chromosome, but they have two X chromosomes rather than one.

“Children with Klinefelter syndrome may have learning disabilities, delayed speech or delayed language development,” Dr. Haidar said. “They are also at higher risk of developing breast cancer,

systemic lupus or osteoporosis, disorders that we consider that females should be monitored for throughout their life.”

In such circumstances, who should be informed of the findings—the patient only, the patient and their family, only the patient’s medical team?

“There’s not one right answer to this question, but the majority of the medical genomic community would agree that the family and the patient should be informed if the patient is less than 18 years of age,” Dr. Haidar said, noting that such a step allows for proactive interventions for the

learning disabilities and other hallmark findings of the condition.

“Since this is an actionable finding that can help patients,” she said, “we will return that to the patient and their family members, and it’s up to them how to proceed, as is the case with so many of these disorders.”

Dr. Haidar reported no relevant financial disclosures. Dr. Manzi reported that she is a scientific advisory board member for Global Gene Corp and a consultant to Stoke Therapeutics.

Pharmacogenomic testing sometimes will yield a positive result for CACNA1S/ RYR1, which predisposes patients to malignant hyperthermia.

explained. “So, when we counsel the patient that they should not receive certain medications, such as inhaled fluorinated anesthetics, because of their risk of developing malignant hyperthermia, we also could provide genetic counseling to family members to explain to them what the implication of this positive test result is for their biological parents and full biological siblings, and offer cascade testing to the first-degree relatives.”

Institutions should have a process set up for handling such findings and discussions, approved by institutional leaders and oversight committees. Questions to be addressed include: • Should counseling of family members be performed?

• Should genotype testing of family members be offered?

• Should the institution follow up with family members in the event of a high-risk result?

• Who will pay for the genotype testing?

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Incidental Findings Often, when pharmacogenomic testing is done, the results include findings that are not related to the original reason the patient underwent testing.

Incidental findings are more likely to be discovered when panel pharmacogenomic testing is performed rather than a single-gene test.

One example, Dr. Haidar noted, is G6PD deficiency, an X-linked recessive disorder, and Klinefelter syndrome. “G6PD deficiency affects about 400 million people across the globe,” she said. “It affects males more than females, and causes hemolytic anemia when patients receive certain medications, eat fava beans or are triggered by certain infections.”

Because male individuals have only a single copy of the X chromosome, they have a single copy of the G6PD allele, while females have two X chromosomes and two copies. If the G6PD genotype

FIND OUT HOW

14 Clinical

Pharmacy Practice News • July 2022

ASHP Meeting

Med Errors Communication Preserves Patient Trust page about what to tell patients and families about the error. As such, it’s important that all front-line clinicians receive some training in communication about harm events.

By Karen Blum

Phoenix—Effective communication with patients and their family members is a critical but uncomfortable step that pharmacists and other care team members must take after a harm event. Done well, it can preserve trust in the healthcare system and potentially reduce clinician stress and legal or disciplinary actions, speakers said at the 2022 ASHP Summer Meetings and Exhibition.

Communication and resolution programs (CRPs)—principled, comprehensive, systematic and compassionate programs for preventing and responding to harm events—are an emerging best practice, said Thomas H. Gallagher, MD, MACP, a professor and an associate chair of the Department of Medicine at the University of Washington, in Seattle.

“In healthcare, all of us aspire to be open and honest with patients and families when there’s been a problem,” said Dr. Gallagher, also the director of the UW Medicine Center for Scholarship in Patient Care Quality and Safety.

“It’s certainly what we would expect as patients. But there are all sorts of reflexes and challenges that get in the way of turning that principle into practice.”

CRPs should involve several elements, he said, including immediate reporting of an incident by clinicians and ongoing transparent communication with patients and families. Events should be thoroughly analyzed and used for quality improvement. For the subset of harm events that occur because of error or system failure, health-system personnel

Truthful and Transparent

should make CRPs a proactive offer of financial resolution rather than waiting for them to file a malpractice claim.

These efforts shouldn’t just be focused on patient and family members, the speakers stressed: Involved caregivers also should immediately be offered some type of care or peer support.

Error Fallout Goes ‘On and On’ Patient and family advocates hate the term “resolution,” Dr. Gallagher noted, because for many of them, the events are never over. “They go on and on and affect multiple members of the family,” he said. “So, the notion that we’ve written a check, or we fix some little system problem, … that’s not at all how it works for the patients and families.”

The benefits of CRPs, when done well, are several, he added. They preserve trust and meet patient/family expectations, reduce clinical distress, reduce the likelihood of litigation or of disciplinary action by regulators, promote learning

within and across institutions, strengthen institutional culture and climate, and increase the public’s trust in healthcare.

A big challenge, however, is that organizations use CRPs inconsistently, applying them to some cases but not others, Dr. Gallagher said. Health systems might use the full approach for some cases or just some elements, such as telling a family what happened or what they plan to do to prevent recurrences, and then assume if a patient’s family is interested in financial compensation, they can just ask. “That’s not consistent with having a highly reliable CRP,” he said.

The way organizations respond initially to harm events is “absolutely critical,” he said. “Oftentimes we just want to go in and tell them what happened, and then run out of the room,” Dr. Gallagher said. “That’s not the approach we want to take. We want to hear what’s on their mind and give them timely responses.”

The work is a team effort, he added, with everyone needing to be on the same

Pharmacist JC Surveyor a Benefit to NCCN

By PPN Staff

Phoenix—The Joint Commission’s addition of a pharmacist to the survey process for certain healthcare facilities has added a new level of expertise and insight to the review of standards compliance for medication-related processes, two leaders of the group announced at the 2022 ASHP Summer Meetings and Exhibition.

Only healthcare organizations that are registered with the National Comprehensive Cancer Network (NCCN) are subject to surveys staffed by a pharmacist, according to a Joint Commission spokesperson.

The decision to add the pharmacist surveyor “is a game changer,” said Jeannell Mansur, PharmD, the principal consultant, medication management and safety, Joint Commission Resources. The expertise of the pharmacist surveyor should reap many benefits, she noted, given the significance that medication processes

play in patient safety.

As for why the pharmacist surveyor initiative is limited to NCCN hospitals, a Joint Commission spokesperson noted that the program “was the result of strong collaboration with the NCCN and their member organizations to better support our collective missions. As the Joint Commission continues to monitor this initiative, next steps will be determined.”

One challenging area that has come up during surveys is complex medication orders, Dr. Mansur noted. To ensure compliance with these medication orders, pharmacists should review policies to ensure they include the required elements for titration, range, taper and other orders for which the Joint Commission requires hospitals to maintain policies, she said.

Dr. Mansur pointed to block charting as one allowance that the Joint

Commission has published for titration orders. Block charting allows for more abbreviated documentation during urgent situations when titration medications are used, but which should not extend beyond four hours, she explained.

Dr. Mansur added that the Joint Commission does not prohibit the adjustment of a titration infusion dose once the patient has met the titration end points.

She also noted that the group does not require titration end points to maintain a maximum and a minimum.

Another Valued Team Member Besides adding a pharmacist surveyor, Dr. Mansur underscored the important role played by a different pharmacist on the Joint Commission team: co-presenter Robert Campbell, PharmD, the director of the Joint Commission’s Standard Interpretation Group. With his pharmacy

Being truthful and transparent about harms or medical errors as soon as possible is important not just for the families but also for practitioners, commented Natasha Nicol, PharmD, FASHP, moderator for the session and the director of global patient safety affairs at Cardinal Health in Houston. She speaks from experience, having been part of a team involved in a medication error years ago that resulted in the death of a 2-year-old girl.

Silence, or an attitude of keeping errors quiet or thinking what families don’t know won’t hurt them, “is so much more damaging to a practitioner in moving forward and being able to stay in the profession,” Dr. Nicol said. “We really need to learn how to communicate effectively when events happen…It’s really about doing the right thing, and at the end of the day knowing that something really terrible happened but we gave the dignity and respect that people deserve.”

It’s crucial to communicate with families throughout the process of reporting and analyzing events, she added. You don’t have to wait to have all of the information before disclosing a harm event to families.

Drs. Gallagher and Nicol reported no relevant financial disclosures.

representation, there is a better understanding of hospital medication issues within the Joint Commission, Dr. Mansur noted, adding: “I have seen medicationrelated issues get addressed more timely” due to his involvement. “We receive a lot of medication-related frequently asked questions for which the Joint Commission provides direction.”

As for his own take on what health systems should expect during surveys, Dr. Campbell stressed that medication management—although critically important—isn’t the only compliance area on which to focus. Regulations from the Occupational Safety and Health Administration (OSHA), for example, prohibit food and drink in areas exposed to blood and infectious or toxic materials. “[OSHA doesn’t] want to see you with one hand in a chest cavity and another eating a banana,” Dr. Campbell quipped.

The sources reported no relevant financial disclosures.

