Pharmacy Practice News - October 2021 by McMahon Group

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OPERATIONS & MGMT

A survival guide for audits and inspections

10 Tips for Adding Quality to Your 503As and 503Bs Profiles of hospitals that saved millions with biosimilars ............... 6 Ethical, financial issues raised by IV tocilizumab shortage ............................... 8 POLICY

COVID-19 reimbursement resources .......................... Should a notorious drug diverter get paroled? ............................

“What is tested is not sold; what is sold is not tested.” That’s an observation from Ian F. Deveau, PhD, the division director of the FDA’s Center for Drug Evaluation and Research’s Office of Manufacturing Quality. And it’s why pharmacies that do sterile compounding cannot rely solely or even primarily on testing of their compounded sterile preparations to ensure sterility and potency, said Amy Summers, PharmD, a consultant to the compounding industry, during a session on “quality built in” at the 2021 Compounding Pharmacies Grand Salon, held virtually. If, for example, you make 100 units of a compounded sterile preparation, you don’t test them all for endotoxins,

Patent dance missteps imperil access to affordable therapy ...... 20 CLINICAL

Pharmacists Get the Call To Help With COVID-19 Rx T

he Department of Health and Human Services’ recent decision to allow licensed pharmacists to order and administer selected COVID-19 therapeutics was welcomed by ASHP and other professional groups that had been pushing for the policy change. But in many facilities, the change codige just codi fied something that pharmacists have ve been doing throughout the pandemic. Whether it’s t’s administering monoclonal antibodies (mAbs) bs) or other COVID-19 therapeutics, front-line line pharmacists have been stepping in for medical staffs overwhelmed by surging ng COVID-19 caseloads. Still, the move by the HHS, based on n an amendment to the COVID-19 Pub-lic Readiness and Emergency Pre-paredness (PREP) Act, is good news ws for COVID-19 care teams, according ng to Tom Kraus, MHS, JD, ASHP’s vice ce

Will Mexico border restrictions squeeze IG supply? .......................

Tips for protecting neonates from nutrition shortages .....

Continued on page 10

A Helping Hand From Leadership Boosts Biosimilars

Hospitals Still Grappling With $1 M+ Price Tag for CAR-T Rx

orporate pharmacy support composed of clinical and financial resources, promotion of best practices, and enhanced communication with the C-suite significantly boosted biosimilar conversion rates and doubled drug savings during a pilot program within a large health system. Such a program can address many of the operational challenges associated with efforts to increase biosimilar use across multiple care sites, according to investigators from Community Health Systems (CHS), based in Franklin, Tenn., Continued on page 5

Amended PREP Act empowers p profession rofession

Continued on page 18

Volume 48 • Number 10 • October 2021

ince the FDA approved the first chimeric antigen receptor T-cell (CAR-T) therapies in 2017, more than 100 medical centers have been certified to offer the treatment. But for Medicare patients, the reimbursement does not cover the cost of the product and services. Given that challenge, how are health systems managing the intricacies of reimbursement and prior authorization (PA) for CAR-T therapies? Getting the payments right is critical, given the unprecedented clinical gains reported with the treatment. A recent study of 74 patients with B-cell lymphoma, for example, found that real-world outcomes for axicabtagene ciloleucel (Yescarta, Kite/Gilead)

To access our latest review articles on COVID-19 vaccine safety, parenteral nutrition, and more,

visit bit.ly/3zbcV6N

or tisagenlecleucel (Kymriah, Novartis) were similar to those in the trials that led to the drugs’ approval, with a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response (ASCO 2021 abstract e19500; bit.ly/3hFPpsJ). But those outcomes came at a high price, the investigators reported. Although the median drug cost alone was $411,278, the median total cost of care for CAR-T therapy was $610,999—and in 12% of cases, the total cost of care exceeded $1 million. Much-needed Medicare adjustments have helped to some degree, but significant financial toxicities remain, experts note. After Continued on page 22

E N T ER A NE W WO R L D O F 72-HOUR POSTOPERATIVE PAIN RELI E F 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 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

EXPLORE THE DATA AT ZYNRELEF.COM/PHARMA

Indication

Contraindications

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.

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.

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.

PP-HTX011-0557 | 07/21

Use in Speciﬁc Populations 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. Hematologic Toxicity: Monitor hemoglobin and hematocrit in patients with any signs or symptoms of anemia. Drug Interactions 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, volumedepleted, 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 effect.

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

REDEFINE POSTOPERATIVE PAIN MANAGEMENT

ZYNRELEF™ (bupivacaine and meloxicam) extended-release solution, for soft tissue or periarticular instillation use BRIEF SUMMARY OF PRESCRIBING 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 INDICATIONS AND USAGE ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty. 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 is not indicated for the following routes of administration: epidural, intrathecal, intravascular or intra-articular, regional nerve blocks, pre-incisional, and 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: The recommended dose of ZYNRELEF (bupivacaine/meloxicam) is as follows: − Bunionectomy: up to 2.3 mL to deliver 60 mg/1.8 mg − Open inguinal herniorrhaphy: up to 10.5 mL to deliver 300 mg/9 mg − Total knee arthroplasty: up to 14 mL to deliver 400 mg/12 mg See full Prescribing Information for all important dosage and administration information, preparation instructions and compatibility considerations. CONTRAINDICATIONS 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 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 benefit 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. Dose-Related Toxicity: The toxic effect 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.

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. 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 benefit 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 with Intra-Articular Infusion: Intra-articular infusions of local anesthetics have been associated with chondrolysis. ZYNRELEF is not approved for intra-articular infusion. 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. Masking of Inflammation and Fever: NSAIDs reduce inflammation, and possibly fever, which may diminish detection of infections. ADVERSE REACTIONS 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: • 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 effect. 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 methotrexate-associated toxicities. Monitor for signs of methotrexate toxicities. 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 patient with creatinine clearance 45 to 79 mL/min, monitor for pemetrexed-associated 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. © 2021 Heron Therapeutics, Inc. All rights reserved. ZYNRELEF™ is a trademark of Heron Therapeutics, Inc.

Manufactured and marketed by: Heron Therapeutics, Inc., 4242 Campus Point Court, Suite 200, San Diego, CA, 92121, USA. PP-HTX011-0102 05/21

Operations & Management

Pharmacy Practice News • October 2021

Finance

Leading With Biosimilars

Table. Biosimilar Conversion Rates

continued from page 1

who described the program during the 2021 ACCP virtual poster symposium (abstract 182). Helene Daskalovitz, PharmD, a health outcomes and analytics fellow with CHS, and her colleagues retrospectively analyzed data on the two pilot outpatient infusion centers, comparing data on conversions to biosimilars for the top five biologic agents (bevacizumab, infliximab, pegfilgrastim, rituximab and trastuzumab) from before (fourth quarter [Q4] 2020) and after (Q1 2021) implementation of a corporate pharmacy–supported initiative. They selected the agents based on their effect on the overall drug budget and overlap with FDA-approved indications. The corporate pharmacy team of pharmacists, technicians and nurses provided clinical support—including review of related trial data, assessment of indications, dosing and pharmacokinetics information—as well as guidance on operational considerations, such as storage, preparation and administration. In addition, the team set up communication channels to promote the sharing of best practices and engage key hospital administrators. They also tracked progress and conducted cost-saving analyses to show the benefit of biosimilar conversions. Having the corporate pharmacy team focus on these activities allowed the affiliate “facilities to allocate their financial resources elsewhere,” such as on operational factors related to conversions and maximizing reimbursement, Dr. Daskalovitz explained. For the study, she and her coinvestigators captured the percentage of biosimilar utilization and savings using purchase data, assessing quanquan tities purchased, strength of product and cost. They did id not evaluate reimbursement data or payor considerations. The team found that biosimilar product use increased at both pilot sites between en Q4 2020 and Q11 2021, from 1.20% to 7.33% at pilot site 1 and from 14.52% to 22.10% .10% at pilot site 2 (Table). able). Biosimilar utilization ion improved for all includncluded biologics except pt for trastuzumab. Infliximab iximab products were not ot purchased at pilot site ite 1 in either quarter. For both sites combined, mbined, savings from drugg spending increased approximately 36% in Q1 2021,

and in Q2, savings doubled, “highlighting the continued success of the pilot,” Dr. Daskalovitz noted. At the end of the pilot study, the team evaluated barriers, successes and opportunities, and then expanded the initiative to seven more sites. After the expansion to nine sites, the biosimilar conversion rate went from 28% in Q1 2021 to 40% in Q2 2021, according to Dr. Daskalovitz. One of the barriers the team faced during the project was related to the pharmacy and therapeutics committee’s formulary approval process. The team recommended that the hospital sites treat biosimilars the way the FDA does. “Essentially, if an innovator product is approved, the biosimilar can be fasttracked onto the hospital’s formulary if it is being used for the same FDAapproved indication,” she said. To overcome the second barrier related to dissemination of information about biosimilars, the corporate pharmacy team provided class reviews, an educational document with available literature pertaining to biosimilars/biologics and presentations on specific terminology related to biosimilars for staff involved with biosimilar decision making. “Of particular importance was explaining to senior leadership that, from a regulatory standpoint, biosimilars are not generic,” Dr. Daskalovitz noted.

Getting Stakeholders Informed Providing such information and getting leadership and other stakeholders up to speed about biosimilars is crucial in such projects. Steven Lucio, PharmD, BCPS, a senior principal of pharmacy

Innovator Product

Biosimilar Conversion Rates, % Biosimilar Product(s) Pilot Site 1 Pilot Site 2 Available for Q4 2020 Q1 2021 Q4 2020 Q1 2021 Conversion

Bevacizumab • Bevacizumab-awwb (Avastin, (Mvasi, Amgen) Genentech)

1.98

9.69

28.7

41.8

Infliximab (Remicade, Janssen)

NAa

8.7

10.9

Pegfilgrastim • Pegfilgrastim-jmdb (Neulasta, (Fulphila, Viatris) Amgen) • Pegfilgrastim-cbqv (Udenyca, Coherus)

3.5

15.6

10.7

34.6

Rituximab (Rituxan, Genentech)

• Rituximab-pvvr (Ruxience, Pfizer)

6.7

11.9

30.3

Trastuzumab (Herceptin, Genentech)

• Trastuzumab-anns (Kanjinti, Amgen)

26.7

13.9

• Infliximab-axxq (Avsola, Amgen) • Infliximab-dyyb (Inflectra, Celltrion)

The health system did not purchase originator infliximab or infliximab biosimilars.

NA, not applicable; Q4, fourth quarter

‘Of particular importance was explaining to senior leadership that, from a regulatory standpoint, biosimilars are not generic.’ —Helene Daskalovitz, PharmD solutions at the group purchasing organization Vizient, which helps its member organizations improve their performance by undertaking initiatives such as biosimilar conversions, underscored the importance of communication in facilitating these types of initiatives. Those embarking on such projects su “need to articulate articulat what biosimilars are in detail,” ensurde ing each stakeho stakeholder knows what that means with respect to clinical factors, factors as well as cost, reimbursem reimbursement, etc. At CHS, the corporate pharmacy team “pro vided a supp supportive role,” Dr. Daskalovitz s ai d, Da ska lo noting that the team approached the system’s t directors of pharmacy and about the program p “to meet their adapted it “t needs.” For eexample, she said, “one fac facility had difgetting biosimificulty gett approved, which lars appr where the expeis whe dited [approval] dite pathway was pa valuable. Othva er facilities had buy-in

barriers. In these cases, members of the C-suite were looped in, given a highlevel overview and presented with savings potential based on tiers of biosimilar conversion.”

Payor Considerations Next steps for the CHS team include continuing to expand the initiative to additional sites within the health system and optimizing factors that payors weigh when evaluating biosimilars, including cost, contracting and the effect on members. Dr. Lucio stressed that to be successful in biosimilar conversion initiatives, health systems need to learn the factors that payors consider, and pharmacists need to work with payor relations teams at their institutions to ensure these teams are aware of the unique clinical and financial dynamics that influence payor decision making. Pharmacy team members can help ensure contracting language is in the best interest of the institution, for example. He said this communication between health systems’ pharmacy and payor relations departments is “where the gaps are” and “the biggest area that requires close coordination.” Noting that some larger health systems tend to be a lot more skilled at this process, he said see LEADING, page 7

6 Operations & Management

Pharmacy Practice News • October 2021

Finance

Success Stories Show Pharms’ Value in Biosimilars D

espite the promise of huge savings with biosimilars—an estimated $140 billion in discounted spending over the next five years—adoption of these agents has been low, accounting for only one-fifth of accessible molecule volume across all markets in 2020 (bit. ly/3xY4TNW). Fortunately, pharmacists can play an important role in increasing biosimilar uptake. Here’s how three hospitals achieved high levels of biosimilar use with the help of their pharmacists, including one large system that racked up $200 million in savings after achieving a 100% conversion rate.