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16 Clinical

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Review Article Part 2

New and Emerging Options For Hypercholesterolemia Bempedoic acid, bempedoic acid plus ezetimibe, and inclisiran

T

C. MICHAEL WHITE, PHARMD, FCP, FCCP

his is a 2-part series designed to provide front-line

Distinguished Professor and Chair, Pharmacy Practice University of Connecticut School of Pharmacy Storrs, Connecticut

pharmacists with knowledge of how to use antihyperlipidemic drugs to reduce low-density lipoprotein (LDL).

The first installment described the most recent lipid guidelines from the American Heart Association/ American College of Cardiology, the role of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in therapy (bit.ly/3xHWhgp-PPN). This second installment explores 3 newer entrants that have been approved by the FDA for LDL cholesterol (LDL-C) reduction: bempedoic acid (Nexletol, Esperion), bempedoic acid plus ezetimibe (Nexlizet, Esperion), and inclisiran (Leqvio, Novartis). This article describes the pharmacologic mechanisms of action of these agents, as well as their pharmacokinetics/drug

interaction potential, and reviews their lipoprotein effects and adverse events.

Pharmacologic Mechanisms Bempedoic acid. Cholesterol in lipoproteins such as LDL and very low-density lipoprotein is created via the cholesterol cascade.1,2 Bempedoic acid blocks the enzyme ATP citrate lyase, which converts citrate into acetyl coenzyme A (CoA), which is subsequently converted into HMG-CoA (Figure). Statins block HMG-CoA reductase downstream, which prevents HMG-CoA from turning into mevalonate. Suppressing cholesterol synthesis with

Cholesterol creation

bempedoic acid, statins, or the combined agents triggers upregulation of LDL receptor expression by hepatocytes and increased clearance of circulating LDL.1,2 To exert their pharmacologic effects, bempedoic acid and its active metabolite (ESP15228) require activation by very long-chain acyl-CoA synthetase I (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively.1,2 ACSVL1 is present in hepatocytes but not myocytes, decreasing the risk for intramuscular suppression of the cholesterol cascade.1,2 Inclisiran. Inclisiran is a small interfering RNA (siRNA) product that contains antisense strands of RNA.

LDL receptor regulation

ACL enzyme

The siRNA enters hepatocytes after binding to asialoglycoprotein receptors on the cell surface.3-5 Once in the cytoplasm, the antisense RNA binds first to an RNA-induced silencing complex and then binds the messenger RNA (mRNA) strands for PCSK9 produced by the DNA in the nucleus (Figure). Reducing the number of mRNA strands reaching the ribosomes diminishes the production of new PCSK9 molecules. Moreover, PCSK9 cross-links LDL-LDL receptor complexes, forcing the LDL receptor to be broken down instead of being recycled. The diminution of available PCSK9 prolongs LDL receptor functionality at the cell surface and reduces circulating LDL concentrations.6 PCSK9 inhibitors work downstream from inclisiran’s effects by blocking PCSK9 from binding LDLLDL receptor complexes so it cannot facilitate lysosomal destruction of the LDL receptor.

Pharmacokinetics Net result: HMG-CoA reductase

Net result: Bempedoic acid and statins reduce formation of new cholesterol, and the body creates more LDLR on cell surface to pull more LDL out of circulation.

Inclisiran and PCSK9 monoclonal antibodies decrease PCSK9 + LDL complexes, enhancing LDLR recycling and LDLR numbers on the cell surface, where more LDL can be removed from circulation.

Figure. Complimentary mechanism of action for bempedoic acid, inclisiran, statins, and PCSK9 inhibitors in hepatocytes.

ACL, adenosine triphosphate citrate lyase; CoA, coenzyme A; LDL, low-density lipoprotein; LDLR, LDL receptor; mRNA, messenger RNA; PCSK9, proprotein convertase subtilisin/kexin type 9.

Based on references 1-6.

Bempedoic acid. In published studies, the maximum plasma concentration (Cmax) and area under the curve (AUC) of bempedoic acid are approximately 12 mcg/mL and 202 mcg*h/mL, respectively.3-5,7,8 The median time to maximum concentration (Tmax) is 3.0 hours. Following multiple-dose administration of bempedoic acid monotherapy, the steadystate Cmax and AUC at 180 mg per day are approximately 21 mcg/mL and 289 mcg*h/mL, respectively. Bempedoic acid steady-state pharmacokinetics are generally linear over a range of doses, and steady state is achieved after 7 days. The combination product yields similar pharmacokinetic parameters for bempedoic acid; however, the ezetimibe in the combination product has a Cmax that is 22%

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Review Article lower than ezetimibe monotherapy.

Taking bempedoic acid with a highfat, high-calorie breakfast reduces the Cmax by 30% and the Tmax is delayed by 2 hours, but this is not clinically meaningful. The bempedoic acid apparent volume of distribution is 18 L, and bempedoic acid and its active metabolite, ESP15228, are both over 99% protein bound. The mean elimination half-life for bempedoic acid is approximately 21 hours at steady state.

Bempedoic acid is eliminated primarily through acyl glucuronide metabolism, but the medication also is reversibly converted to ESP15228 based on aldo–keto reductase activity, with a plasma AUC metabolite/ parent drug ratio for ESP15228 of 18%. ESP15228 is converted to inactive glucuronide conjugates in vitro

by UGT2B7. Approximately 70% of the sum of bempedoic acid and its metabolites is recovered in urine and approximately 30% is recovered in feces. Less than 5% of bempedoic acid is eliminated unchanged in the urine and feces combined.3-5,7,8 Compared with patients who have normal renal function, the mean bempedoic acid exposures are 1.4- and 1.9-fold higher in patients with mild or moderate renal impairment versus those with normal renal function, respectively.3-5,7,8 These differences are not clinically significant. There are no data in severe renal impairment or end-stage renal disease on dialysis patients. Compared with patients who have normal hepatic function, the bempedoic acid mean Cmax and AUC are decreased by 11% and 22%, respectively, in patients with mild hepatic impairment, and by 14% and 16%, respectively, in patients with moderate hepatic impairment.

This difference should not impede bempedoic acid’s efficacy. Bempedoic acid has not been studied in patients with severe hepatic impairment (Child-Pugh class C).7,8

Drug Interaction Potential There are several important drug interactions with bempedoic acid or the bempedoic acid plus ezetimibe combination product (due to the ezetimibe constituent).7,8 Simvastatin and pravastatin.

Increased concentrations of simvastatin and pravastatin are associated with an increased risk for simvastatin- or pravastatin-related myopathy when used with bempedoic acid.

Do not use more than 20 mg of simvastatin or 40 mg of pravastatin with bempedoic acid. Of note, there are no known issues with atorvastatin or rosuvastatin, regardless of FDAapproved dosage.

Cyclosporine.

Cyclosporine increased exposure to ezetimibe in the combination product, which also could increase cyclosporine exposure. Monitor cyclosporine concentrations in patients receiving the combination product.

Fibrates. Coadministration of the combination product with fibrates other than fenofibrate is not recommended. Fenofibrate and the ezetimibe component may increase cholesterol excretion into the bile, leading to cholelithiasis.

Bile acid sequestrants. Cholestyramine may decrease ezetimibe concentrations, which may result in reduced efficacy. Administer the combination product either at least 2 hours before, or at least 4 hours after, bile acid sequestrants.

Inclisiran. Inclisiran exhibits approximately dose-proportional pharmacokinetics over the dose range of 24 to 756 mg following a single administration.3 Studies have shown that the medication’s Cmax is approximately equal to 4 hours after subcutaneous administration, with no detectable drug by 48 hours after single-dose administration. After multiple-dose administration, no accumulation was observed. Inclisiran is 87% bound to plasma proteins, with an apparent volume of distribution of approximately 500 L after subcutaneous administration of a single 284-mg dose to healthy adults.3 Inclisiran is metabolized primarily by nonspecific nucleases and is not a substrate, inhibitor, or inducer of the cytochrome P450 system.3 As such, no pharmacokinetic drug interactions with inclisiran are anticipated. Published data show no clinically meaningful interactions with atorvastatin or rosuvastatin. However, pharmacodynamic interactions, whereby lipoproteins are further reduced than with other cholesterol-lowering drugs, have been seen. Inclisiran has a terminal elimination half-life of approximately 9 hours, with only 16% being renally cleared.3 No dose adjustments are required in patients with mild (creatinine clearance [CrCl], 60-89 mL/min), moderate (CrCl, 30-59 mL/min), or severe (CrCl, 15-29 mL/min) renal impairment, with only 2.0- to 3.3-fold increases in inclisiran’s Cmax and 1.6- to 2.3-fold increases in AUC in severely impaired patients.3 LDL-C reductions were comparable across renal function groups. However, hemodialysis should be postponed for at least 72 hours after administration of inclisiran to prevent diminishing its effectiveness. In patients with mild to moderate hepatic impairment, no dose adjustments are required, with increases of

only 1.1- to 2.1-fold for Cmax and 1.3to 2.0-fold increases in AUC. Inclisiran was not studied in severe hepatic impairment (Child-Pugh class C), and therapy in these patients should be used with caution.3