Boston Medical Center’s Comprehensive Approach After the FDA approved infliximabdyyb (Inflectra, Pfizer) in 2016, at 20% to 30% less than the cost of originator infliximab (Remicade, Janssen), pharmacy leadership at Boston Medical Center (BMC) was eager to provide the biosimilar to existing patients receiving infliximab and to patients starting treatment with the drug. However, according to Shubha Bhat, PharmD, who was a clinical pharmacy specialist in gastroenterology at BMC at the time of biosimilar adoption and is now a clinical pharmacy specialist in inflammatory bowel disease at Cleveland Clinic, physicians had concerns. “There wasn’t full confidence that the biosimilar was as safe and effective as the originator product and there was concern that a switch might not lead immediately to less spending for patients,” Dr. Bhat said. As a first step in allaying providers’ concerns, the BMC pharmacy team recruited gastroenterologists, dermatologists and rheumatologists from the hospital to champion the idea of a biosimilar infliximab switch to their various specialties. “A really important part of obtaining provider buy-in was getting these key stakeholders involved in the process, including in P&T [pharmacy and therapeutics] committee meetings,” Dr. Bhat said. The team gathered published findings (Inflamm Bowel Dis 2018;24[3]:490-501; others) on the safety and efficacy of infliximab-dyyb and consulted with specialists in Europe who had already used the biosimilar for several years. In addition to sharing these data, they reassured providers that they would be analyzing clinical outcomes for BMC patients who were switching to infliximab-dyyb. They took several other steps to address uncertainty about biosimilar use, including developing an internal “drug monograph.” In addition to a summary of the evidence supporting the drug’s safety and efficacy, the

biosimilar uptake and lead to significant cost savings without compromising clinical outcomes,” Dr. Bhat said.

At Providence St. Joseph’s Health System, a $27 Million Payoff

The Case for Bioequivalency Bevacizumab-awwb (Mvasi, Amgen) and bevacizumab (Avastin, Genentech) yielded six-month NSCLS survival rates of 72% and 79%, respectively (P=0.27), with no differences in serious adverse events between the two groups.a 90% of IBD patients in remission at the time of a switch to infliximab-axxq (Avsola, Amgen) maintained remission at least three months after the change.b NSCLS, nonsquamous non-small cell lung cancer; IBD, inflammatory bowel disease Sources: a Kaiser Permanente study presented at the 2021 annual meeting of the International Society for Pharmacoeconomics and Outcomes Research. b Internal data, Boston Medical Center.

monograph also detailed infliximabdyyb’s pharmacokinetics and specified the optimal timing of a switch to the biosimilar—six months or longer of being stable on originator infliximab, according to Dr. Bhat. The monograph also included the projected annual cost of the drug, and the criteria patients would need to qualify for a switch to infliximab-dyyb, she noted. “For a patient to be eligible for a switch, the agent needed to be approved by the prescriber, covered by the insurer and administered at the BMC outpatient hospital clinic,” explained Dr. Bhat, noting that they excluded patients receiving infliximab infusions at non-BMC facilities because “we couldn’t guarantee those other facilities had infliximabdyyb on their formulary.” To avoid medication administration delays if a payor refused to reimburse for the biosimilar, Dr. Bhat’s team completes the prior authorization process for each switch four weeks before the proposed switch date. Each patient who switches to biosimilar infliximab also receives a call from a pharmacist. During the call, the pharmacist obtains patient consent for a switch, which is required since reference infliximab and infliximab-dyyb are not interchangeable, and the encounter provides an opportunity to address any questions patients may have and to direct them to online resources and provide them with written educational

materials, which are also made available by their providers and infusion nurses. “Patients can refuse to transition to a biosimilar, but this has been rare given the advance patient notice, comprehensive education and provider buy-in to the process,” Dr. Bhat noted. Indeed, an analysis of records from March 2018 to June 2019 showed that 97% of 151 outpatients who were eligible to switch to, or start, infliximab-dyyb during that time did so (J Manag Care Spec Pharm 2020;26[4]:410-416). Payor denial was the primary reason for patients who did not initiate or switch to the biosimilar, Dr. Bhat noted. “The most common reasons for payor denial included preference for reference infliximab and also that the patient must fail Remicade [infliximab; Janssen Biotech] first, which is not a clinically appropriate action,” Dr. Bhat said. “Now, it seems that landscape is shifting and more payors are willing to cover biosimilars.” Confirming the drug’s efficacy, a subanalysis of data from inflammatory bowel disease patients in the study found that 90% of those in remission at the time of a switch maintained remission at least three months after the change. The annual savings from the switch to infliximab-dyyb has amounted to an estimated $500,000 for the health system, Dr. Bhat’s team found. “Our experience demonstrates that targeted education for both providers and patients can overcome barriers to

At Providence St. Joseph Health (PSJH), a 52-hospital nonprofit health system, headquartered in Renton, Wash., Sophia Humphreys, PharmD, MHA, and her colleagues have maximized savings from biosimilars by focusing on biosimilar contracting negotiations and formulary management, as well as electronic health record (EHR)-guided inpatient prescribing. “Time is money, so if you’ve prepared thoroughly in advance of a biosimilar product launch, you can start saving as soon as it comes to market,” said Dr. Humphreys, PSJH’s director of system pharmacy clinical services. The thorough preparation that she and her colleagues do begins by closely monitoring the biosimilar pipeline for upcoming approvals, she said. As a biosimilar approaches an anticipated FDA approval date, the P&T committee evaluates the available data on efficacy, safety and tolerability, and “well ahead of product launch,” establishes the biosimilar’s formulary status. Once a biosimilar is placed on the organization’s formulary, but still in advance of the product market launch, the contracting team begins negotiating with the manufacturer for the best purchasing terms “so they can begin saving as soon as the biosimilar product is available,” Dr. Humphreys said. An important component of their biosimilar use strategy has been building the biosimilars into their EHR system, she explained. “We use a direct therapeutic interchange function to automatically guide inpatient physicians to prescribe our preferred biosimilar for all hospital inpatient administration,” Dr. Humphreys said, noting that outpatient biologic infusions are selected by providers based on payor preferences. According to internal data, the approach at PSJH has paid off. In 2019 and 2020, after the health system introduced four preferred biosimilars, including biosimilar versions of peg-filgrastim, infliximab, epoetin alfa and filgrastim, the system achieved an estimated $27 million in savings, Dr. Humphreys said. “These cost reductions are not only beneficial for the health system and patients’ pocketbooks; they also increase access to care and thus may help improve patient clinical outcomes,” she said, pointing to data from the United Kingdom showing a 13% increase in

Operations & Management

Pharmacy Practice News • October 2021

Finance overall granulocyte colony-stimulating factor use in the year after a biosimilar version was introduced in that country in September 2008 (Support Care Cancer 2013;21[10]:2925-2932).

$200 Million Saved A Kaiser Permanente At Kaiser Permanente, where acceptance of some of the roughly 30 biosimilars on its formulary has stood at 100%, gathering and disseminating clinical evidence was pivotal to the successful uptake of biosimilars. “Focusing on the evidence—both what is published and our own patient outcomes—has been so important to building physician confidence,” said Kim Le, PharmD, the executive director of drug evaluation, strategy and outcomes, National Pharmacy Services at Kaiser Permanente, in Downey, Calif. The focus on evidence starts with an analysis of available data before a biosimilar receives formulary approval and continues after implementation, when biosimilar recipients are monitored, Dr. Le said. Patient outcomes are analyzed and the results are shared with physicians in order to continue to build confidence in biosimilars, she explained. The strategy first demonstrated its

LEADING continued from page 5

he still sees “a lot of opportunity for better alignment of efforts to facilitate biosimilar use.” Efforts to promote biosimilars are underway on the payor side as well. For example, pharmacy benefit manager (PBM) Prime Therapeutics is working to help its Blue Cross Blue Shield plan clients—23 plans covering 33 million people—optimize biosimilar use. In late May, Prime launched a medical drug management program called MedDrive to manage high costs associated with medically billed drugs, including biosimilars. Joseph Leach, MD, Prime’s chief medical officer, told Pharmacy Practice News that a lack of integrated data can make it challenging for payors to manage pharmacy and medical spending. But, when health plans merge their efforts related to biosimilar interchangeability and “prefer the lower cost options instead of high-cost referencebrand biologics, they can obtain marketleading savings,” noted Dr. Leach, who also is a practicing oncologist with Minnesota Oncology. MedDrive is “the first program that aligns its health plan clients to leverage market share and drive savings,” Dr. Leach said, and it also brings “key

‘The secret ingredient of this success was early engagement with physician champions and identifying eligible patients for conversion.’ —Kim Le, PharmD value in 2015, when Kaiser Permanente added the first biosimilar, filgrastimsndz (Zarxio, Sandoz), to the formulary. “We were fortunate that this was a supportive care drug, rather than a curative treatment or a chronic disease therapy, so our physicians were more amenable to using it,” Dr. Le acknowledged. With published (Support Care Cancer 2018;26[3]:1013-1016; others) and internal data confirming filgrastim-sndz is as safe and effective as the reference filgrastim, several physician champions at Kaiser Permanente have endorsed use of the agent, and it is now prescribed in 100% of cases where the agent is used, Dr. Le said. With the successful rollout of filgrastim-sndz, Kaiser Permanente next introduced infliximab-dyyb in March 2017, and uptake of that biosimilar stands at about 80%, which is well above the national average for

biosimilar infliximab uptake, Dr. Le noted. “The secret ingredient of this success was early engagement with physician champions and identifying eligible patients for conversion,” she said. When the time came for deploying oncology biosimilars, “we already had lots of experience that we could share with physicians so that they had a lot of confidence in biosimilars,” Dr. Le said. In fact, within three months of the launches of bevacizumab-awwb (Mvasi, Amgen), trastuzumab-anns (Kanjinti, Amgen) and rituximab-abbs (Truxima), the organization achieved 90% uptake of the three drugs for both new starts and patients switching to one of the biosimilars. Dr. Le said her team continues to gather and share post-implementation data on biosimilars in order to build and maintain

6 Tips for Health Systems Implementing Biosimilar Conversions Every hospital is unique, so there is no one-size-fits-all approach to improving biosimilar conversions, according to Helene Daskalovitz, PharmD, a health outcomes and analytics fellow with Community Health Systems, in Franklin, Tenn. Still, she outlined several strategies that likely will work across multiple care sites: 1. Teamwork. “Success is dependent on interprofessional collaboration, open lines of communication and flexibility,” Dr. Daskalovitz said, adding that it’s also important to adapt your approach to meet the needs of any particular team, facility and/or system. 2. Flexibility. This quality is crucial for systems with multiple hospitals across multiple states. 3. Keep an eye on key variables. These may include payor mix, site of care, team dynamics, interdepartmental relationships, etc. 4. Involve senior leadership early when possible. Members of the senior leadership can empower pharmacy, reduce barriers and improve adoption of biosimilars. 5. Provide resources. This can help alleviate the operational burden of the initiative. Materials can include class/literature reviews, cost analysis, tiered biosimilar preference lists, etc. The goal is to ensure that all of the key stakeholders understand biosimilar concepts and terminology. Such outreach is critical, because biosimilars can be complicated, especially to those without a clinical background. 6. Provide actionable data. Quarterly updates describing biosimilar/innovator spending, conversion rates, total savings date, rebates earned, savings projections and opportunity, among ther data points, are helpful.

—S.T.

confidence in biosimilars. For example, findings presented at the 2021 annual meeting of the International Society for Pharmacoeconomics and Outcomes Research included 58 bevacizumabawwb recipients and 295 reference bevacizumab patients, all of them with nonsquamous non-small cell lung cancer at Kaiser Permanente. The results showed six-month survival rates of 72% and 79% with the two drugs, respectively (P=0.27) and no differences in serious adverse events between the two groups. Biosimilar-related cost savings for Kaiser Permanente, which is both a health system and health plan, have been significant, Dr. Le said. Since filgrastim-sndz was first introduced in 2015 at the organization, it has seen an estimated $200 million in savings from use of all biosimilars. “I think our success demonstrates that if you really deliver the data to providers and make sure there is a good understanding of the facts behind biosimilars, you can greatly increase the confidence of physicians in prescribing these drugs,” Dr. Le said. —David Wild The sources reported no relevant financial disclosures.

parts of the health care industry together—such as payors, PBMs, providers, specialty pharmacies and manufacturers—to help ensure biosimilars are accepted and used as equally safe and effective treatments, so people can benefit from the most appropriate drug at the lowest net cost.” Dr. Leach noted that Prime has worked “to understand differences from the lens of each stakeholder. What might be the lowest net-cost biosimilar for a payor could be different than that of a health system based on procurement differentials. Providers, especially bigger integrated delivery networks, are thinking about the clinical, operational and financial considerations—meaning purchasing, stocking and margins—so communicating early [and] often and finding a middle ground [are] important,” he said, adding that “member considerations should also not be forgotten.” —Sarah Tilyou The sources reported no relevant financial disclosures other than their stated employment.

For more biosimilars coverage, see pages 20–21.