Lipoprotein Concentrations Bempedoic acid. The FDA approved bempedoic acid and bempedoic acid plus ezetimibe for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL after employing maximum tolerated statin therapy, which could mean no statins prescribed for the intolerant.1 The FDA-approved dose is 180 mg administered orally once daily with or without 10 mg of ezetimibe. This approval is supported by the results of several phase 3 clinical trials.1

CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) HARMONY was a randomized, placebo-controlled trial of 2,230 patients with HeFH, ASCVD, or both.9 The mean age was 66.1 years, with a baseline mean LDL level of 103.2 mg/dL. Patients were randomized 2:1 to 180 mg of bempedoic acid daily or placebo. Patients had to be receiving maximally tolerated statin therapy, with an LDL level of at least 70 mg/dL. At 12 weeks, patients in the bempedoic acid group had their LDL level reduced 16.5% more than placebo (P<0.001).9 CLEAR WISDOM was a randomized, double-blind, placebo-controlled trial enrolling 1,049 patients with HeFH, ASCVD, or both.10 The mean age was 64.3 years, with a baseline mean LDL level of 120.4 mg/dL. Patients were randomized 2:1 to 180 mg of bempedoic acid daily or placebo. Patients had to be receiving maximally tolerated statin therapy with

a residual LDL of at least 70 mg/dL. The bempedoic acid treatment arm demonstrated a 15.1% reduction in LDL-C levels versus a 2.4% reduction with placebo (P<0.001). Non– high-density lipoprotein (non-HDL; –13.0%, P<0.001), total cholesterol (TC; –11.2%, P<0.001), and apolipiprotein B (apo B; –13.0%, P<0.001) were significantly reduced, as was the inflammatory marker highly specific C-reactive protein (hsCRP; –8.7%, P=0.04) compared with placebo.

CLEAR SERENITY was a double-blind, placebo-controlled trial of 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins.11 Patients with HeFH or ASCVD needed to have an LDL level of at least 100 mg/dL, but primary prevention patients could also be enrolled if their LDL-C level was at least 130 mg/dL. The mean age was 65.2 years, the baseline mean LDL level of 157.6 mg/dL, and 93% of patients had a history of statin-associated muscle symptoms. Patients were randomized 2:1 to 180 mg of bempedoic acid daily or placebo. The group receiving bempedoic acid had a 23.6% reduction in LDL-C levels versus a 1.3% reduction in the placebo treatment arm (P<0.001). Non-HDL (–18.6%; P<0.001), TC (–15.5%; P<0.001), apo B (–15.3%; P<0.001), and hsCRP (–28.1%; P<0.001) levels were significantly reduced versus placebo.

CLEAR TRANQUILITY was a randomized, double-blind, placebocontrolled trial of 269 patients with a history of statin intolerance and an LDL level of at least 100 mg/dL.12 Overall, 20% of patients had ASCVD, the mean age was 63.8 years, and the mean baseline LDL-C level was 127.6 mg/dL. All patients received a 4-week run-in with 10 mg of ezetimibe daily and were then randomized to 180 mg of bempedoic acid daily or placebo. The bempedoic acid group had a 23.5% reduction in LDL levels versus a 5.0% increase with placebo (P<0.001).

Non-HDL (–23.6%; P<0.001), TC (–18.0%; P<0.001), apo B (–19.3%; P<0.001), and hsCRP (–34.5%; P<0.001) were statistically lowered vs. placebo.

The final phase 3 study by Ballantyne et al was a double-blind, placebo-controlled trial of 301 patients with established HeFH, ASCVD, or multiple cardiovascular risk factors.13 Overall, 62.5% of participants had established ASCVD and/or HeFH, the mean age was 64.3 years, and most patients had a baseline LDL-C level greater than 130 mg/dL. All patients were randomized to the combination product of 180 mg of bempedoic acid plus 10 mg of ezetimibe daily, 180 mg of bempedoic acid see LIPIDS, page 18

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LIPIDS continued from page 17

daily, 10 mg of ezetimibe daily, or placebo. The bempedoic acid plus ezetimibe group had a 36.2% reduction in LDL-C levels versus a 17.2% reduction in the bempedoic acid arm (P<0.001), a 23.2% reduction in the ezetimibe arm (P<0.001), and a 1.0% increase in the placebo treatment arm (P<0.001).

For hsCRP, there was a 35.1% reduction with bempedoic acid plus ezetimibe versus 31.9% with bempedoic

acid (P>0.05), 8.2% in the ezetimibe arm (P=0.002), and a 21.6% increase with placebo (P<0.001).13 Inclisiran. Inclisiran is FDA approved as a treatment to be used along with diet and maximally tolerated statin therapy for adults with HeFH or ASCVD who require additional lowering of LDL.14 ORION-9 was a randomized (1:1), double-blind, placebo-controlled trial of 482 adults who had HeFH and received 300 mg of inclisiran sodium subcutaneously or matching placebo

on days 1, 90, 270, and 450.15 Overall, 90% of the patients were receiving statins, 75% received high-intensity statins, and over 50% received ezetimibe. The median age of the patients was 56 years, with a mean baseline level of LDL-C of 153 mg/ dL. At day 510, the LDL level was reduced by 39.7% in the inclisiran group and increased by 8.2% in the placebo group (P<0.001). Although statistical tests were not run, nonHDL (–43.6%), TC (–32.9%), and apo B (–36.9%) were reduced with only

a slight reduction in hsCRP (–4.0%) versus placebo.15 The ORION-10 and ORION-11 trials were reported together.16 A total of 1,561 and 1,617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Patients (mean age, 64.8-66.4 years, depending on trial and group) were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg subcutaneously) or matching placebo on days 1 and 90, and every 6 months thereafter for 540 days. Mean LDL levels at baseline were 104.7 and 105.5 mg/dL, respectively. Inclisiran reduced LDL-C levels by 52.3% (P<0.001) in the ORION-10 trial and by 49.9% (P<0.001) in the ORION11 trial. Non-HDL (–47.4, P<0.001; –43.3%, P<0.001), TC (–33.1%, P<0.001; –29.8%, P<0.001), and apo B (–43.1%, P<0.001; –38.9%, P<0.001) levels were significantly reduced more with inclisiran versus placebo.16

Adverse Events Bempedoic acid. The most common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials included upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza.7,8 Bempedoic acid may increase blood uric acid levels inducing hyperuricemia. Hyperuricemia may occur early after initiation, persist throughout treatment, and lead to the development of gout. Clinicians should assess uric acid levels periodically as clinically indicated, especially in those with a history of hyperuricemia; monitor for signs and symptoms of hyperuricemia; and initiate treatment with urate-lowering drugs as appropriate. Bempedoic acid rarely induced tendon rupture (0.5% of patients treated) versus placebo (0%), and the tendons attached to the shoulder joint, biceps, or calf (Achilles tendon) have been affected.

Tendon rupture may occur more frequently in patients over 60 years of age, patients taking corticosteroid or fluoroquinolone drugs, patients with renal failure, and patients with previous tendon disorders. Avoid bempedoic acid in patients who have a history of tendon disorders.7,8 Discontinue bempedoic acid products during pregnancy or breastfeeding because of its cholesterol cascade impeding mechanism of action.7,8 Like with statins, impeding the cholesterol cascade may be linked to fetal harm.

Inclisiran. Subcutaneous injection of inclisiran was generally safe and well tolerated.3 In the ORION-9,

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19

Review Article ORION-10, and ORION-11 clinical trials, adverse reactions at the injection site were seen most commonly (8.2% of inclisiran recipients vs 1.8% of placebo recipients), which included inclisiran injection site irritation (3.1%), pain (2.2%), redness (1.6%), and rash (0.7%).16 However, adverse reactions at the injection site rarely led to treatment discontinuation (0.2% with inclisiran vs 0.0% with placebo).16 Serious adverse events occurred in 20% of inclisiran patients compared with 23% of placebo recipients in phase 3 trials.3,15,16 Treatment-emergent adverse events led to treatment discontinuation in 2.5% of inclisiran recipients compared with 1.9% of placebo recipients. During the pivotal clinical trials, 4.9% of patients tested positive for anti-inclisiran antibodies over 18 months of inclisiran treatment, but neither safety nor efficacy differed in any clinically significant manner.3,15,16

inclisiran injections are only given periodically, there is a very low risk for pharmacokinetic drug interactions, and there is no increased risk for uric acid or tendon rupture associated with therapy.

5. Jahangir A, et al. Cureus. 2021;13(7):e16664.

6. Rashid S, et al. Proc Natl Acad Sci U S A. 2005;102(15):5374-5379.

7. Bendepoic acid [prescribing information].

Esperion Therapeutics; September 2021.

Accessed June 8, 2022. https://pi.esperion. com/nexletol/nexletol-pi.pdf

Marrs JC, et al. Drugs Context. 2020;9: 2020-6-5.

8. Bempedoic acid with ezetimibe [prescribing information]. Esperion Therapeutics; September 2021. Accessed June 8, 2022. https://pi.esperion.com/ nexletol/nexletol-pi.pdf

2. Di Minno A, et al. J Am Heart Assoc. 2020; 9:e01626.

9. Ray KK, et al. N Engl J Med. 2019;380(11): 1022-1032.

3. Lamb YN, et al. Drugs. 2021;81(3):389-395.

10. Goldberg AC, et al. JAMA. 2019;322(18): 1780-1788. [Published correction appears in JAMA. 2020;323(3):282].

References 1.

4. Cupido AJ, et al. Cardiovasc Res. 2020; 116(11):e136-e139.

11. Laufs U, et al. J Am Heart Assoc. 2019;8(7): e011662.

12. Ballantyne CM, et al. Atherosclerosis. 2018; 277:195-203.

13. Ballantyne CM, et al. Eur J Prev Cardiol.

2020;27(6):593-603.

14. FDA. FDA approves add on therapy to lower cholesterol among certain high risk adults. December 22, 2021. Accessed June 8, 2022. https://www.fda.gov/drugs/newsevents-human-drugs/fda-approves-addtherapy-lower-cholesterol-among-certainhigh-risk-adults 15. Raal FJ, et al. N Engl J Med. 2020;382(16): 1520-1530.

16. Ray KK, et al. N Engl J Med. 2020;382(16): 1507-1519.

Place in Therapy Bempedoic acid, bempedoic acid plus ezetimibe, and inclisiran offer new options for patients who require LDL lowering. Bempedoic acid works in the cholesterol cascade in a step preceding that of statins. Patients with HeFH or ASCVD require more intensive LDL lowering, and statins alone may not be able to achieve the patient’s goals due to their limited efficacy at maximum doses or from intolerance that precludes use or limits the statin doses that can be used. Bempedoic acid plus ezetimibe offers additional reductions in LDL levels with a similar safety profile to bempedoic acid alone and provides the convenience of a single pill instead of 2-pill therapy.

While therapy is well tolerated, the risk for hyperuricemia requires uric acid monitoring; the rare risk for tendon rupture and risk for drug interactions need to be appreciated. LDL levels can be reduced by 15% to 24% with the addition of bempedoic acid and by 36% with the combination of bempedoic acid with ezetimibe.

Inclisiran works by suppressing the production of PCSK9, which is a complementary mechanism to the PCSK9 monoclonal antibodies that prevent PCSK9 from binding to LDL receptors. Patients with HeFH, ASCVD, or those who are statin intolerant can benefit from the potent 40% to 52% reductions in LDL that inclisiran provides, but without causing the same extent of inflammation suppression as seen with bempedoic acid and bempedoic acid plus ezetimibe. Inclisiran requires subcutaneous injection instead of oral therapy, which yields injection site reactions that should be heeded. However,

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Pain Medicine

OUD Pharmacists continued from page 1

Dr. Hagedorn and her colleagues want to increase access to buprenorphine and other OUD medications in the primary care setting as well as at pain and mental health clinics. “Traditionally, within the VA, medications for OUD have been provided in specialty care settings for people with substance use disorders,” she said. “But there’s a need to expand access as much as possible.”

Clinical pharmacists involved in the Minneapolis program are partnering with physicians who have buprenorphine prescribing powers under a collaborative care agreement, specifically managing patients with chronic pain.

Under the agreement, pharmacists can prescribe naloxone but not buprenorphine, and they can prescribe nonopioid medications for pain as well as drugs for

opioid withdrawal and alcohol use disorder. They also: • coordinate social services; • assess medication efficacy and safety; • make necessary drug adjustments; • order and address urine drug screens; • query the prescription drug monitoring program database to reduce the risk for opioid-related harms; and • provide medication education to patients.

“The pharmacists provide important support to physicians, who already have large caseloads and might not

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have the time to follow up and support buprenorphine recipients as much as they would like to,” Dr. Hagedorn said.

Clinical pharmacists perform initial patient questionnaire-based screenings, then refer patients who screen positive for OUD to the partner prescriber for a diagnosis of OUD and obtain a prescription for buprenorphine. The pharmacist can then initiate treatment and provide regular follow-up appointments with the patient.

“The pharmacist might check in with the patient every week or few weeks at the start of treatment and reduce the frequency as the patient stabilizes, and the prescriber would only need to follow up in the clinic every six months to a year,” Dr. Hagedorn said.

A feasibility study published in 2021 looked at the effectiveness of the program. The researchers found that the percentage of Minneapolis VA Health Care System primary care patients with OUD who received medical OUD treatment increased from 33.8% during a three-month period in 2017, to 46.7% during a three-month period in 2019, after the program was rolled out (Am J Health Syst Pharm 2021;78[4]:354-359).

Of 109 patients managed by pharmacists during the post-implementation study period, 47 had their buprenorphine treatment initiated by the clinical pharmacist.

“The program demonstrated that clinical pharmacists can play a key and essential role in the management of patients with OUD,” Dr. Hagedron said. Not only does this benefit patients, “it allows for closer monitoring of patients than would otherwise fit within the prescriber’s scheduling capability,” Dr. Hagedorn noted. She added that the program’s success prompted the VHA to implement the model at other VA sites nationwide.

Transition of Care As an Opportunity Although new models of outpatient access to medications for OUD are being investigated in the community pharmacy setting, health-system pharmacists in the emergency department can play an important role in helping patients with OUD access treatment, said Courtney Givens, PharmD, the mental health and pain clinical pharmacy program manager at the VA North Texas Health Care System, in Dallas. She told ASHP attendees that 5.5% of patients admitted to the emergency department for a nonfatal opioid overdose succumb to a subsequent overdose within 12 months of discharge, and the highest risk for fatal overdose is in the first two to 30 days after discharge (Ann Emerg Med 2020;75[1]:13-17).

Clinical 21

Pharmacy Practice News • July 2022

E L I R E T S

Pain Medicine “It’s really important to act in a timely fashion and intervene in these patients, particularly to initiate buprenorphine in the emergency department,” Dr. Givens said. Doing so can increase levels of patient engagement in outpatient treatment more than when a patient is simply handed a referral for outpatient care and they leave the emergency department without starting buprenorphine and medications in hand, she noted (JAMA 2015;316[16]:1636-1644).

“Patients are often the most motivated during the transition of care, and we shouldn’t miss these opportunities for treatment engagement,” Dr. Givens stressed.

Reducing Stigma Another Care Component Providing more low-barrier, pharmacy-based access to medications for OUD could change the OUD treatment landscape and help control the ongoing opioid epidemic, but “addressing stigma may just be as important as anything else that pharmacists can do in practice,” said Tera Moore, PharmD, the national program manager of integration and

model advancement at the VA Administration, in Washington, D.C. “We challenge you to be leaders in change to eliminate stigma,” Dr. Moore told ASHP meeting attendees. “Whether it’s family members, other healthcare providers or patients themselves, always remind people that opioid use disorder—and other substance use disorders—should be thought of the same as any physical chronic disease.”

Jeffrey Bratberg, PharmD, a clinical professor at the University of Rhode Island, in Kingston, and a coordinator of the initiative, echoed this call to action. Dr. Bratberg added that the quality of pharmacist–patient interactions can have a profound impact on a patient’s willingness to engage in treatment. “One friendly, empathetic pharmacist treating a patient with OUD— whether they’re getting medication or buying syringes—can go a long way in getting them to engage in treatment.”

O M E H C HCL S T A M PREP ®

The sources reported no relevant financial disclosures.

More on the Web For a ‘no-barrier’ OUD community practice model, see expanded version on www. pharmacypracticenews.com.

6 Tips on Transitioning To Outpatient OUD Care

E

mergency department pharmacists and providers have a unique opportunity to help patients with opioid use disorder (OUD) receive treatment, according to Courtney Givens, PharmD, the mental health and pain clinical pharmacy program manager at the VA North Texas Health Care System, in Dallas. In addition to initiating buprenorphine in the emergency department, she shared some tips on how to increase the likelihood that patients will remain in treatment after their transition to the community or primary care setting.

Arrange follow-up. This can take some work in getting to know what resources are available to the patients served in your practice area and which providers are available to prescribe buprenorphine or other medications for OUD. Provide education. Engage the patient and make sure they know what their treatment options are. Empowering them can increase the likelihood of treatment retention.

Ensure continuity of treatment. If the patient is started on buprenorphine or other medications for OUD, make sure there’s a plan in place for how they will continue their therapy outside the hospital. Interruptions in therapy can be very detrimental and they increase the risk for overdose.

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Provide a warm handoff, when possible. Personalizing the experience for the patient and making sure they are presented to other providers as a unique individual can go a long way in making them feel valued and respected.

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Consider a harm reduction approach. Ensure patients have the resources they need to protect themselves and prevent worst-case scenarios, rather than simply aiming to achieve opioid use abstinence.

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Pharmacy Practice News • July 2022

COVID-19 Pandemic Table. The Ups and Downs of CYP3A4 Drug Interactions

Paxlovid: Know the Risks continued from page 1

Jason Gallagher, PharmD, BCPS, a clinical professor at Temple University School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital, in Philadelphia, said there are, without a doubt, instances when not prescribing nirmatrelvir-ritonavir is completely justified. “Sometimes interactions exist that are manageable, and sometimes there are interactions that preclude the use of the combination altogether,” he said.