8 Operations & Management

Pharmacy Practice News • October 2021

COVID-19 Pandemic

U.S. demand up 400%

Calculating the Costs of IV Tocilizumab Shortage I

n a troubling echo of last year's pandemic-induced critical drug shortages, at press time, health systems were still grappling with a sharp decrease in the supply of IV tocilizumab (Actemra), Genentech’s treatment for rheumatoid arthritis (RA). The shortage escalated rapidly after the FDA’s June 28 emergency use authorization (EUA) of the drug for hospitalized COVID-19 patients. By late August, Genentech said demand for the specialty drug was up “well over 400% of pre-COVID levels in the last two weeks alone, and it continues to increase.” Regardless of how the shortage ultimately pans out, many health systems were caught off guard by the drug’s plummeting availability—a supply headache that may carry with it prolonged billing issues, not to mention ethical concerns about how to manage future pandemic-related shortages. “The speed with which this shortage occurred was startling and difficult to navigate, since there was no advance notice and the communication from Genentech has been very opaque,” said Eric M. Tichy, PharmD, MBA, the vice chair for supply chain management at Mayo Clinic in Rochester, Minn. Genentech said it was “working to expedite replenishments and increase manufacturing capacity and supply wherever possible.” However, the company also noted “that all Actemra patients’ needs may not be met during this time,” and added that “we also anticipate additional periods of stockouts in the months ahead if the pandemic continues at the current pace.” Tocilizumab is a workhorse antiinflammatory drug. Aside from its use for RA, juvenile idiopathic arthritis and other conditions, it also is approved by the FDA for the treatment of cytokine release syndrome, the potentially severe and life-threatening side effect of chimeric antigen receptor T-cell (CAR-T) therapy.

The Ethics of a Drug Shortage At Mayo Clinic, Dr. Tichy said the shortage had caused “many ethical issues about how to ration use of tocilizumab. For example, do we prioritize CAR-T, RA and other FDAapproved uses [box] or do we prioritize COVID-19? Unfortunately, Genentech is not maintaining supply for previously established patients, and this has created ethical challenges.” Through early September, the shortage had affected only the tocilizumab IV dosage forms, 80 mg/4 mL, 200 mg/

10 mL and 400 mg/20 mL in singleuse vials. The subcutaneously administered versions—the pre-filled syringe and ACTPen autoinjector—remained in adequate supply. Dr. Tichy said although these alternative forms are available, “there are challenges with billing, reimbursement and the ability to deliver the right dose with the subcutaneous product that make switching difficult.” He added, “These challenges put the patients and health care organizations at risk, and [they] are very disruptive and stressful for the patients.” Erin R. Fox, PharmD, the senior director of drug information and support services at the University of Utah Health, in Salt Lake City, said she was “not sure why Genentech was surprised” by the sharp increase in demand for tocilizumab after FDA's EUA for COVID-19 patients. When it comes to potential COVID-19 treatments, “you can just expect the demand to increase,” she said. “It’s an example of how manufacturers really need to put in some contingency plans to ensure they're going to have adequate supplies.”

Tocilizumab Indications Rheumatoid Arthritis Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs

Giant Cell Arteritis Adult patients with giant cell arteritis

Systemic Sclerosis–Associated Interstitial Lung Disease (SSc-ILD) Slowing the rate of decline in pulmonary function in adult patients with SSc-ILD

Polyarticular Juvenile Idiopathic Arthritis (JIA) Patients 2 years of age and older with active polyarticular JIA

Systemic Juvenile Idiopathic Arthritis (SJIA) Patients 2 years of age and older with active SJIA

Cytokine Release Syndrome (CRS) Adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening CRS

ASHP’s Take Michael Ganio, PharmD, BCPS, the senior director of pharmacy practice and quality at ASHP, said the organization “started to get reports of shortages of tocilizumab” in early August, which dovetails with the supply constraints reported by Genentech. “It quickly escalated,” he noted. The FDA's tocilizumab EUA was issued for the treatment of hospitalized adult and pediatric patients, aged 2 years and older, who receive systemic corticosteroids and require supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation. “We have sites that want to continue to use that drug for those indications,” Dr. Ganio said, “but they're having a hard time getting it.” Dr. Ganio said, “We've had drug shortages going back at least 20 years,” but the ones related to the pandemic, including last year’s shortages of sedatives and paralytics, are different, because they are based on increased demand. “The typical evolution of a drug shortage has to do with the manufacturing quality,” he said. “When we see an increase in demand like this, it obviously points to a different cause, and maybe different solutions are needed—whether it is reimagining the strategic national stockpile or the adoption of new manufacturing technologies that allow rapidly increasing production to meet that demand.”

‘There are challenges with billing, reimbursement and the ability to deliver the right dose with the subcutaneous product that make switching difficult [and] put the patients and health care organizations at risk.’ —Eric M. Tichy, PharmD, MBA WHO Gets Involved The tocilizumab shortage isn’t limited to the United States; worldwide supplies of the medication are in low supply, according to Roche, which markets the drug overseas (bit.ly/3gZX2tL). According to the company, demand for tocilizumab has increased 300% in developing countries compared with prepandemic orders. Coupled with the 400%-plus spike in U.S. demand, “we will experience shortages of Actemra/RoActemra globally over the weeks and months ahead,” the company stated. “This is due to global manufacturing capacity limits, raw material supply constraints, the complex, labour-intensive process of manufacturing biologics and the dynamically evolving nature of the pandemic.” Roche noted that it is “doing everything possible to minimize the impact of supply constraints,” including increasing its manufacturing of tocilizumab

more than 100% over prepandemic levels. The company added that it has “a controlled distribution strategy in place for people with conditions for which [tocilizumab] is approved.” The company’s announcement prompted concern from the World Health Organization. “While we welcome and acknowledge that Roche has announced measures to address the shortage, we call on the company to ensure equitable allocation of current stocks of this medicine for all countries, including low- and middle-income countries,” WHO officials said (bit.ly/2WSLDoH). “We also strongly encourage Roche to facilitate technology transfer and knowledge and data sharing to broaden access to this important treatment.” —Bruce Buckley The sources reported no relevant financial relationships.

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10 Policy

Pharmacy Practice News • October 2021

COVID-19 Pandemic

Making mAbs Work

to pharmacists and help shore up the nation’s public health infrastructure against future pandemics.”

continued from page 1

president of government relations. “[It] will significantly expand patient access to needed treatments and post-exposure prophylaxis, particularly in medically underserved areas,” Mr. Kraus said, adding that the amendment will allow “broader patient access to COVID-19 therapies that can prevent severe illness.” The amendment broadly addresses COVID-19 therapeutics given orally, subcutaneously or intramuscularly, including current and future medications that are approved, authorized, cleared or licensed to treat/prevent COVID-19. Licensed pharmacists, licensed or registered pharmacy interns, and qualified pharmacy technicians who meet the criteria in the amendment are also authorized to administer certain COVID-19 therapeutics, according to the HHS.

A Joint Effort ASHP had led a joint effort with other pharmacy organizations urging the HHS to act after the FDA authorized the first antibody (casirivimab-imdevimab [REGEN-COV, Regeneron]) to be used for post-exposure prophylaxis for COVID-19 emergency use in August, saying that allowing pharmacists to administer the treatment could ensure rapid access to therapy. “Initiation of therapy is particularly likely to be delayed in rural and underserved communities that lack access to infusion services and other health care provers,” the joint letter told the HHS; pharmacists can provide that access (bit.ly/3lmW1xi). Scope-of-practice rules vary widely from state to state. Most states have not granted pharmacists unrestricted authority to prescribe mAbs or any other therapy for COVID-19 infection independently. In fact, Florida, New Hampshire, Washington, D.C., and Puerto Rico do not allow pharmacists to administer medications to patients under any circumstances. The amended PREP Act standardizes the authority for pharmacists to order and administer COVID-19 therapeutics nationwide, Mr. Kraus explained. “HHS has previously made clear that state scope-of-practice laws cannot prohibit covered persons from providing the services authorized in a PREP Act declaration,” he said (bit.ly/393Tbrd).

A Permanent Solution Although the ability to deliver mAbs will be welcome for many health systems that are overrun by the current delta variant surge, a permanent solution is needed, especially for states with limited access to health care providers, Mr. Kraus noted. “Pharmacy’s rapid response to the COVID-19 health emergency—setting up testing sites, overseeing mass

vaccination clinics and administering vaccines—underscores the essential role pharmacists can play in pandemic preparedness,” he said. “Over the last year, several states have acted to authorize reimbursement for pharmacists’ patient care services, but Medicare does not have a similar payment mechanism. ASHP continues to advocate for federal and state laws that will expand patient access

Getting mAbs to Rural Areas To underscore the value pharmacists bring to the COVID-19 care team, particularly in medically underserved areas, consider the case of the University of Florida Health (UF Health) Shands Hospital, in Gainesville. Since February 2021, under a pilot program coordinated by the HHS, pharmacists have been part of a multidisciplinary clinical

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Policy

Pharmacy Practice News • October 2021

COVID-19 Pandemic team tasked with delivering mAbs to rural communities in North Florm ida. Amy Rosenberg, i PharmD, the health P system’s interim direcs ttor of pharmacy, said tthe program leverages ag the ordering, distribution and educatrib tional tiona outreach skills that her pharmacists have been pha using from tthe very beginning of the COVID-19 pandemic. “Almost from

the start, we were sought out for our expertise,” Dr. Rosenberg said. Those skills, she noted, included developing a storage and distribution plan for getting IV bamlanivimab (Lilly), the first mAb designated for use in the pilot, to multiple care sites. Her team also was directly involved in acquiring the drug, preparing mAb IV doses and building order sets into the health system’s electronic health record (EHR) to ensure proper tracking and documentation. Educational outreach to other caregivers involved in the pilot also was

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Byfavo, a CYP450-independently metabolized benzodiazepine, helps you to get your patients rapidly in and out of procedures lasting up to 30 minutes.1-5 Learn more at Byfavo.com $ VHGDWLYH HǺHFW ZDV GHǻQHG DV D 02$$ 6 VFRUH RI Ɯ $W DQG PLQXWHV DQG RI SDWLHQWV KDG D 02$$ 6 VFRUH RI Ɯ UHVSHFWLYHO\

age in humans. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, DQG QR VSHFLƓF PHGLFDWLRQV KDYH EHHQ VKRZQ WR EH VDIHU WKDQ DQ\ RWKHU Decisions regarding the timing of any elective procedures requiring anesthesia VKRXOG WDNH LQWR FRQVLGHUDWLRQ WKH EHQHƓWV RI WKH SURFHGXUH ZHLJKHG DJDLQVW the potential risks. Adverse Reactions: 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV UHSRUWHG LQ ! of patients (N=630) receiving Byfavo 5-30 mg (total dose) and undergoing colonoscopy (two studies) or bronchoscopy (one study) were: hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension. 8VH LQ 6SHFLƓF 3RSXODWLRQV Pregnancyŋ7KHUH DUH QR GDWD RQ WKH VSHFLƓF effects of Byfavo on pregnancy. Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation and respiratory depression. Lactation—Monitor infants exposed to Byfavo through breast milk for sedation, respiratory depression, and feeding problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 5 hours after Byfavo administration. Pediatric Use—Safety and effectiveness in pediatric patients have not been established. Byfavo should not be used in patients less than \HDUV RI DJH Geriatric Use—No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, there is a potential for greater sensitivity (eg, faster onset, oversedation, confusion) in some older individuals. Administer supplemental doses of Byfavo slowly to achieve the level of sedation required and monitor all patients closely for cardiorespiratory complications. Hepatic Impairment—In patients with

One sedative. Many patients.™

severe hepatic impairment, the dose of Byfavo should be carefully titrated to effect. Depending on the overall status of the patient, lower frequency of supplemental doses may be needed to achieve the level of sedation required for the procedure. All patients should be monitored for sedation-related cardiorespiratory complications. Abuse and Dependence: Byfavo is a federally controlled substance (CIV) because it contains remimazolam which has the potential for abuse and physical dependence. %<) +&3 ,6,

Please see the Brief Summary of Prescribing Information for Byfavo on next page. ASA=American Society of Anesthesiologists Physical Status. &<3 F\WRFKURPH 3 02$$ 6 0RGLƓHG 2EVHUYHUōV $VVHVVPHQW of Alertness/Sedation. 1. %\IDYR >SDFNDJH LQVHUW@ ,QGLDQDSROLV ,1 $FDFLD 3KDUPD ,QF 2. Pastis NJ, et al. Chest 3. Rex DK, et al. Gastrointest Endosc 4. Data on File. Acacia Pharma Inc. 5. Pambianco D, Cash B. Tech Gastrointest Endosc.

Byfavo® is a registered trademark of Acacia Pharma Limited. k $FDFLD 3KDUPD ,QF $OO ULJKWV UHVHUYHG 33 %)9 Acacia Pharma Limited and Acacia Pharma Inc. are wholly owned subsidiaries of Acacia Pharma Group Plc.

critical, given the rapidly changing nature of research into COVID-19 therapeutics. Those outreach skills were put to the test when data began to show that monotherapy with bamlanivimab lacked efficacy against certain COVID-19 variants when compared with combination mAbs such as REGEN-COV. “This was a strong indication of the kind of pivot we often have to make,” Dr. Rosenberg said. “Our infectious disease pharmacists, working in conjunction with our ID physicians, are adept at tracking the COVID-19 literature see mAbs, page 12

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Pharmacy Practice News • October 2021

COVID-19 Pandemic

mAbs continued from page 11

and paying attention to new evidence. When it became clear we had to switch from bamlanivimab to REGEN-COV, we communicated the reasons why to our team, and we used the same infrastructure we built around bamlanivimab to quickly get REGEN-COV to our patients.” Although the pilot is over, “federal funds are still covering 100% of the cost of the drug, and there also has been some private funding to support the program,

so we are continuing to provide this service to our patients,” Dr. Rosenberg said.