There are sufficient resources available to help practitioners make the right decisions about prescribing nirmatrelvir-ritonavir to the patients who may benefit, Dr. Gallagher noted.

That position was echoed by Melanie Thompson, MD, the co-chair of the HIVMA/IDSA HIV Primary Care Guidance Panel, during the briefing.

Last December, the FDA issued an emergency use authorization for Pfizer’s oral tablets for adults and children 12 years of age and older and weighing at least 88 pounds who have tested positive for SARS-CoV-2 and are at high risk for hospitalization and death.

dispensing the medication to reduce the severity of COVID-19 is crucial.

The guidelines (bit.ly/3zgoMnL) help reduce confusion over nirmatrelvirritonavir to speed administration during the critical period following the presentation of symptoms.

Dr. Gallagher stressed the importance of the guidelines and education, because some patients may receive their routine medications from one pharmacy while receiving nirmatrelvirritonavir from another. And if “those two pharmacies aren’t talking to each other, there is obviously the concern that something could be missed.”

Of the top 100 prescribed drugs, the guidelines flag only two—rivaroxaban and salmeterol— that have interactions so severe that nirmatrelvir-ritonavir should be avoided altogether. Dr. Gallagher said the interaction

‘Sometimes interactions exist that are manageable, and sometimes there are interactions that preclude the use of the combination altogether.’

—Jason Gallagher, PharmD Nirmatrelvir-ritonavir should be administered within five days of symptom onset, and can be prescribed to people who have been vaccinated and boosted. The FDA issued a variety of videos and fact sheets on the regimen, including a healthcare provider fact sheet (bit.ly/3MgLlf4), which details interactions due to CYP3A4 drug metabolism (Table) and other considerations affecting medication management.

Dr. Gallagher said nirmatrelvirritonavir only works on the viral phase of the disease. The timing for

with these commonly prescribed medications might be managed by withholding them during the short course of nirmatrelvir-ritonavir treatment, if that can be done without severely adversely affecting the patient.

Dr. Thompson said drug interactions with nirmatrelvir-ritonavir are mostly manageable but not necessarily easy.

“One of the things that IDSA has done so well with the guidance is to really spotlight the commonly used drugs. I think this will be very helpful to clinicians,” she said.

Special Dosing Considerations: Renal Function eGFR 30 to 59 mL/min: Nirmatrelvir 150 mg and ritonavir 100 mg taken together orally twice daily for 5 days. eGFR <30 mL/min: Nirmatrelvir-ritonavir is not recommended.

Severe hepatic impairment (Child-Pugh class C): Nirmatrelvir-ritonavir is not recommended. eGFR, estimated glomerular filtration rate.

Source: University of Waterloo School of Pharmacy; bit.ly/3Nfux9C.

Nirmatrelvir and ritonavir are both CYP3A4 substrates. Thus, the combination is contraindicated in patients taking medications that are: • highly metabolized by CYP3A4, where elevated concentrations can be life-threatening; and • potent CYP3A4 inducers, which may reduce the efficacy of nirmatrelvirritonavir and contribute to the development of drug resistance.

Drugs That Cause Reduced Concentrations

Drugs That Cause Elevated Nirmatrelvir-Ritonavir Concentrations • Alpha1-adrenoreceptor antagonist: alfuzosin • Analgesics: pethidine, propoxyphene • Antianginal: ranolazine • Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine • Anti-gout: colchicine • Antipsychotics: lurasidone, pimozide, clozapine • Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine • HMG-CoA reductase inhibitors: lovastatin, simvastatin • PDE5 inhibitor: sildenafil when used for PAH • Sedative/hypnotics: triazolam, oral midazolam

• Anticancer drugs: apalutamide • Anticonvulsant: carbamazepine, phenobarbital, phenytoin antimycobacterials: rifampin • Herbal products: St. John’s wort (hypericum perforatum)

CYP3A4, cytochrome P450 3A4; HMG-CoA, hydroxy-methylglutaryl-CoA; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase-5.

Source: University of Waterloo School of Pharmacy (bit.ly/3Nfux9C); FDA Fact Sheet (bit.ly/3MgLlf4).

However, she said, many of the less frequently prescribed medications also have very important interactions with nirmatrelvir-ritonavir. They are not listed in the IDSA guidelines, “which is where all the complexity really comes in,” she said.

Dr. Thompson said ritonavir boosts the levels of many drugs, which can cause side effects, such as toxicities.

But some drugs are inducers instead of inhibitors that actually can diminish nirmatrelvir-ritonavir’s efficacy, and they are handled differently.

“Some of the drugs whose concentrations are increased by ritonavir can either be held or the dose can be reduced, so the side effects can be managed by holding the drug, changing the drug or dose reduction,” Dr. Thompson said. “There are a few drugs, the inducers, that will lower levels of nirmatrelvir-ritonavir and threaten its efficacy. Their activity lasts several weeks even after being stopped, so nirmatrelvir-ritonavir cannot be used if these drugs have been taken recently. Some seizure medications and tuberculosis medications are strong inducers.”

Dr. Thompson listed a variety of medications that are not among the top 100 prescribed drugs that have interactions with nirmatrelvir-ritonavir, such as antiarrhythmics, seizure medications, immunosuppressants, cancer drugs, migraine

medications, treatments for gout, pulmonary hypertension medications and some mental health drugs. Even St. John’s wort, which is an herbal remedy often used for depression, is a strong inducer, and nirmatrelvir-ritonavir cannot be used within two weeks of the last dose of the herb, she said.

“Some drugs just can’t be used, while others can be managed with dose changes,” she said. “This is an area where I think clinicians are going to need help. We don’t want clinicians to say, ‘Oh, I’m not going to bother with it because it’s way too complicated.’ We can all learn this. It’s something that you don’t have to memorize. There are resources that are very helpful in terms of drug interactions.”

In addition to the IDSA guidelines, Dr. Thompson highlighted two additional valuable sources, both of which focus on COVID-19 drug interactions.

One is from the University of Liverpool, England, which is famous for its pharmacology department (bit.ly/3ami7xQ).

“It has a wonderful drug interaction website for COVID-19 drugs,” she said. The other, from the University of Waterloo in Ontario, Canada, “has a really good handout [bit.ly/3Nfux9C] that you can print out, preferably in color, to cover drug interactions.”

As for risk stratification, older patients need special attention, Dr. Thompson said, because “they [have] the most comorbidities and are precisely the population most likely to benefit from Paxlovid. But they’re also the most likely to be on the most drugs.

This becomes very complicated.”

Dr. Thompson stressed, “We need a 24/7 clinician hotline for Paxlovid.”

The sources reported no relevant financial disclosures.

Clinical

Pharmacy Practice News • July 2022

23

COVID-19 Pandemic

Pediatric COVID-19 Label Mix-Ups continued from page 1

pharmacists, pediatricians and parents to a March 29, 2021 congressional report “Initially, sites should have no problem in the fight against the COVID-19 pan- (bit.ly/3R9bCQd-PPN). (As an example, using the 10 doses [in each vial] in six demic, which is why the two mRNA on June 29 Pfizer announced a new hours, but as interest in vaccinating this vaccines by Pfizer-BioNTech and Mod- vaccine supply agreement with the U.S. age group declines, there will be wasted erna are now recommended for chil- government that includes 3-mcg doses vaccine, even if a 12-hour in-use time is followed.” valued at $3.2 billion.) dren as young as 6 months old.

“The labeled six-hour in-use time However, the vial label for the PfizerBioNTech vaccine meant for this age may lead to waste,” said Michael Ganio, Moderna Discrepancy group and the box label for the Mod- PharmD, MS, the senior director of Moderna’s inconsistency occurs on erna vaccine meant for children 6 to Pharmacy Practice and Quality at ASHP. the purple box for children 6 to 11 years 11 could cause confusion—and actually hinder this vaccination mission, according to the experts interviewed.

old. The pink box for those 6 months to 5 years is correctly labeled, Moderna said in an email.

The purple box label says the bottle contains “booster” doses, rather than vaccines to be used for the primary series in children 6 to 11 years.

This could lead to someone believing they have the wrong product and not providing people with vaccination, according to Mr. Cohen.

“These discrepancies really bother me,” said Mr. Cohen, who has dedicated his life see LABEL MIX-UPS, page 24

2 Pfizer-BioNTech Discrepancies The Pfizer-BioNTech vaccine label has two discrepancies.

The first concerns the age of vaccination. The label says the vaccine should be used for children “2y to <5y,” when it should, in fact, be used for children as young as 6 months old.

What could happen, according to experts, is that clinicians will see that label, believe they have the incorrect product and send the child home without being vaccinated. Parents would have to bring their infants and toddlers back. Many might not.