One Patient’s Experience Martin D. Clemens, PharmD, the coordinator of pharmacy resource utilization at UF Health Shands Hospital, who also helped coordinate the pilot, emphasized how important it is for patients outside of the Gainesville area to have a local option for getting COVID-19 therapeutics. “Many of these patients have very limited financial resources, and something seemingly as simple as driving into Gainesville

&VMIJ 7YQQEV] SJ 4VIWGVMFMRK -RJSVQEXMSR for Byfavo© VIQMQE^SPEQ JSV -RNIGXMSR 7II TEGOEKI MRWIVX TVMSV XS YWMRK &]JEZS ;%62-2+ 4)67322)0 %2( )59-41)28 *36 132-836-2+ %2( 6)797'-8%8-32 %2( 6-7/7 *631 '32'31-8%28 97) ;-8, 34-3-( %2%0+)7-'7 %2( 38,)6 7)(%8-:) ,=4238-'7 4IVWSRRIP ERH )UYMTQIRX JSV 1SRMXSVMRK ERH 6IWYWGMXEXMSR • Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Byfavo. • Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. • Byfavo has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period. • Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of Byfavo. 6MWOW *VSQ 'SRGSQMXERX 9WI ;MXL 3TMSMH %REPKIWMGW ERH 3XLIV 7IHEXMZI ,]TRSXMGW Concomitant use of benzodiazepines, including Byfavo, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative IǻIGX SJ MRXVEZIRSYW &]JEZS GER FI EGGIRXYEXIH F] GSRGSQMXERXP] EHQMRMWXIVIH '27 HITVIWWERX QIHMGEXMSRW including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation. -RHMGEXMSR %\IDYR UHPLPD]RODP IRU LQMHFWLRQ LV D EHQ]RGLD]HSLQH LQGLFDWHG IRU WKH LQGXFWLRQ DQG PDLQWHQDQFH RI SURFHGXUDO VHGDWLRQ LQ DGXOWV XQGHUJRLQJ SURFHGXUHV ODVWLQJ PLQXWHV RU OHVV (SWMRK ERH %HQMRMWXVEXMSR ,QGLYLGXDOL]H DQG WLWUDWH %\IDYR GRVLQJ WR GHVLUHG FOLQLFDO HǺ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Ǻ ZKLWH O\RSKLOL]HG SRZGHU HTXLYDOHQW WR PJ UHPLPD]RODP EHV\ODWH 'SRXVEMRHMGEXMSRW %\IDYR LV FRQWUDLQGLFDWHG LQ SDWLHQWV ZLWK D KLVWRU\ RI VHYHUH K\SHUVHQVLWLYLW\ UHDFWLRQ WR GH[WUDQ RU SURGXFWV FRQWDLQLQJ GH[WUDQ

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Pharmacy Practice News • October 2021

COVID-19 Pandemic can be a nonstarter,” he said. One patient’s feedback has stayed with Dr. Clemens, he noted. “They came into one of our local infusion centers and could not be more appreciative of the support they received from our pharmacists, nurses and technicians. Not having to drive all the way to Gainesville was just icing on the cake.”

‘Pharmacy’s rapid response to the COVID19 health emergency—setting up testing sites, overseeing mass vaccination clinics and administering vaccines—underscores the essential role pharmacists can play in pandemic preparedness.’

Tocilizumab Shortages UF Health Shands pharmacists also have been busy on the inpatient side of COVID-19 management. One recent challenge has been the IV tocilizumab

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—Tom Kraus, MHS, JD shortage (page 8), “which has hit us pretty hard,” Dr. Clemens said. “When the FDA issued its EUA for the drug, we

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were OK for a few weeks. But then it really became a supply-side headache for us, and tocilizumab continues to be very hard to get.” As a result, Dr. Clemens and his colleagues have been scrambling to research and obtain alternative agents, “which is perfectly fine,” he said. “That’s our job as pharmacists.” But it can be an involved process, he stressed. “Whenever you order an alternative agent that often is not on formulary, onboarding that drug is no easy task. What’s our reimbursement for the drug going to be? How quickly can we build order sets for it into the EHR? Do we have to educate our providers on dosing?” Dr. Clemens added that “we have a cascading order pathway for COVID-19 therapeutics, and we are skilled at adjusting what is first-line, then second-line and even third-line options. So, we are well-equipped to pivot when drugs go in short supply.” Now that the PREP Act has been amended to allow pharmacists to dispense COVID-19 therapeutics (page 1), he noted, “we will be even more empowered to be part of the COVID-19 care team.”

Mass Vaccinations UF Health Shands pharmacists also have been actively involved in coordinating the administration of COVID-19 vaccines to health care workers throughout the health system. That was no small undertaking, Dr. Rosenberg stressed. “We are a very large facility; we have thousands of employees, so getting all of them vaccinated was, in and of itself, a mass vaccination event. Plus there’s all of the Health Science Center faculty and staffs at all of our colleges. We worked with the local health department and our Health Science Center colleges to set up and do those mass vaccinations at the Ben Hill Griffin Stadium at the University of Florida.” UF College of Pharmacy students and faculty “also did incredible work at the stadium,” she said. “For six to eight weeks, this was a big focus for us, and our pharmacists and pharmacy technicians really stepped up to make that huge public health effort work as seamlessly as possible.” —Marie Rosenthal, David Bronstein The sources reported no relevant financial disclosures.

14 Policy

Pharmacy Practice News • October 2021

Reimbursement Matters

Key updates on vaccine and monoclonal antibody payments

COVID-19 Reimbursement Resources T

he continuing march forward with COVID-19 vaccinations and the substantial surge in the utilization of monoclonal antibody (mAb) drugs both consume vast health care resources. Has your facility designated a team, perhaps someone in your department, to ensure that available payments actually are flowing into your health care system?

For instance, the current rate for mAb administration is approximately $450 plus the cost of the product itself. This is $45,000 in revenue per 100 administrations. Never make assumptions that this actually is happening! Have you built the necessary files into your CPOE system? Does your EMAR contain the required documentation?

Does your revenue cycle team understand NTAP billing for inpatients? Are the HCPCS codes accurate with new ones added as soon as they are released? Is IT on it? In addition to payment for the first two doses of vaccine, now that the FDA has authorized a third dose of COVID-19 vaccines for immunocompromised

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Peace of mind begins with a consistent, reliable supply of high-quality compounded products. SterRx® ready-to-use compounded products are manufactured using advanced automation with minimal human intervention and no hoods. When you outsource your compounding to SterRx, you can be conﬁdent in the quality of the product and the efﬁciency of your operation. Discover how SterRx ready-to-use compounded products can help you achieve your goals.

To learn how SterRx products can beneﬁt you, visit SterRx.com or call 1-844-319-7799

Products compounded by SterRx in accordance with Section 503B are statutorily exempt from FDA’s drug approval and adequate directions for use requirements in FDCA Sections 505 and 502(f)(1). SterRx compounded formulations are not FDA-approved or reviewed by FDA for safety or efficacy. *Automation is used in compounding, sterilizing, filling and sealing of the finished product. Post-production processes such as labeling and packing are performed manually. SterRx is a registered trademark of SterRx, LLC

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health. Please email the author at bonniekirschenbaum@ gmail.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP, FCSHP

A Reimbursement Lexicon CDC, Centers for Disease Control and Prevention; CMS, Centers for Medicare & Medicaid Services; CPOE, computerized physician order entry; CPT, Current Procedural Terminology; EMAR, electronic medication administration record; EUA, emergency use authorization; HCPCS, Healthcare Common Procedure Coding System; HHS, Department of Health and Human Services; IPPS, Inpatient Prospective Payment System; IT, information technology; NTAP, new technology add-on payment; PHE, public health emergency

people, CMS announced on Aug. 13 that Medicare will continue to pay physicians, hospitals, pharmacies and many other immunizers the national average payment rate of $40 for each dose of a COVID-19 vaccine given on or after March 15, 2021. This Medicare reimbursement rate will apply to all third doses of the vaccines, and each will have its own administration codes, according to CMS (go.cms. gov/3laqLkN). Here’s how CMS officially refers to these immunizations, for the purposes of reimbursement: Pfizer: 0003A - Immunization administration by intramuscular injection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease [COVID-19]) vaccine, mRNALNP, spike protein, preservative free, 30 mcg/0.3 mL dosage, diluent reconstituted; third dose. Moderna: 0013A - Immunization administration by intramuscular injection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease [COVID-19]) vaccine, mRNALNP, spike protein, preservative free, 100 mcg/0.5 mL dosage; third dose. It’s important to note that the American Medical Association, collaborating with the Centers for Disease Control and Prevention, released multiple 2022 revisions to CPT codes that include 15 vaccine-specific codes. Correlating each coronavirus vaccine and dosing schedule with its own unique CPT code will help you track, allocate, and optimize resources for immunization programs. Also be sure to familiarize yourself

Policy

Pharmacy Practice News • October 2021

Reimbursement Matters with some of the recently published COVID-19 immunization resources from CMS. Definitely bookmark them or save them in your e-library! To start, CMS has developed an extensive tool kit for providers with frequent updates. These tool kits contain valuable resources for enrollment, payment, coding and billing (www.cms.gov/covidvaxprovider). Topics include: • How you can enroll in Medicare to bill for administering COVID-19 vaccines: go.cms.gov/3DXLeSN • The COVID-19 vaccine Medicare coding structure: go.cms. gov/38UKUWA • Medicare payment rates for administering COVID-19 vaccines: go.cms. gov/3niMfyU

that established NCTAPs under IPPS. These payments are designed to mitigate potential financial disincentives for hospitals to provide new COVID-19 treatments. This payment policy will be in effect until the end of the COVID-19 PHE (go.cms.gov/3ngc3eK).

Ordering and Distribution For more details on ordering mAb therapy for COVID-19, email the White House COVID-19 Response Team at COVID19therapeutics@hhs.gov. It also may be helpful to establish an HHS

Protect account for weekly utilization reporting: Email hhs-protect@teletracking.com. While you are focused on learning all of these new payment and related issues surrounding COVID-19 vaccines and mAbs, remember that Medicare also covers the following vaccines: • Influenza: See flu shot frequency, coverage, payment, coding and billing at www.cms.gov/flu-provider. • Pneumococcal: An initial shot and a different, second shot per pneumococcal vaccine.

• Recommendations can be accessed at bit.ly/2YGjIce. • Hepatitis B: For certain patients at intermediate or high risk, check out these guidelines at go.cms. gov/3E1RMQ1.

Booster Update! After the FDA recently authorized a booster dose of the Pfizer-BioNTech COVID-19 vaccine for certain high-risk populations, CMS announced that it will pay for the booster shots. For more information, visit go.cms.gov/3CTd0y7. 1. ■

Discover the S.M.O.F. difference • How to bill correctly for administering vaccines, including roster and centralized billing: go.cms. gov/3yVNyWv

mAb Resources During the COVID-19 PHE, Medicare will cover mAb infusions for treating COVID-19 (when furnished consistent with their respective EUAs) the same way it covers and pays for COVID-19 vaccines. This includes administration in a variety of sites, including at home. The main COVID-19 vaccine provider link (go.cms.gov/3EcdZey) explains Medicare coverage for COVID-19 mAb products and their administration; specific product and administration codes for each product are provided in an easy-to-use chart. Covering these infusions allows “a broad range of providers and suppliers to administer these treatments, including but not limited to: Freestanding and hospital-based infusion centers, Home health agencies, Nursing homes and Entities with whom nursing homes contract to administer treatment,” according to CMS. Health care providers administering mAbs to COVID-19 patients will follow the same enrollment process as those administering COVID-19 vaccines. In addition, new COVID-19 treatments have been given New COVID-19 Treatments Add-On Payment (NCTAP) status, which provides an enhanced payment for eligible inpatients given certain new products that have been approved by the FDA or granted EUAs to treat COVID-19. CMS issued an Interim Final Rule, with a comment period,

SMOFlipid is the FIRST and ONLY lipid injectable emulsion (ILE) with 4 oil sources.

oybean oil = omega-6 fatty acids

edium chain triglycerides = rapidly available energy1

O F

live oil = omega-9 monounsaturated fatty acids ish oil = omega-3 fatty acids containing EPA and DHA Learn more about the SMOF difference and innovations that nourish at www.FreseniusKabiNutrition.com.

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

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

16 Policy

Pharmacy Practice News • October 2021

Opinion

Institutional Drug Diversion: 1991-2021 By John Burke

recently saw an article about the potential parole of David Kwiatkowski, a radiology technician who had been sentenced in 2012 to several decades in a federal penitentiary for his drug diversion activity at Exeter Hospital, in New Hampshire. I became very familiar with this case because it was one of the most egregious examples of institutional

drug diversion in the United States. I wrote several articles about it, traveled to Exeter to help train their employees and provided my expertise on a limited basis. Mr. Kwiatkowski was employed as a traveler with a national agency, and he was sent to various locations in the United States, where he worked oftentimes in and around the operating room of these health care facilities. However, he had a secret: He was addicted to

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

WARNING: DEATH IN PRETERM INFANTS • Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm infants and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. INDICATIONS AND USAGE SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. DOSAGE AND ADMINISTRATION The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk Package for admixing only and is not for direct infusion. Prior to administration, transfer to a separate PN container. CONTRAINDICATIONS Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL. WARNINGS AND PRECAUTIONS • Death in Preterm Infants: (see BLACK BOX WARNING) • Hypersensitivity Reactions: SMOFlipid contains soybean oil, fish oil, and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut oil. Signs or symptoms of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and undertake appropriate treatment and supportive measures. • Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can support microbial growth and is an independent risk factor for the development of catheter-related bloodstream infections. The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions or drugs. • Fat Overload Syndrome: This is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, fatty liver infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). • Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop.

several substances, with fentanyl being his drug of choice when he could obtain the pharmaceutical meant for patients. One of his first encounters occurred in Phoenix, where he was found by staff in the restroom, passed out, with a fentanyl syringe swirling in the toilet bowl. Law enforcement, along with Mr. Kwiatkowski’s traveling agency supervisor, were contacted. When the officer arrived, she was told by someone

• Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum. During prolonged PN administration in patients with renal impairment, the aluminum levels in the patient may reach toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, including preterm infants, who receive parenteral intakes of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products. • Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction. • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. • Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. • Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. ADVERSE REACTIONS Most common adverse drug reactions >1% of patients who received SMOFlipid from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device-related infection. Less common adverse reactions in ) 1% of patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis. The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Infections and Infestations: infection. Respiratory, Thoracic and Mediastinal Disorders: dyspnea. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters. USE IN SPECIFIC POPULATIONS • Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women. • Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients. • Hepatic Impairment: Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure. OVERDOSE In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid infusion until triglyceride levels have normalized. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum. REFERENCE: 1. Deckelbaum RJ, et al. Biochemistry (Mosc). 1990;29(5):1136-1142.

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

at the hospital that her services were not needed, and she left. However, the traveling agency supervisor arrived in short time and was able to whisk his employee away quickly, with no resistance from hospital staff. At this point, all the future crimes and human destruction could have come to an abrupt halt, and Mr. Kwiatkowski might very well have gotten the drug rehabilitation that he needed. If the officer had been allowed to do her job and Mr. Kwiatkowski faced criminal charges, or even if the hospital and/or traveling agency had reported the offense as required, this incident would have had a positive adjudication. Unfortunately, none of that happened and the radiology technician was placed in several other hospitals across the country, with no reporting or notification to those facilities about the previous diversion-related offenses. As a result, at least 10 health care facilities across the country were victimized by his criminal activities. Somewhere along the way, Mr. Kwiatkowski contracted hepatitis C virus (HCV), a disease at the time that did not have the luxury of the modernday substantial cure rate. His primary method of diversion was to pay attention in the OR for anesthesiologists or nurse anesthetists to leave their medications unattended. He would remove one or more fentanyl syringes, move quickly to the restroom and inject himself. He would then replace the liquid in the syringe with water and return the now-tampered syringe back into the unknowing health professional’s drug bag or kit. The patient then received water instead of fentanyl during their procedure. When these kinds of cases are investigated or monitored, the investigator is carefully looking for signs of diversion. This could include many things, but charting and wastage might be at the top of the list. However, in this situation, none of that would have been askew because the drugs were being diverted by someone who had no legal access to the medications. In other words, on the surface, there would have been no telltale signs of diversion. Mr. Kwiatkowski’s path included the infection of individuals along the way with HCV, because he was sometimes under suspicion or even caught at various institutions, and always allowed to

Policy

Pharmacy Practice News • October 2021

Opinion

move on without a report to local law enforcement, the Drug Enforcement Administration (DEA), or state boards of pharmacy. Things came to a halt at Exeter Hospital when Mr. Kwiatkowski came under suspicion and tested positive for HCV, and had obvious signs of drug addiction. By this time, several patients who had had procedures at Exeter when he was working had contracted HCV—a nightmare for the patients and the hospital. This time, an investigation was conducted, and Mr. Kwiatkowski was charged with multiple federal felonies and incarcerated. His parole request, after nine years of a 30-year sentence, was denied. As you might imagine, the lawsuits that resulted against multiple health care facilities and others were staggering. The dollar amounts of the settlements are unknown, but they were substantial. Any of the facilities, starting with the one in Arizona, could have put a stop to this trail of misery by merely reporting the offenses as required by law! These were crimes—federal and state felonies—and by reporting to local law enforcement and notifying DEA Diversion via a Form 106 for loss of controlled substances, Mr. Kwiatkowski’s addiction could have been curtailed earlier, and innocent patients would not have suffered. I truly thought that this incident would be a wake-up call for health care facilities around the country. I thought it would make them realize that the results of not reporting drug diversion in their facility were so severe that policies would be developed to do the right thing and follow the law and regulations of their states. I come from a background of law enforcement, almost 50 years total. In 1990, I was able to form and command the Cincinnati Ohio Police Department’s Pharmaceutical Diversion Squad. This was very new to law enforcement, and if the Ohio Pharmacy Board had not provided grants to cities in Ohio, we likely would never have discovered the problems with health care facility diversion. With the Ohio Pharmacy Board’s help, we quickly realized the scope of the problem in our city. In short order, we were averaging almost a nurse arrest per week, 50 per year for almost nine years. This was a staggering number, in my opinion,

and only happened after we and the board pharmacists went to each hospital and nursing home group to remind them of their responsibilities to report to us. Of course, we didn’t get every health care professional who was diverting drugs, but it was 50 more per year than had ever been reported in Cincinnati. Our efforts received lots of media attention, and we were featured on “Dateline” for our work, but we never revealed the health care facility or those arrested, although the information was available as public record. One constant question

from the media was how bad this problem really was across the nation. This prompted me to do an unscientific study of my own by using the population of Cincinnati and comparing our number of cases with the population of the United States. The numbers again were hard to believe. It amounted to approximately 30,000-plus cases nationwide, and over 100 per day from 1991 to 1999. Modern-day statistics put the number of reported health care facility diversion cases at 350 or less. In other words, less than four days of likely cases

are reported each year to authorities. Have things changed in 30 years? I think there are many more institutions that have implemented checks and balances, and are trying to do their best. This is encouraging, but much more needs to happen to safeguard patients and find meaningful rehabilitation for offenders. Mr. Burke is the co-founder and president of the International Health Facility Diversion Association, a nonprofit 501-C3 dedicated to providing education on the topic of drug diversion in health care facilities.

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18 Policy

Pharmacy Practice News • October 2021

Sterile Compounding

10 Tips for 503A/Bs continued from page 1

sterility and subvisible particulates; instead, you test a small percentage of the batch. Those that come back having passed obviously will not be delivered to a patient, unlike the remaining untested units. “You can’t rely on testing to say that you produce quality preparations,” Dr. Summers said. She noted that, in 2020, the FDA began teaching boards of pharmacy how to apply Current Good Manufacturing Practice standards to the compounding pharmacy setting, and predicted an impending paradigm shift. “The regulators will be expecting you to scientifically justify everything you do,” Dr. Summers explained. “Saying you follow the standards just won’t be good enough. We’re going to need to have quality built in, not tested in, to our systems from the facility and equipment to materials and personnel. Quality has to be at the center of everything that you do.” Scientific approaches to ensuring sterility or potency include process validations, media fills, best practices in gowning and cleanroom behavior, appropriate environmental and personnel monitoring, and appropriate cleaning and disinfection programs. “If you have all that working for you, you know you are making a good-quality product,” Dr. Summers said. She broke down quality management systems for sterile compounding pharmacies into 10 key categories: 1. Organization and personnel. “Who’s responsible and who does what? A clear organizational chart provides a visual overview that helps everyone understand, from a legal standpoint, which personnel are allowed or not allowed to perform certain functions,” she

‘Coach your personnel to respond truthfully only to the questions [a cleanroom inspector asks], and not to volunteer any additional information.’ —Helen McKnight, PharmD

said. “Make sure you have one and keep it current. For personnel, you need clear training and competency requirements in aseptic operations, documents, visual inspection, labeling and packaging, cleaning and disinfection, and SOPs [standard operating procedures] like gowning and handwashing. Lots of folks just have their employees read the SOPs, provide one demonstration and then jump into qualification without providing proper mentorship and training. You must document that training and how it was performed.” 2. Building and facilities. “Your primary and secondary engineering controls, such as ISO [International Organization for Standardization class] 5 and ISO 7 environments, must work as intended. Air movement patterns, air exchange, particle counts, pressure differentials, temperature and so on must meet defined industry standards,” Dr. Summers said. If you have an aging facility, she recommended certifying spaces semiannually. “Don’t just take the certifier’s word for it. Study your reports, watch the unidirectional air flow patterns in dynamic smoke studies to ensure there are no weak points anywhere near the critical site or aseptic working area. And don’t stress your cleanrooms beyond their studied maximum capacity. If there are two people allowed at a time in fill suite A, then you’d better not have three in there.” 3. Equipment. SOPs should exist for the calibration, qualification, maintenance and documentation of all equipment. “Don’t say, ‘Use pH meter per manufacturer instruction,’” Dr. Summers said. “Go into detail about how to use it at your organization. What is the relative humidity of the room while the meter is in use? Will you use one particular pH meter for

preparations having highly acidic values and another for highly basic, or will you use the same one? Your SOPs need to be highly specific.” 4. Critical supplies. A lack of qualifying materials has led to several recalls in compounding pharmacies and compromises in patient safety, Dr. Summers noted. “It’s not enough to buy from a supplier that ‘everyone uses.’ Each must be qualified, with the latest regulatory audit report, and if you’re a 503B, complete testing of the first three lots of materials and complete testing of one lot per year.” 503As that use active pharmaceutical ingredients (APIs) to compound sterile preparations from non-sterile materials “should consider testing critical parameters of APIs (e.g., assay, endotoxins, bioburden) to confirm they meet specification, and therefore quality,” Dr. Summers stressed. She also advised pharmacies to create a survey outlining what you want to know from each supplier, and if you can’t travel to them, perform a “desk audit” by asking for SOPs or validation documents of interest to you. 5. Production and process controls. Stability and beyond-use dating (BUD) assignments for all preparations are essential elements of process and production controls in compounding. “How should this preparation be stored once it’s finished; how long is it good for? Do pertinent staff know how to assign BUD and store each product?” Dr. Summers asked. “Is that information easy to find on the master formula and compounding record for each compound?” She added that pharmacies relying on USP or manufacturer directions for BUD assignment should still perform period spot testing regularly. For both 503As and 503Bs, Dr. Summers recommended that those tasked with overseeing compounding quality make it a daily habit to walk the floor and audit the process firsthand.

‘Don’t stress your cleanrooms beyond their studied maximum capacity. If there are two people allowed at a time in fill suite A, then you’d better not have three in there.’ —Amy Summers, PharmD

“This doesn’t have to be lengthy if you do it daily,” she said. “Even 10 minutes will help you gauge the quality built-in status of your organization.” 6. Labeling and packaging controls. “Whether you’re a major 503B or a small compounding pharmacy, proper labeling procedures include security, selection, printing, application and reconciliation,” Dr. Summers said. Security: Where are your labels stored, and who can access them? Selection: Are they all blank, white and similar in appearance, or at least partially preprinted? How do you prevent mix-ups? Printing and application: Who prints and applies them, and when is this done? Reconciliation: If you’re batch labeling, is each label accounted for at the end of preparation? Does the preparation count match the label count? What happens to any leftover labels? 7. Holding and distribution/dispensing. 503B outsourcers have no choice but to hold batches in quarantine until batch release results are back, but for 503As, there’s no quarantine period for single-unit preparations associated with a prescription. “Nonetheless, there is a short period where the compound is on hold waiting for pharmacist approval, and there need to be controls in place preventing compounds from going to the floor or being dispensed prior to that approval,” Dr. Summers said. 8. Laboratory controls. “If you use a third-party lab for stability studies or production batch release, qualify them like you did your suppliers,” Dr. Summers recommended. 9. Documentation. Your pharmacy should have documentation control and security for handling the generation or updating of SOPs, master formulas, protocols, compounding records and other such documents. “A good records management system assigns numbers to each control document, tracks revisions over time and maintains retrievable copies for review in a second location or electronically,” Dr. Summers said. 10. Returned and salvaged drug products. “Make sure to define a rework procedure if you intend to allow one for salvaging drug preparations,” she concluded. “This is used typically when

Policy

Pharmacy Practice News • October 2021

Sterile Compounding a warning notice, a written correction order, a citation, to even criminal charges. “That’s rare, but it could happen, and has happened,” Dr. McKnight said. “An appropriate response to a citation should be written, formal and address each one of the citation areas, whether or not the facility agrees with the findings.”

at your pharmacy. “Ask for their credentials, and have an assigned person to accompany the inspector throughout the facility,” she said. “It’s helpful to have a designated area where the inspector can review documents and meet with staff. Coach your personnel to respond truthfully only to the questions they are asked, and not to volunteer any additional information.” Regulatory preparation teams also should be prepared to outline an appropriate response to any citation that might be received, which could range from

a batch or compound fails the acceptance criteria and needs to be reprocessed before release or dispensing. Examples include pH readjustment, filtering, relabeling and repackaging. It’s also advised from a regulatory compliance perspective to have a written policy describing that returned drugs that have previously left the pharmacy are not allowed to be dispensed to a different patient.”