“I [fear that] people are going to pick up the vial that says it’s for a 2-year through 5-year-old, and they are just going to think, ‘This is not appropriate for a 12-month-old or an 18-month-old, or a 6-month-old.’ They are going to [assume] they got the wrong [vaccine]. It is going to delay vaccination, and it is going to inconvenience people,” said Michael Cohen, RPh, MS, ScD (hon.), DPS (hon.), the founder and president emeritus of the Institute for Safe Medication Practices.

Buddy Creech, MD, MPH, the Edie Carell Johnson Chair and a professor of pediatrics in the Division of Pediatric Infectious Diseases at Vanderbilt University School of Medicine, in Nashville, Tenn., agreed that the labeling is problematic. “Since the dosing is the same for 6 months to under 5 years [as it is for those 5 years and older], thankfully, we shouldn’t run into errors; however, vaccine waste is definitely an issue,” he said. “I can see clinics following the label, drawing up vaccine at 8 a.m. and discarding by 2 p.m., since that is what the label says.”

Dr. Creech’s comment on waste highlights the second label discrepancy.

The label says the vaccine should be discarded after six hours, when it actually can be discarded after 12 hours, according to the CDC (bit.ly/3RmzwI2).

This could be a very expensive error.

Although patients are not paying for COVID-19 vaccines or their administration, the government has spent hundreds of billions of dollars to develop, purchase and administer the vaccines, according

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24 Policy

Pharmacy Practice News • July 2022

COVID-19 Pandemic

LABEL MIX-UPS

cause an administration error, since no ages. I hope this label is being corrected other vaccine can be used for children as soon as possible.” continued from page 23 However, it does not appear as if under 2 years old,” Dr. Ganio said. “Howto helping people avoid making errors in ever, as noted, it may lead to confusion the label is being corrected—at least the healthcare system. “They [clinicians] and possibly delay vaccination. Age- not immediately, according to the CDC, are going to think they have the wrong related vaccine mix-ups have been the which said it was also concerned about [vaccine], so it is going to delay [vaccina- most common vaccination errors, so it the discrepancies. “This mislabeled prodwill be important for vaccinators to be uct may cause confusion,” said Elisha tion] and inconvenience people,” he said.

Hall, PhD, the clinical guidelines lead at Experts told Pharmacy Practice News aware of this discrepancy.”

Jason G. Newland, MD, MEd, a pro- CDC. Dr. Hall was scheduled to present that the labeling isn’t likely to cause an administration error or safety issue, but fessor of pediatrics at Washington Uni- the label information at a June Advisory The CDC instead cited the potential for missed versity in St. Louis, agreed that these Committee on Immunization Practices worklabeling discrepancies “obviously will (ACIP) meeting, but could not, so CDC’s “is vaccinations and waste. ing diligently “We would not expect the labeling to result in [vaccine] not being used for all Sara Oliver, MD, MPH, presented it. to communicate information about the label to vaccine providers to avoid and correct any confusion,” Dr. Hall told Pharmacy Practice News. (See box.)

The correct label will appear on vaccine vials manufactured after the EUA was granted for this age group, Pfizer stated in an email.

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At the ACIP meeting, ACIP member Sarah S. Long, MD, a professor of pediatrics at Drexel University College of Medicine, in Philadelphia, suggested the company print new labels with an adhesive back that could be placed over the incorrect information, but there was no indication that that would be done.

The FDA, which did not respond to multiple requests for comment, also has provided information about this label discrepancy on the first page of the emergency use authorization (EUA) fact sheet for healthcare providers in bold print (bit.ly/3nD52nk).

Mr. Cohen said the Pfizer-BioNTech label for 2-year-olds has been available and discussed since December 2021, so he is unsure why that label is being used.

“I never thought the 2-year label would be used as a label for those vials [for 6-month-olds].”

Dr. Creech said good communication, such as the CDC is doing, as well as training should improve the situation and ensure that children are vaccinated.

“Realistically, I think these are preventable issues.”

However, both Drs. Newland and Long said the complicated logistics involved in getting a vaccine from the

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The Moderna box for its COVID-19 vaccine says the bottle contains “booster” doses, rather than telling clinicians it should be used for the primary series in children 6 to 11 years.

Policy 25

Pharmacy Practice News • July 2022

COVID-19 Pandemic allowed,” he said, “but the product is “Given the at-risk manufacturing, labels not an FDA-approved product; it is an on the doses initially shipped after the EUA may not reflect the final age group EUA product.”

Pfizer also cited the EUA process authorized by the FDA or the final as a partial explanation for the label authorized storage conditions.”

Pfizer also stressed that the vaccine discrepancies. “In order to ensure rapid access to the Pfizer-BioNTech doses “meet all the appropriate stanCOVID-19 vaccine for ages 6 months to dards and authorizations,” and reiterless than 5 years as soon as possible fol- ated that “the updated labels have been lowing the FDA granting an [EUA], the applied to all doses manufactured since companies manufactured and labelled the EUA was granted.”

Mr. Cohen said throughout the pandoses at-risk—as has been the case with all previous formulations of the demic, information about the EUA vaccine,” the company said in the email. products has changed, and the FDA has

manufacturer to the physician’s office, pharmacy or vaccination center into a patient’s arm could be a hindrance to any type of communication.

“It is a challenge to reach every practice/other site where vaccinations may be given,” said Dr. Long, who added that she has received several missives from the producers to be aware of these issues.

updated fact sheets and sent announcements highlighting the changes. These steps were taken repeatedly for the monoclonal antibodies as their efficacy changed against different variants.

“So, changes in some of the information is not unusual,” he said. “But I have not seen a label discrepancy like this before.”

Dr. Creech is a principal investigator for the KidCOVE study by Moderna, with NIH funding. The other sources reported no relevant financial disclosures.

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EUA Versus Approval The FDA would never have let these types of packaging inconsistencies fly with an approved product, according to Mr. Cohen. “Absolutely, for an approved product, this would never be

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Highlighted the COVID-19 vaccine labeling discrepancies on multiple webinars and calls that have been “highly attended,” and distributed written information to attendees; Posted its Interim Clinical Considerations for Use of COVID-19 Vaccines, which includes information about the label error (bit.ly/3NF6qAl).

Provided printable products that include a storage and handling label (bit.ly/3R9NPj0) with the correct age and beyonduse time that can be put on the vaccine carton, as well as a printable infographic (bit. ly/3IdYPaW) providers can hang in their designated vaccine preparation area to reminder vaccinators about the label discrepancy.

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26 Technology

Pharmacy Practice News • July 2022

Automation IV-WMS and robotics:

9 Steps for Implementing Tech Solutions in the IV Room

By Gina Shaw

Phoenix—At least nine different IV workflow management systems (IVWMS) and seven different IV robotics systems are available for hospital pharmacies’ IV compounding needs as of this summer. Choosing the right one depends on several key factors that technology leaders should heed when evaluating a purchase, two compounding experts noted at the 2022 ASHP Summer Meetings and Exhibition.

The technology ranges from basic, affordable but still very functional systems to multimillion-dollar, fully automated robotic IV compounding systems, noted Michael Freudiger, PharmD, the compounding and regulatory compliance supervisor at Valley Children’s Healthcare, in Madera, Calif.

“What you select will depend on your institution’s needs, but it is common sense that any hospital that does IV compounding should have at least one of these solutions,” Dr. Freudiger told Pharmacy Practice News. “IV workflow management systems may not be mandated as of yet, but they should be the industry standard.”

Dr. Freudiger and Patricia Kienle, RPh, MPA, BCSCP, the director of Accreditation and Medication Safety for Cardinal Health, offered nine recommendations for choosing the right IV-WMS and/or robotics system:

Do a gap analysis. “Bring together a team to assess where errors are most likely to occur in your IV compounding setup based on your work practices,” Ms. Kienle said. “That team should ideally include not only leadership from the pharmacy, but also the risk manager for your facility, who likely knows about safety gaps that have occurred that may be confidential to the rest of the organization. They see the bigger picture.”

Ms. Kienle also advised involving nursing expertise, including an infection control nurse and, if you have a significant oncology practice, an oncology nurse. “These nurses can see gaps from an end-user perspective that may be missed in the pharmacy.”

Know your options (see Table 1) and use a scorecard to rate them. “After you’ve assessed your system’s needs, review the available technologies and see where those systems would line up with your requirements,” Dr. Freudiger said. For IV-WMS, he suggested starting with several fundamental desired features, including barcode scanning and automation (a must); gravimetric verification, which the Institute for Safe Medication Practices (ISMP) states is optimal; electronic documentation for remote verification; dose tracking; and integration with other systems.

“That last item can be particularly variable and institution-specific,” he said.

Table 1. What’s Currently in Use IV workflow management systems • BD Pyxis IV Prep (Becton Dickinson)—formerly BD Cato • IVX Workflow (Omnicell) • i.v.SOFT Assist (Omnicell)—discontinueda • DoseEdge (Baxter) • Dispense Prep (Epic) • PharmacyKeeper (Grifols) • Assure-Trak (ConsortiEX) • DrugCam (Eurekam) • Diana Compounding Workflow System (ICU Medical) IV robotic systems • APOTECAchemo (Loccioni) • RIVA (ARxIUM; Intelligent Hospital Systems) • INTELLIFILL I.V. (Baxa Healthcare)—discontinued

A don’t-miss resource for health systems interested in specialty pharmaceuticals and services.