Aim for ‘Quality Built In’ If you have a philosophy of “quality built in” at your compounding pharmacy, you will probably perform well on any inspection by the FDA or state board of pharmacy. But it can be helpful to build your facility’s “inspection readiness,” said Helen McKnight, PharmD, MBA, BCSCP, the director of pharmacy at Princeton Baptist Medical Center, in Birmingham, Ala., in another Grand Salon session. “You should be ready to be inspected at any time, with a regulatory preparation team,” said Dr. McKnight, who is the first pharmacist in Alabama to earn the board-certified Sterile Compounding Pharmacist designation. That team should include your facility’s compliance officer, clinical staff members who work directly with patients, a representative from human resources, your engineering manager, a construction director if your facility has one, and legal counsel if your compliance officer is not an attorney. Dr. McKnight recommended that the team meet at least once a month, especially if there is a scheduled regulatory inspection coming up soon. “In 2019 and 2020, inspection trends really focused on hand hygiene, forced air mixing, and documentation and follow-up,” Dr. McKnight said. “A lot of inspectors have been asking compounding pharmacies to pull their certification records and documentation of staff training. They have been particularly interested in ensuring that the person who is most responsible for <797> has an understanding of the records they’re looking at, particularly from certification companies.” She suggested establishing an inspection protocol so that staff know exactly what to do if an inspector shows up

Avoid Informal Responses

fine. That’s not the case. You need to have documented all your communications with the agency and review your plans for implementation of responses to every violation. If you’re going to suggest that the pharmacy is exempt from any of [the violations], then you should pull those exemption guidelines and publish references to those in your response.”

A common error made by many facilities, she said, is sending a response that is too informal. “Many places believe they can send a quick letter and that will be

—Gina Shaw The sources reported no relevant financial disclosures.

New products Reference guide

As a leading manufacturer of serialized, barcoded unit-dose medications, our growing product formulary continues to support your patient safety and pharmacy efficiency initiatives. Review the most recent additions below, now available through partner wholesalers and GPOs. For the full product catalog, visit www.americanhealthpackaging.com. Unit dose oral solids AB # 10251783 10254220 10124030 10251956 10251974 10254113 10260469 10258312 10258877 10254284 10254285 10252050 10252051 10252014 10254190 10258311 10258383 10254966 10252801 10254154 10252199 10258394 10255420 10250600 10258893 10254155 10254131 10258214 10258196 10260085 10260130 10180508 10258624 10258623 10258635 10259425

Cardinal Health #

McKeson #

Morris & Dickson #

5686407 3703665 4907010 5687223 5687330 5703590 5740444 4149654 5728696 5704143 5704150 5688189 5688197 5688205 5703012 5724828 5724836 5709282 5692983 5703616 5689559 4858015 5711163 5687215 5728688 5703574 5703582 5726450 5726468 5736483 5736178 5391024 5728233 5728241 5728258 5731617

1581669 2302917 2027480 1583525 1584333 3790623 2349314 3274917 2334258 3901725 3901741 1584887 1584903 1584911 2302966 2329746 2329761 2303436 1591213 3409216 1585892 2016327 2308062 1575356 2333243 3691490 3693793 2329555 2329571 2343838 2343168 3700200 2333557 2333581 2333649 2338465

930750 981878 612515 921866 921882 981910 106591 956623 040410 982025 982033 921783 921791 921817 981886 032094 032110 045013 944314 042218 922336 257253 019042 927640 039784 981803 981845 035055 035220 103572 102426 075291 039560 039602 039594 114736

Product description

Strength

Atomoxetine Capsule Budesonide Capsule (Enteric Coated) Calcium Acetate Capsule Diltiazem HCl Tablet Diphenoxylate HCl/Atropine Sulfate Tablet (CV) Famotidine Tablet Febuxostat Tablet Fenoﬁbrate Capsule (Micronized) Fenoﬁbrate Tablet Fluphenazine HCl Tablet Fluphenazine HCl Tablet Gabapentin Capsule Gabapentin Capsule Gabapentin Capsule Hydrochlorothiazide Tablet Hydromorphone HCl Tablet (CII) Hydromorphone HCl Tablet (CII) Ketorolac Tromethamine Tablet Levothyroxine Sodium Tablet Lisinopril Tablet Mesalamine DR Capsule Potassium Chloride ER Tablet Prazosin HCI Capsule Propafenone HCI Tablet Propranolol HCl Tablet Rifampin Capsule Rifampin Capsule Ropinirole Tablet Ropinirole Tablet Omeprazole DR Capsule Sennosides and Docusate Sodium Tablet Tolterodine Tartrate ER Capsule Valsartan Tablet Valsartan Tablet Valsartan Tablet Valacyclovir Tablet

UD size

25 mg 3 mg 667 mg 60 mg 2.5 mg / 0.025 mg 20 mg 40 mg 200 mg 145 mg 5 mg 10 mg 100 mg 300 mg 400 mg 25 mg 2 mg 4 mg 10 mg 200 mcg 2.5 mg 400 mg 10 mEq 5 mg 150 mg 10 mg 150 mg 300 mg 0.25 mg 1 mg 40 mg 8.6 mg / 50 mg 4 mg 40 mg 80 mg 160 mg 500 mg

30 UD 20 UD 100UD 100 UD 100 UD 100 UD 30 UD 30 UD 30 UD 100 UD 100 UD 100 UD 100 UD 100 UD 100 UD 100 UD 100 UD 30 UD 100 UD 30 UD 20 UD 100 UD 20 UD 100 UD 100 UD 30 UD 100 UD 100 UD 100 UD 100 UD 100 UD 30 UD 30 UD 100 UD 100 UD 30 UD

NDC 11 60687-0567-21 60687-0596-32 68084-0479-01 60687-0573-01 60687-0569-01 60687-0595-01 60687-0538-21 68084-0329-21 60687-0629-21 68084-0846-01 68084-0950-01 60687-0580-01 60687-0591-01 60687-0602-01 60687-0593-01 60687-0579-01 60687-0590-01 60687-0104-21 60687-0552-01 68084-0765-21 60687-0556-32 68084-0632-01 60687-0572-32 60687-0537-01 60687-0587-01 60687-0575-21 60687-0586-01 60687-0577-01 60687-0588-01 60687-0608-01 60687-0622-01 60687-0330-21 60687-0612-21 60687-0623-01 60687-0634-01 68084-0215-21

Liquid unit dose AB #

Cardinal Health #

McKesson #

Morris & Dickson #

Product description

Cup delivery

10249925 10258469 10258500

5676135 5725668 5725676

1574276 2328805 2328821

914382 034397 034371

Atovaquone Oral Suspension Midazolam HCL Syrup (CIV) Midazolam HCL Syrup (CIV)

5 mL 2.5 mL 5 mL

10251651

5699970

3579828

971820

Milk of Magnesia Saline Laxative (Magnesium Hydroxide)

30 mL

Cup strength 750 mg / 5 mL 5 mg / 2.5 mL 10 mg / 5 mL 2400 mg / 30 mL

Pack size

NDC 11

42 ct 30 ct 30 ct

60687-0534-78 60687-0576-10 60687-0576-86

100 ct

60687-0429-76

Hitting the mark AHP unit dose simpliﬁes one of the most complex parts of your job – reliably obtaining ready to dispense medications – in a format that promotes positive outcomes for your patients.

800.707.4621 americanhealthpackaging.com AH-100033 21.09

20 Policy

Pharmacy Practice News • October 2021

Drug Development

The Patent Slow Dance Trips Up Access to Rx Savings T

he Biologics Price Competition and Innovation Act (BPCIA), passed by Congress in 2010, aimed to streamline the process of getting biosimilar drugs to market by creating an abbreviated approval pathway for these versions of the original high-priced biologic drugs. Given that potential for savings, where has the process gone awry? At first glance, BPCIA seems to have worked: Approximately 30 biosimilars have been approved by the FDA since 2015 (bit.ly/2XtPc4U). Unfortunately, at least eight cannot enter the market between two and nine years because of patent litigation and exclusivity.

The result is that originator and biosimilar manufacturers often reach confidential settlements to avoid the patent dance, settlements that may be satisfactory to the parties involved but ultimately delay the availability of biosimilars and cost the health care system additional billions of dollars. “The BPCIA was envisioned as a complicated, but clearly laid out, stepwise process of litigation,” said co-author Ameet Sarpatwari, MD, JD, an assistant professor of medicine and the assistant director of the Program on Regulation, Therapeutics and Law in the Division of Pharmacoepidemiology

‘While these [patent] settlements may be in the interest of both parties, they aren’t in the best interest of the public if they result in delayed access to biosimilars.’ —Isha Rana, PharmD According to a new analysis by authors from Brigham and Women’s Hospital and Harvard Medical School, in Boston, published in Health Affairs, two factors play a key role in these delays: Biosimilar manufacturers frequently fail to comply with steps in the complex litigation process—colloquially known as the “patent dance”—established by the BPCIA, and originator manufacturers enforce a large number of patents, the exact number and nature of which are commonly unknown to the biosimilar manufacturers (Health Aff 2021;40[8]:1198-1205).

and Pharmacoeconomics. But that’s not how it played out in the real world. When Dr. Sarpatwari and his co-authors reviewed all 21 lawsuits identified as related to the BPCIA litigation process that had been filed as of Aug. 1, 2020, which involved nine originator biologics and 21 biosimilars, they found that 19 of the 21 included claims that the biosimilar manufacturer had not complied with that process. The claims included “failure to share an [abbreviated Biologics License Application],” “failure to exchange patent lists” and “failure to

engage in good faith negotiations.” That’s actually not surprising, Dr. Sarpatwari said. “No biosimilar company would really want to share this sensitive information. And the Supreme Court’s June 2017 ruling in Sandoz v Amgen said the ramifications for not following the process aren’t that consequential, which leaves biosimilar manufacturers the flexibility to decide not to follow the process if they don’t want to.” For their part, originator manufacturers have built up large portfolios of patents on their innovator drugs, with no single resource available to iden-

tify those patents. The Health Affairs analysis found that, across the 21 cases, a median of six patents were alleged to have been infringed per suit, with nine cases involving 20 or more patents each. That’s a small fraction of the patents established on the drugs in question. “For example, although an estimated sixty-six patents protected infliximab [Remicade], Janssen litigated only six patents with biosimilar manufacturers Celltrion and three with Samsung Bioepis,” Dr. Sarpatwari and his colleagues wrote. “The originator drugs adalimumab, bevacizumab, etanercept, infliximab, rituximab and trastuzumab were protected by a median of ninety patents.” In the small-molecule space, the originator company is required to report the patents protecting its property to the FDA, but that’s not the system established by BPCIA. Instead, until recently, originator manufacturers were not required to report patents protecting their products to the FDA. “Biosimilar

manufacturers thus had to compile a comprehensive patent landscape analysis to gauge potential risk when determining whether market entry was possible,” Dr. Sarpatwari said. The Consolidated Appropriations Act of 2020 now requires originator manufacturers to report patents listed as part of the BPCIA litigation process to the FDA for public disclosure in the “Purple Book,” the equivalent of the “Orange Book” in the small-molecule world. “Clinically, that may not hold much bearing, but it will certainly help from an educational perspective to know which patents there are on these products,” said Isha Rana, PharmD, a pharmacy administrative specialist in formulary management and drug information at Houston Methodist. Although Sandoz v Amgen found that the BPCIA’s procedural process was not mandatory for biosimilar manufacturers that preferred to launch “at risk,” as a practical matter, the fortress of intellectual property protections and the uncertainty among biosimilar manufacturers as to whether they have even identified all the patents means that most of them have elected to settle with the originators. “You’ll hear from both sides that this is not a problem. It resolves uncertainty and there is no litigation cost,” Dr. Sarpatwari said. “But while these settlements may be in the interest of both parties, they aren’t in the best interest of the public if they result in delayed access to biosimilars. The quality of these secondary patents on biologics [isn’t] that great, and if biosimilar manufacturers were aggressively challenging them, it’s likely that for at least some of the products, biosimilars would come to market earlier and we would see millions—if not billions—in savings.” He cited one example: adalimumab (Humira, AbbVie). As of January 2021, six adalimumab biosimilars had been approved by the FDA, but the first expected to come to market, adalimumab-atto (Amjevita, Amgen), likely won’t be available in the United States until January 2023—nearly seven years after its approval in September 2016. In another recent study, Dr. Sarpatwari and his colleagues calculated that if biosimilar versions of adalimumab had launched when they were approved, it would have saved $2.6 billion in Medicare costs alone (Clin Pharmacol Ther 2021 Jun 18. doi:10.1002/cpt.2322). The analysis provides muchneeded insight for pharmacists who are trying to clarify for providers and patients why an approved biosimilar might not yet be available or might not be approved for all the indications the originator was

Policy

Pharmacy Practice News • October 2021

Drug Development

‘The originator drugs adalimumab, bevacizumab, etanercept, infliximab, rituximab and trastuzumab were protected by a median of ninety patents.’ —Ameet Sarpatwari, MD, JD

approved for, Dr. Rana said. “This article elucidates the problem that I’ve come across in my own background research, trying to figure out what the reasons are why one biosimilar may be approved in one indication while another is not,” she said. “For example, Ruxience [rituximab-pvvr, Pfizer] is not approved for rheumatoid arthritis [RA], but Truxima [rituximab-abbs, Teva] is. A lot of the reasons for these differences may stem from patent settlements. What’s helped me a lot in educating providers is benchmarking some of these approvals to other countries that have these biosimilars approved. Ruxience is approved for RA in the [European Union], Canada and Australia, for example, meaning that this lack of approval is a uniquely American issue and not necessarily a clinical question. That still impacts our practice, because payor policies dictate coverage, but clinically there is more confidence in considering this product to be appropriate for the indication despite not having the approval.”