• Equashield Pro (Equashield LLC) (CSTD robot) • KIRO Oncology (Grifols USA) • i.v.STATION (Omnicell) • i.v.STATION ONCO (Omnicell)

Brought to you by the same team who publish

• IVX Station (Omnicell)—new in 2022 a

Discontinued systems are included if they are still deployed in health systems.

CSTD, closed system drug-transfer device Source: Michael Freudiger, PharmD.

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Pharmacy Practice News • July 2022

Automation Table 2. The Pros and Cons of IV Robotic Systems Benefits • Increase patient safety (medication safety) • Standardize products to meet the hospital’s needs • Create a more reliable supply of compounded preparations (less need for premade products) • Batch produce high-use (high-volume) preparations • Control and reduce costs; reduce waste • Reduce the workloads from manual (human) compounding • Record all steps of production process • Increased efficiency in workflow • Bags from 25–1,000 mL can be produced quickly • Syringes from 0.3–60 mL can be produced quickly • Gravimetric checks of stock items with barcodes • Step-by-step checks during compounding • Step-by-step photo log of each compounding step • Internal automated labeling of the final product • Some robots can compound hazardous drugs Disadvantages • Time to prepare products can be slower in some situations • More employee training involved • Higher costs (should be offset by savings) • Need for frequent updates to drug libraries Source: Michael Freudiger, PharmD.

“Everyone will have a different combination of electronic health records and other technologies at their hospital, so check with the vendor to see if it integrates with what you have.” You can then add other items to your scorecard that might be helpful to have, such as integration with other hardware, realtime video recognition of drug vials and syringe volumes, or incorporation of closed system drug-transfer devices for chemotherapy, he noted.

Understand the capital requirements. The cost of these systems can range from the low five figures for a basic IV-WMS to well over $1 million for IV robots. “You need to convince your hospital administration of the need to make these technologies a budget priority, and that best practices are evolving fairly quickly because of the growing number of systems that are out there,” Ms. Kienle said. If you’re putting an IV robot system in place, continuing costs also are significant. “You will also need an annual budget for maintenance and replacement parts, calibration of the equipment, cleaning of machinery, personnel, training of new staff, and training of the robot or robots for new drug vials,” Dr. Freudiger said.

For robotic systems, consider return on investment. “The significant costs associated with an IV robot mean that you have to make a lot of product for it to be a good return on your investment,” Dr. Freudiger noted. “In a large hospital or healthcare system, a robot makes a lot of sense because it will allow you to produce enough preparations to reduce your reliance on outsourced products. If you only make a handful of IV preparations per day, however, you are probably better off with a

good IV workflow management system alone. With robots, you also need to think about space—many of these systems are extremely large—and how you will physically get it into your facility.”

Assess staffing. For most IVWMS, you probably don’t need any new staffing, but training of existing staff should be a priority. “With IV workflow systems, you buy it, put it in the hood, get training on the program and follow the steps. It alters your methods but not that much,” Dr. Freudiger said. “The robot, on the other hand, requires a whole new dedicated staff to operate and maintain it.”

Prepare an implementation plan.

“Review your pharmacy sterile products workloads and identify your needs based on your patient population,” he said. “You will want to coordinate with your IT department, particularly networking, and consider extra staffing during the implementation period. Develop a very detailed calendar with all the steps involved, and consult with the vendor on your time line for implementation.”

Go live gradually. “Formulate a plan for starting with a few highvolume use products and do a gradual ‘go-live’ with the systems,” Dr. Freudiger said.

Expect system downtime and have a backup plan. “We know that IV workflow and IV robotics systems will go down at times, so don’t make the mistake of replacing your current system with this technology and forgetting how to do things the old-fashioned way,” Dr. Freudiger noted. “Put a backup plan in place for unexpected downtime, and practice your backup plan every three to six months. If the system goes down, could you still function?”

Understand and prepare to overcome potential barriers to success. For IV robot systems, Dr. Freudiger said, obstacles can include inadequate space to install the robot, insufficient staff members to operate the machine(s), suboptimal employee education and support, inability to integrate the robot into other hospital systems, acquiring a robot that can only produce syringes and not bags, and the need to always add new National Drug Code (NDC) numbers and barcodes into the system. For IV-WMS, these barriers can include drug shortages requiring frequent addition of new NDC numbers and barcodes to the system, failure to interface with existing computerized prescriber order entry systems, and

unexpected costs for things like maintenance, cleaning, upgrades and staff training, as well as construction costs for installation of larger systems.

Use ISMP Guidelines Dr. Freudiger also recommended that institutions employing these technologies or considering their implementation make use of the ISMP’s May 2022 publication, “Guidelines for Sterile Compounding and the Safe Use of Sterile Compounding Technology,” available online (bit.ly/3AdM2U9).

Dr. Freudiger reported no relevant financial disclosures. Ms. Kienle is an employee of Cardinal Health and a member of the USP Compounding Expert Committee. The comments in this article are her own.

28 Technology

Pharmacy Practice News • July 2022

Specialty Pharmacy ‘Pragmatic study design’ lauded

Research Tool Ups Adherence for SP Therapies

By David Bronstein

Phoenix—Using a research tool known as pragmatic study design, investigators at Vanderbilt Specialty Pharmacy identified a large cohort of patients who were nonadherent to their medications and developed several targeted interventions that yielded significant improvements in compliance.

But it was the value of the methodology, as much as the study results, that Autumn Zuckerman, PharmD, BCPS, AAHIVP, CSP, the director of Health Outcomes and Research at Vanderbilt Specialty Pharmacy, in Nashville, Tenn., emphasized. “Contrary to a controlled clinical trial, pragmatic studies must fit into normal workflow and allow for

variation in practice,” Dr. Zuckerman said during a Specialty Pearls session at the 2022 ASHP Summer Meetings and Exhibition. “This is important for those of us integrating research into practice, because it takes into account the challenges, intricacies and behaviors of patients and clinicians in a nonclinical trial setting.”

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Vanderbilt’s health information technology partner helped build a connection between Vanderbilt’s pharmacy software and its Research Electronic Data Capture (REDCap) system.

The Vanderbilt team, led by specialty pharmacist Amanda Kibbons, PharmD, considered this research approach “about three years ago, when we wanted to evaluate our adherence rates and any opportunities to improve them,” Dr. Zuckerman said. Their initial investigations showed they had more than 1,000 patients with a proportion of days covered (PDC) of less than 80%, versus a baseline overall rate of 95%.

So, the next question was how to identify the key drivers of nonadherence in that cohort, as well as strategies to address them, in a way that worked with the demanding schedule of pharmacists tasked with performing the prospective research.

A Tale of 2 Databases One key piece of this puzzle was to engage with a health information technology partner within the medical center to build a connection between the pharmacy software system and Vanderbilt’s Research Electronic Data Capture (REDCap) system.

“REDCap is actually external to our electronic health record, but it allowed us to efficiently perform randomization and collect patient and intervention data,” Dr. Zuckerman said. “We then developed a daily report of patients who met our inclusion criteria, which was securely transferred to a server. An API [Application Programming Interface] was built between the server and REDCap, such that we had automatic importing of the data into REDCap each evening.”

When the pharmacist who was assigned to the research project had dedicated time to devote to it, “she would review the newly imported patients for reasons for nonadherence,” Dr. Zuckerman explained. “If they had no appropriate gaps in treatment, she would randomize them within REDCap.” see PRAGMATIC STUDY, page 30

Technology

Pharmacy Practice News • July 2022

29

Diversion, Other Hot Topics in the Digital Space

By David Wild

W

TECH•TRENDS

Watermarking Unit-of-Use Medications

postdoctoral research fellow at Weldon School of Biomedical Engineering, Purdue University, in West Lafayette, Ind., and colleagues developed an edible watermark that can be applied to individual doses with an inkjet printer using FDA-approved food coloring.

These printers can be located at many points in the drug distribution process, including the hospital pharmacy, and the watermark can be read by anyone using a scanner or smartphone camera.

“Patients can identify their medicines in real time with important dose information at the point of administration,” while hospital pharmacies can use the technology to “lower the risk of dispensing errors, improve inventory tracking, enhance security, and minimize labor costs,” the authors wrote.

The technology is yet to be commercialized.

Dr. Aguero: Sale of counterfeit medications is a problem in the United States, but it is a true barrier to care in other parts of the world. The baseline technology now exists to watermark highly acute or expensive medications, and to scan the pedigree using a smartphone, which are prolific even in the developing world.

However, scaling this technology in the manufacturing phase is a huge challenge at this point.

elcome to the inaugural installment of “TechTrends,” hosted

by David Aguero, PharmD, the director of medication use systems and informatics, Division of Pharmaceutical Services, at St. Jude Children’s Research Hospital, in Memphis, Tenn.