Solving the Patent Morass So, what’s the solution? Dr. Sarpatwari’s team has several recommendations, some more feasible under current conditions than others. They note that

new federal legislation could reform the he BPCIA to increase transparency and/orr to limit the amount of time patents on biologics could be enforced, suggesting the 12-year postmarketing period imposed by the BPCIA during which biosimilars cannot be approved is “arguably adequate for biologic manufacturers to recoup their investments.” They also point to the Affordable Prescriptions for Patients Through Improvements to Patent Litigation Act of 2019, introduced by Reps. Hank Johnson (D-Ga.) and Martha Roby (R-Ala.), which would cap the number of non–method-of-use patents (patents that protect the biologic product or formulation or a method or product used in the manufacturing process) that could be litigated to 20. These options, however, involve getting Congress to take action. “It’s a tough ask to do through legislation,” Dr. Sarpatwari said. Other options the authors recommend include increasing the oversight of these anticompetitive settlements, both by allotting additional resources to the Federal Trade Commission as well as through state action, such as a law enacted in California in 2019 that makes “reverse payment settlements”

If biosimilar versions of

adalimumab had launched when they were approved, it would have saved

$2.6 billion in Medicare costs alone. Source: Clin Pharmacol Ther 2021 Jun 18. doi:10.1002/cpt.2322

like these presumptively anticompetitive under state law. They also recommend addressing excess patenting by allotting more resources to patent examiners at the U.S. Patent and Trademark Office to ensure that fewer unmerited drug patents are granted. “In one study, a 50% increase in examination time was associated with a 10% decrease in the issuance of invalid secondary patents,” Dr. Sarpatwari noted (NBER Working Paper No. 27579. https://www.nber.org/papers/w27579). He and his colleagues pointed out the startling fact that a single person in the U.S. Patent and Trademark Office assesses each pharmaceutical patent application, compared with three in the European Patent Office (which processes fewer than half the number of claims reviewed by the U.S. counterpart). “We’re probably granting patents that we shouldn’t be,” Dr. Sarpatwari said. “If we can pour more resources into the process early on, we can filter out bad patents.” Even if some of these issues are addressed, it doesn’t solve the overall problem, said Gillian Woollett, MA,

DPhil, the senior vice president of Avalere Health and author of a recent paper supporting regulatory consistency for the evaluation of all biologics, including biosimilars (BioDrugs 2021;35[4]:379-387). “We have the candid conversation We have to h that the natur nature of the U.S. health care system does not necessarily [incentivize] the cheaper products,” she said. “Even use of cheape if we become more efficient and get these market in half the time at half products to m the price—and I do think that’s possible— wouldn’t solve that problem.” it still wouldn Dr. Woollett Woollet believes the patent hurdles are only hal half the equation. “Approvals too long and we’re repeating are taking to too many studies, especially clinical have to incentivize efficienones. We h said, citing an October 2020 cy,” she sa draft guidance from the U.K. dra Medicines and Healthcare M Products Regulatory AgenP ccy, finding that comparative eefficacy trials for biosimilars are not needed except in rare cases, as biosimilarity can typically be demonstrated by analytical testing and a pharmacokinetics trial. “Taking this approach in the U.S. wouldn’t require any legislative action at all,” she said. “The FDA could do it overnight. The reimbursement system also has to incentivize the use of the lower-cost product. What we’re seeing with these arguably very old biologics is that we’ve built a regulatory system that is too cumbersome and too expensive for all biologics, and where even the originators are forced to spend their resources on patent litigation rather than on innovation.” —Gina Shaw Dr. Rana reported that she is the primary investigator for a research study funded by a grant from Pfizer and the National Comprehensive Cancer Network evaluating the impact of discordant preferred biosimilars between payors and hospitals. Dr. Sarpatwari reported that his research on biosimilars was funded by Arnold Ventures. Dr. Woollett reported that she is an employee of Avalere Health and works with multiple stakeholders in health care, including biopharma companies (originator and generic), health insurance plans, providers and patients’ groups.

22 Clinical

Pharmacy Practice News • October 2021

Oncology

High Cost of CAR-T Rx continued from page 1

first assigning Medicare inpatient stays involving CAR-T treatment to the existing diagnosis-related group code DRG 016 (autologous bone marrow transplant with CC/MCC or T-cell immunotherapy), with an average national reimbursement rate of $43,094, in fiscal year (FY) 2021, the Centers for Medicare & Medicaid Services began using the new DRG 018 (chimeric antigen receptor [CAR] T-cell immunotherapy), with an average national reimbursement rate of $239,933. That figure is much closer to the actual drug cost than DRG 016, but even with adjustments such as new technology add-on payments (NTAP)—which are no longer available for existing CAR-T therapies but may be applied to new products in FY 2022—hospitals often do not break even on these cases. “Even with these adjustments, Medicare reimbursement for CAR-T cases today often fails to cover total hospital costs, with potential negative impacts on provider uptake and patient access,” experts from Avalere wrote in a May 2021 analysis (bit.ly/3yeAY5j). “The DRG bundle is not comparable to our costs, not by a long shot,” said Sarah Perreault, PharmD, BCOP, a clinical pharmacy specialist with the cellular therapy program at Yale New Haven Smilow Cancer Hospital, in Connecticut. “Usually, we are left picking up the tab.”

Proposed Changes Fall Short The situation is unlikely to improve significantly with the new FY 2022 Inpatient Prospective Payment System (IPPS) proposed rule, released by CMS at the end of April 2021. It proposes an increase to the base operating and capital rates for all IPPS payments, as well

as an increase in the proposed relative weight for DRG 018, which would boost the base payment for CAR-T therapy cases by 3.2%, to $247,584. CMS also proposes using 2019 Medicare Provider Analysis and Review data to set relative weights for DRGs, rather than the 2020 data that typically would be employed, given that the COVID-19 pandemic distorted utilization patterns last year. Combining the DRG payments with outlier payments, fixed-loss payments and add-on payments (assuming at least some of the four products being considered for 2022 NTAP status are approved), Avalere reached an example total Medicare payment of $370,229 for one CAR-T case in FY 2022, compared with $369,839 in FY 2021. In both cases, reimbursement lags behind the average drug cost alone, and doesn’t come close to meeting the other hospital costs. “The 3% increase is not significant. It’s minuscule when you think of the costs we’re facing,” said Ankit Kansagra, MD, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center, in Dallas, who specializes in stem cell transplants and CAR-T therapy. “The products have been going up in cost by $40,000 or more, so the norm is becoming more like $400,000 to $420,000.” In the United States, 11 cancer hospitals fall under the Prospective Payment System (PPS)-Exempt Cancer Hospital Quality Reporting Program and are reimbursed on a “reasonable cost” basis rather than by DRG. But they also have been challenged in terms of Medicare reimbursement for CAR-T, said

$411,278 Median drug cost $610,999 Median total cost of care $1 million+ Total cost of care

‘There has been a huge drive, not just at our institution but across all the CAR-T programs, to push more to the outpatient setting to drive costs down and recoup some of the losses.’ —Sarah Perreault, PharmD, BCOP Julie Kennerly-Shah, PharmD, the assistant director of pharmacy at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, in Columbus, one of the 11 hospitals. “We have a maximum case rate we can receive for any case with Medicare, and the cost of CAR-T far exceeds that maximum case rate.” Dr. Kansagra also is concerned about another element in the IPPS proposed rule, which would rename MS-DRG 018 to “Chimeric antigen receptor (CAR) T-cell and other immunotherapies”—adding new procedure codes for non–CAR-T therapies and other immunotherapies. “Trying to lump all immunotherapies in with CAR-T in this DRG is disastrous and doesn’t make sense,” he said. “You can’t put bispecific therapies into the same category as CAR-T.” Bispecific therapies, he explained, are bispecific monoclonal antibodies, engineered to bind to two types of antigen— for example, a tumor antigen and an immune T-cell—as opposed to standard monoclonal antibodies, which can bind only to their single target protein. These drugs have shown promise in cancer immunotherapy, and would be more “off the shelf” treatments than CAR T. Combining the two categories, he warned, “may lead to even larger deltas between the costs of these treatments to institutions and what we are being

reimbursed, and some hospitals may not be able to handle those deltas.”

Newer Agents Pending NTAP decisions on newer products could make the agents more attractive in the short run. As of Sept. 30, 2020, NTAP payments expired for the first two CAR-T therapies, axicabtagene ciloleucel and tisagenlecleucel. But applications for NTAP payments for four newer agents were included in the 2022 proposed rule: idecabtagene vicleucel (Abecma, Bristol Myers Squibb), approved in March 2021 for heavily pretreated relapsed or refractory multiple myeloma; lisocabtagene maraleucel (Breyanzi, Juno), approved in February 2021 for relapsed or refractory large B-cell lymphoma; brexucabtagene autoleucel (Tecartus, Kite), approved in July 2020 for relapsed or refractory mantle cell lymphoma; and Janssen’s ciltacabtagene autoleucel, also known as cilta-cel, under priority review at the FDA, with a target action date in November. “If NTAP were to go forward for [lisocabtagene maraleucel], that could really catapult that product ahead of the firstgeneration CAR-Ts for large B-cell lymphoma,” said Ajeet Gajra, MD, MBBS, the chief medical officer for Cardinal Health Specialty Solutions. “Right now, there’s a lot of competition among CAR-Ts within relapsed B-cell lymphoma, with three approved products for that indication. In the near future, we can expect there to be a lot more use of CAR-T in myeloma as the therapy evolves and new agents are approved. Most myeloma patients are older and likely have Medicare, so that issue will be even more magnified.” Most CAR-T centers are relatively well compensated by commercial insurers, Dr. Gajra said. “The bottom line is that they likely end up using the funds they are making up on commercially insured patients to support their Medicare patients to keep the program afloat.”

Figure. The cost of CAR-T therapy. a

In 12% of cases.

Source: ASCO 2021 abstract e19500.

Outpatient Setting However, it’s unclear how long that “borrowing” will remain sustainable, and the push is on to limit costs by moving CAR-T to the outpatient setting whenever possible, Dr. Gajra said. “This is already starting to happen in the outpatient practices of larger academic centers and integrated delivery networks on a limited basis. These larger practices have the ability to manage complex patients and acute toxicity in a REMS [Risk Evaluation and Mitigation

Clinical

Pharmacy Practice News • October 2021

Oncology Strategies]–compliant manner,” he said. “There has been a huge drive, not just at our institution but across all the CAR-T programs, to push more to the outpatient setting to drive costs down and recoup some of the losses,” Dr. Perreault noted. “We haven’t started doing that yet here, since it has been difficult because of the side effects. But now that we have the newer agents with a lower side effect profile, … we expect to be targeting those for more outpatient CAR-T,” she said. Dr. Gajra noted that cytokine release syndrome and neurotoxicity, the most severe adverse effects associated with these therapies, are less common with the newer agents, and typically occur later in the cycle, if at all. “With the initially approved products, you saw those effects within the first three days. Now, they’re happening five to seven days out, if they’re happening at all. The oncology community also has learned to prevent and mitigate these complications through the use of prophylactic medications, paving the way for increased outpatient administration.” “We try to administer CAR-T therapy in the outpatient setting when possible. That significantly changes the financial outlook of these therapies, particularly in the context of Medicare,” Dr. Kennerly-Shah agreed. “We have invested a lot of resources into infrastructure to ensure that we can appropriately monitor patients in this setting.”

‘Trying to lump all immunotherapies in with CAR-T in this DRG is disastrous and doesn’t make sense. You can’t put bispecific therapies into the same category as CAR-T.’

with a specific insurance company. There are many different models, and we have to find something that doesn’t break the bank and makes the process quicker and smoother.” —Gina Shaw

—Ankit Kansagra, MD the indication was just lymphoma, we got into a good rhythm with the insurance companies; but within the last year or so, as there has been more activity in different diseases and lines of treatment, the

PA process has become harder. It’s been proposed that we move to less of a case agreement approach and more bucketed, predetermined lump-sum payments, with one contract in place for all indications

Dr. Gajra is an employee of Cardinal Health Solutions. Dr. Kansagra reported financial relationships with Alnylam, BMS/ Celgene, Cota Health, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptide, Pfizer, Pharmacyclics, Sanofi and Takeda. Dr. Perrault reported no relevant financial disclosures.

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On the Horizon Dr. Gajra also speculated that the current reimbursement picture may be time-limited. “All of the approved CAR-T products are autologous, requiring the complicated individualized process of leukapheresis, freezing and reprogramming,” he said. “The development of allogeneic, or so-called ‘off the shelf,’ CAR-T therapies is moving fast, and if successful, will simplify the process immensely. The biggest fear with this approach was graftversus-host disease [GVHD], but early reports don’t suggest that [GVHD] is frequent or unmanageable in these patients, and early outcomes look very promising for many of the products’ efficacy.” Allogeneic CAR-T therapies also could simplify the complicated PA dance between providers and commercial payors. “Our most significant commercial reimbursement challenge in the beginning was obtaining single-case payor agreements,” Dr. Kennerly-Shah said. “A lot of payors pushed for bundled payments, which is certainly an option. You also can negotiate a rate specifically for the CAR-T therapy itself, while everything else is reimbursed at your normal rate with that payor,” she added. “Right now, our prior authorizations for CAR-T involve a single case agreement for every single patient,” Dr. Kansagra said. “As more products come into place, that becomes more complicated. When

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24 Clinical

Pharmacy Practice News • October 2021

Immunology

Plasma donations at risk

Will Restrictions at the Border Lead to IG Shortages? F

or well over a year, pharmacists, physicians and patients have been anticipating the possibility of a shortage of immune globulin (IG) products, as the COVID-19 pandemic led to a significant decline in donations of the blood

plasma that is the primary component of these therapies. According to the Plasma Protein Therapeutics Association, plasma donations fell by 20% in 2020. Because the fractionation process that turns

donated plasma into IG can take nine to 12 months from “needle to needle,” it was expected that shortages might first appear in the beginning of 2021, but as Pharmacy Practice News reported in May 2021, the IG supply in the United

‘Nearly 125,000 people in the U.S. with rare diseases, as well as countless others facing trauma and emergency medical needs every day, rely on medicines that are only available because of the commitment of dedicated plasma donors, and this new policy risks hindering the availability of these lifesaving medicines.’ —The Plasma Protein Therapeutics Association

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States remained relatively robust well into this spring (bit.ly/3AOgBNp). However, that may change with the imposition of new restrictions on cross-border plasma donations. Because Mexico does not allow monetary compensation for plasma donations, many Mexican citizens cross the border on a regular basis to donate plasma in the United States. On June 15, the U.S. Customs and Border Patrol (CBP) agency announced that it was putting a stop to that practice and would no longer permit Mexican citizens to cross the border on temporary visas to sell blood plasma.

“Effective immediately, U.S. Customs and Border Protection advises that donation of plasma for compensation in the U.S. by B-1/B-2 nonimmigrant visa holders is a violation of the terms of their visa, and crossing the border for that express purpose will no longer be permitted under any circumstances,” said a CBP official in a media statement. “Selling plasma constitutes labor for hire in violation of B-1 nonimmigrant status, as both the labor (the taking of the plasma) and accrual of profits would occur in the U.S. with no principal place of business in the foreign country.” With the U.S.–Mexico border closed to nonessential travel since March 2020—a policy that has been extended through September, at press time— plasma donation centers at the border had already experienced significant declines in donations, said Matthew Hotchko, PhD, the president of the Marketing Research Bureau, which

Clinical

Pharmacy Practice News • October 2021

Immunology supplies market data and intelligence on the global blood and plasma industry. “There had already been a steep dropoff. I don’t have exact figures, but I believe somewhere between 70% to 80% of plasma donors coming from Mexico had already dropped out of the regular donor pool because of the challenge of getting across the border.” Before the pandemic, the approximately 40 border centers contributed about 10% to 12% of total plasma collections in the United States, with the majority coming from Mexican citizens living in Mexico, Dr. Hotchko said. He estimated that between the border closures and the new CBP ruling, plasma donations at border centers have been reduced by more than half. “I would say that probably about 3% to 4% of total plasma collections in the U.S. are now coming from those border centers after the recent CBP policy change.” Organizations that advocate for patients with primary immunodeficiencies (PIs), such as the Immune Deficiency Foundation, have urged the Biden administration to rethink this policy change. “This action could reduce the plasma supply used to make lifesaving therapies by 5% to 10%,” said IDF vice president of public policy Lynn H. Albizo, JD, in a letter sent on June 29, 2021, to Health and Human Services Secretary Alejandro Mayorkas. “If these changes are implemented, we will see further pressure on the supply of plasma that will jeopardize the health of Americans with PI and other conditions.”

Manufacturers Also Concerned The Plasma Protein Therapeutics Association, which represents private sector manufacturers of IG products such as CSL Behring, Grifols and Takeda, also issued a statement. “The change by U.S. Customs and Border Protection to limit the ability of people to cross the border to donate plasma is bad policy that risks American lives. Nearly 125,000 people in the U.S. with rare diseases, as well as countless others facing trauma and emergency medical needs every day, rely on medicines that are only available because of the commitment of dedicated plasma donors, and this new policy risks hindering the availability of these lifesaving medicines.” So, why hasn’t the United States seen an IG shortage to date? In short, it’s likely because this country is the thousand-pound gorilla of the plasma therapeutics field. “The reimbursement for a gram of plasma in the United States is so much more than in any other country, the manufacturers moved all that they possibly could from the rest of the world into the U.S. to meet that demand, because economically that just makes the most sense

‘I would have said [plasma collections would stabilize] by end of this year but the delta variant has thrown a monkey wrench into that, and it might be mid-2022 before we see supply growing again.’ —Matthew Hotchko, PhD for them,” said Stacey Ness, PharmD, the vice president of clinical services at Managed Health Care Associates, and president of the Immunoglobulin National Society (IgNS). Not only does the United States pay more for plasma products than other countries, but it supplies most of it as well. “The U.S. supplies approximately 70% of the source plasma used to manufacture plasma therapies for the entire world,” said Peter Jawoski, PhD, an associate teaching professor in strategy, ethics, economics and public policy at Georgetown University’s McDonough School of Business, in Washington, D.C., and an advocate of compensation for plasma donors. “Virtually the entire world is dependent on the U.S.” Although there’s no shortage of IG in the United States—at least for now— shortages are beginning to appear in other countries. “The reduction in plasma collections has resulted in countries with lower prices for plasma products not getting enough supply, including many European countries and many other countries around the world,” Dr. Hotchko said.

‘The Canary in the Coal Mine’ Spain, which began reporting on shortages of IG products in early July in local and regional news outlets, may be the “canary in the coal mine” for other countries, Dr. Jaworski suggested. The newspaper La Razon reported on July 5, 2021, that hospitals are significantly lowering doses of IG products given to patients with chronic neuropathies in order to preserve supplies for those with primary immunodeficiencies. In an opinion piece published in Redaccion Medica on July 12, Teresa Lluch, the vice president of GBS/CIDP Espana, reported that La Paz Hospital, in Madrid, had to suspend all IG treatments, while La Fe Hospital, in Valencia, was receiving 30% of its normal IG supply. The National Health Service in the United Kingdom, which reinstated plasma donations in April 2021 after banning them in 1998 due to fears of Creutzfeldt-Jakob disease, has initiated its first national campaign calling for plasma donations. “They are perilously short of supply,” Dr. Jaworski said. The CBP order just makes the current trend even more negative, Dr. Hotchko said. “Countries that are struggling

now will struggle even more, but the U.S. will still have a prioritized supply because of our pricing and because we are the location of most of the source plasma. We still may see lowered supplies in the U.S. if the suppliers cannot redirect enough supply to the United States for various reasons, but I don’t see that yet.”

Shortages ‘Unavoidable’ Although this country has avoided shortages so far, Sohail Masood, PharmD, the founder and CEO of KabaFusion, which specializes in IV and subcutaneous IG therapies and operates 28 accredited home infusion specialty pharmacies nationally, thinks that is likely to change. “We do still have ample supplies of IG now, but if the border restrictions continue, I think it’s unavoidable that

shortages will hit us in the U.S., as well. It will tend to impact companies that are more dependent on the border centers first. I’m hoping we will not see any shortages, but it looks likely that we will this time around.” Dr. Hotchko predicted that collections will rebound with time, however. “I would have said by end of this year but the delta variant has thrown a monkey wrench into that, and it might be mid-2022 before we see supply growing again,” he said. “There are now more places to donate and a lot more marketing with higher donor compensation offered. There were about 100 new centers added nationwide last year, and there will be about the same number added by the end of this year.” Because the cost of collecting plasma is also going up, including increased remuneration to donors, Dr. Hotchko also predicted rising prices for IG therapies. “They are likely to rise faster than inflation, probably around the 3% to 5% per year range in the U.S., and faster in other markets.” —Gina Shaw The sources reported no relevant financial disclosures beyond their stated employment/affiliation.

26 Clinical

Pharmacy Practice News • October 2021

Nutrition

Managing Micronutrient Shortages in Neonates D

ealing with drug shortages has become standard operating procedure in the parenteral nutrition (PN) world over the past decade—and these shortages are putting hospitals’ smallest and most vulnerable patients at risk, said experts in a webinar on the ramifications of nutrient shortages in the neonatal population at the American Society for Parenteral and Enteral Nutrition’s (ASPEN) Malnutrition Awareness Week, held Oct. 4-8, 2021. As of this summer, the FDA had at least six nutrients or categories of nutrients on its list of drug shortages: 23.4% sodium chloride, amino acids, calcium gluconate, multivitamins (both adult and pediatric), potassium acetate and sodium acetate. A check of the FDA’s website as well as ASHP’s Current Drug Shortages database showed that, as of late September, with the exception of calcium gluconate, all of the nutrients still were in short supply (bit.ly/3ueE3AW). (The amino acid shortage listing was last updated on Aug. 31.) As of late September, both the FDA and ASHP also had added sodium phosphates to their shortage lists. Nutrient shortages are particularly dangerous for neonatal patients, said Ruba Abdelhadi, MD, the director of nutrition support at Children’s Mercy Hospital and a professor of pediatrics at the University of Missouri-Kansas City School of Medicine. “The risk of micronutrient deficiencies has a negative impact on neonatal growth and development,” Dr. Abdelhadi said. “There are certain vitamins that need to be administered daily, so if they are not provided, symptoms and signs of their deficiencies appear sooner than others. The longer the shortage or unavailability of the micronutrient, the more negative the impact.” These shortages have multifactorial causes, including a limited number of manufacturers, natural disasters affecting production, regulatory issues, voluntary recalls and increases in demand. According to ASPEN, since 2010, almost every component used in PN has been on shortage at least once.

Management Tips Since the challenge of PN component shortages is unlikely to be resolved in the foreseeable future, how

is greater than 50% of their needs, and reserving pediatric IV multivitamins for children under 2.5 kg or below 36 weeks’ gestational age. “To conserve your supply of pediatric products for these smaller neonates, you can consider using 5 mL of adult multivitamins in all children weighing at least 2.5 kg or at least 36 weeks’ gestational age,” Dr. Cober said.

Missing Multivitamins

‘To conserve your supply of pediatric products for these smaller neonates, you can consider using 5 mL of adult multivitamins in all children weighing at least 2.5 kg or at least 36 weeks’ gestational age.’ —M. Petrea Cober, PharmD can they be managed? “Shortages are never ideal situations, but sometimes we have to make do with options we have,” acknowledged M. Petrea Cober, PharmD, a clinical pharmacy coordinator at Akron Children’s Hospital, in Ohio, who spoke during the webinar. “Pediatric IV multi-trace element and multivitamins should be reserved for neonatal patients due to concerns regarding toxicity and excipients.” Given the vulnerability of this population, Dr. Cober said, adhering to ASPEN’s recommendations for allocating scarce trace elements and nutrients is essential (bit.ly/3ALkUcd). “For trace elements, providers should consider switching to oral or enterally administered multivitamin/multi-mineral supplements when oral/enteral intake is initiated,” she said. “It’s important to remember that not all products contain the full spectrum of trace elements, nor daily enteral maintenance dose.” Multi-trace elements should be reserved for those patients receiving PN,

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or those with a therapeutic medical need for IV trace elements. If IV multi-trace elements are no longer available, individual entities of parenteral trace elements should be administered rather than using adult multi-trace elements in neonatal and pediatric patients, Dr. Cober said. “The most important of these are zinc, copper and selenium. You may need dilutions of these products to measure dose.”

Tracing te Risk But the use of these individual trace elements is not without its own risks, Dr. Abdelhadi noted. “Every time you add a component to a bag of TPN, there’s more risk for errors and contamination,” she said. “So, if you are adding five micronutrients to a bag individually, instead of one product with multiple trace elements, that’s an increased risk with each component and addition.” For multivitamins, ASPEN recommends that you consider switching to oral or enterally administered multivitamins when a patient’s oral/enteral intake

What if no pediatric multivitamins are available at all? In that case, ASPEN recommends that infants less than 2.5 kg or 36 weeks’ gestation receive adult IV multivitamin at a daily dose of 1 mL/kg up to a maximum of 2.5 mL per day, with supplementation of IV vitamin K daily for a total daily dose equaling 200 mcg. The vitamin K content of the adult multivitamin used should be noted when supplementing vitamin K. But caution is necessary: These products contain propylene glycol, polysorbate and aluminum, which may be toxic to neonates. “Clinical judgment must prevail by weighing potential vitamin deficiencies against potential toxicities,” Dr. Cober said. “And supplemental dosing of intravenous vitamin K can be particularly challenging.” Whatever plan you develop for managing shortages has to be realistic and able to be conducted safely. “As you are moving between adult and pediatric formulations, be careful with dosing units and remember that you need standard nomenclature,” she said. “And always monitor for deficiencies.” —Gina Shaw Dr. Cober disclosed that she has a consulting relationship with Baxter, BBraun/ CAPS, Fresenius Kabi, and Wolters Kluwer (Lexi-Comp). Dr. Abdelhadi reported no relevant financial disclosures.

Resource Box ASPEN Recommendations on Shortages: Trace elements: bit.ly/3ob0eHj Multivitamins: bit.ly/3AKHv96

Neonatal Care Resources: bit.ly/3kRoL23

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