Dr. Aguero also leads St. Jude’s pharmaceutical analytics and supply-chain service line–related technologies. His interest in technology—and ultimately in pharmacy technology—can be traced back to his youth.

“I broke my parent’s IBM [computer] as a child and have been interested in solutions to technology-related problems ever since, and have found a way to combine my passion for pharmacy with this love for technology,” he said.

In this issue of the series, Dr. Aguero highlights growing interest in the hospitalat-home model, research in sophisticated tech-based techniques to prevent drug diversion in the hospital, and technology to ensure only genuine medications make their way into the drug supply.

Researchers have developed a watermarking method to identify medications on the unit-dose level (Adv Funct Mater 2022;32[18]:2122479). The technique can be used to help patients avoid using counterfeit medications and also to enhance the safety of the medication use process in the hospital setting, the researchers said.

4 out of every 10 counterfeit pills contain a potentially lethal dose of fentanyl.

Source: DEA.

The technology could help address a striking crime trend. In 2021, the Drug Enforcement Administration reported seizing more than 20 million counterfeit pills, many of which were laced with fentanyl, also noting a “dramatic rise” in the circulation of pills containing 2 mg of fentanyl or more. Digging a bit deeper into this troubling trend, DEA lab testing reveals that four out of every 10 counterfeit pills contain a potentially lethal dose of fentanyl (bit.ly/3QFsI7K).

Fake cancer drugs have even been found in legitimate supply chains (Lancet Oncol 2018;19[4]:e209-217), and Gilead reported a “criminal counterfeiting network” that has been distributing counterfeit bictegravir-emtricitabinetenofovir alafenamide (BIC/FTC/TAF; Biktarvy) and FTC/TAF (Descovy) used to treat HIV (bit.ly/3Osdnpp).

To reduce the risk for counterfeit medication use, Hee-Jae Jeon, PhD, a

Machine-Learning System Expedites Diversion Identification A machine-learning–based algorithm identified cases of in-hospital drug diversion up to 19 months ahead of manual methods, researchers found (Am J Health Syst Pharm 2022;zxac035). Such expedited identification of diversion incidents can mitigate the impact on patient and worker safety and reduce staff time required to investigate diversion, the authors said.

“The combined improvement in both effectiveness and efficiency shows great promise that automating currently manual methods for detecting and in-

diversion vvestigating using machine learning will offload timeconsuming pharmacy operations tasks, allowing pharmacists to focus on more high-value patient care activities,” they wrote.

As the authors noted, the incidence of diversion nationally is unknown because many occurrences go undetected. To help overcome this challenge, developers at Invistics Corp., in Peachtree Corners, Ga., created a machine-learning algorithm. First, they trained the system using data from two large real-world data sets representing the movement of medications in the hospital setting. The resulting algorithm classifies the diversion risk associated with individual medication movements based on several variables.

As examples, a delay in documentation; failure to chart the total amount of medication administered, wasted or returned; charting of the wrong medication; gaps in the chain of medication custody; or administration of medications in the wrong order are all red flags for the algorithm.

To test the accuracy of the algorithm, the software developer recruited four health systems including 10 acute care hospitals to apply the software to their data from sources such as records from pharmacy inventory and automated dispensing cabinets as well as electronic health record systems. The hospitals’ data sets included 27.9 million medication movements.

There were 22 known cases of diversion detected manually by the health systems during the period covered in the data set, and according to the analysis, the software detected all of these cases.

The researchers estimated that if the software had been in place at the time of the diversion incidents, they would have been detected a mean of 160 days earlier (range, seven to 579 days) and would have required 10 to 30 minutes to investigate instead of the four to 20 hours spent investigating instances of diversion manually.

“Given these results, all participating

hospitals expanded their use of the technology, and the National Institute on Drug Abuse funded additional research to accelerate commercialization of the software,” the authors wrote.

Dr. Aguero: Front-line practitioners often ask how machine learning or artificial intelligence is being applied successfully to pharmacy practice. As this study shows, commercially available supervised machine learning can detect known diversion cases faster than existing detection methods. Machine learning has great potential to improve both detection and to reduce the human effort in detecting and investigating high-risk scenarios for diversion. Although this study was performed based on the use of Flowlytics (Invistics), there are other vendors in the field offering diversion monitoring solutions.

The Hospital at Home The hospital-at-home model received a profound boost during the early days of the COVID-19 pandemic, when many other health services nearly ground to a halt. Payal Sharma, DNP, MSN, RN, a nurse practitioner in the gastrointestinal and metabolic surgery department at New-York Presbyterian Hospital/Weill Cornell Medicine, in New York City, and colleagues wrote that the model meets the needs of inpatient acute care with an “intensive at-home hospital admission enabled by technology, multidisciplinary teams and ancillary services” (J Sci Commun 2022;29[3]:113-115).

They called for wider implementation of the model, citing outcomes such as: • reduced risk for delirium (because patients are in their familiar surroundings); • increased mobility; • less sleep disruption; • improved patient and family satisfaction; • up to 38% reduction in mortality; • fewer readmissions; • cost savings of up to 30% compared with acute inpatient care in the hospital setting; • reduced risk for hospital-acquired infections and injuries; and • frees up health-system capacity.

Dr. Aguero: Although brick-andmortar hospitals in the United States have been the dominant care setting, is that what’s best for our patients going forward? If the home is the best place to empower patients and caregivers to engage in self-management, then pharmacy needs to be prepared to meet this need through broad adoption of telepharmacy services.

Dr. Aguero reported no relevant financial disclosures.

30 Technology

Pharmacy Practice News • July 2022

Specialty Pharmacy

PRAGMATIC STUDY continued from page 28

But the effort wasn’t only about numbers: “We also engaged patients in the process by asking them about the main medication adherence barriers they were facing,” she emphasized.

The prospective study that emerged focused on patients who had more than four fills of the same specialty medication in the previous 12 months and a PDC of less than 90%. A total of 439 patients were included in the final analysis, with an even split between patients given usual care and those who received pharmacist interventions to address key drivers of medication noncompliance.

The most common interventions were related to memory (27% of all reasons for nonadherence), which included setting up memory aids on patients phones or sending pill boxes.

Additionally, for patients who were unreachable to schedule a refill (20%), the pharmacist attempted to contact them via phone, patient portal, and finally mail, Dr. Zuckerman noted.

“Our primary outcome was PDC at eight months, post-enrollment,” she said. “We found that at that time point, intervention patients were 1.8 times more likely to have a higher PDC than usual care, illustrating the effectiveness of the interventions.”

Diving a bit deeper into the data, median PDC at six months was 0.95 versus 0.90 for patients in the intervention and usual care arms, respectively (P=0.003); at eight months, 0.94 versus 0.88 (P<0.001); and at 12 months, 0.93 versus 0.87 (P<0.001).

Overcoming Challenges The pragmatic study design approach taken by the Vanderbilt team allowed for several invaluable tweaks, Dr. Zuckerman noted. For example, “we found that reviewing patients when they showed up on the nonadherence report was burdensome and required

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‘Contrary to a controlled clinical trial, pragmatic studies must fit into normal workflow and allow for variation in practice.’

—Autumn Zuckerman, PharmD, BCPS, AAHIVP, CSP

significant manpower,” she said. “So, we enlisted an additional floater pharmacist to help with patient review.”

As for when to consider employing

a pragmatic study design in clinical practice, “if you’re planning to develop a new service or change services, maybe this is how you assess its

effectiveness,” Dr. Zuckerman said.

She also stressed the benefits of involving your IT department in the process.

“By all means, engage health IT and your research experts. They are likely at your institution, so the good news is that you don’t have to necessarily reinvent the wheel.”

Finally, when doing any type of research, it’s important not to lose sight of the importance of providing highquality care amid all of the data crunching, Dr. Zuckerman noted. “We certainly don’t want to reduce the care we’re

Technology

Pharmacy Practice News • July 2022

31

Specialty Pharmacy providing,” she said. “Rather, we want to optimize it by identifying an add-on service or a better method for providing patient care.”

Excited by Study Design “There is so much about this study design that excites me,” commented JoAnn Stubbings, BSPharm, MHCA, a clinical associate professor emerita in the Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, and one of the founding members of UIC’s Specialty Pharmacy

‘There is so much about this study design that excites me. The interface between the pharmacy software system and REDCap was innovative and efficient.’

—JoAnn Stubbings, BSPharm, MHCA

program. “The interface between the pharmacy software system and REDCap was innovative and efficient.”

Dr. Stubbings, a member of the

advisory board for Pharmacy Practice News and Specialty Pharmacy Continuum, also lauded the research approach taken by the Vanderbilt team. “I like the

prospective study design with a control group and the PDC measures taken after a reasonable time—four months for baseline and eight months for intervention,” she said. “The Vanderbilt group demonstrated that monitoring adherence and targeted interventions such as memory aids can significantly improve adherence in the long run. We can all put these findings into action to improve patient outcomes.”

The sources reported no relevant financial disclosures.