Specialty Pharmacy Continuum - January / February 2022 by McMahon Group

Serving managed care, health-system and specialty decision makers Volume 11 • Number 1 • January/February 2022 • specialtypharmacycontinuum.com

Pharmacy groups call for investigation, regulation

CLINICAL Flu shot cuts influenza-related hospitalizations ..................

Rx options for hitting 75% prevention goal for new HIV infections ...

Can an immunedeficient child respond to COVID-19 vaccine? ....

Direct Access Infusion Businesses Under Fire

3 biosimilars yield a $4.1 billion windfall ...............................

argeted clinical protocols can help specialty pharmacies ensure every patient with a particular condition receives the same, high-quality level of service. Such an approach yields many benefits—not the least of which is improved compliance with accreditation standards aimed at encouraging more targeted clinical interventions. Historically, some specialty pharmacies took a different tack by offering generic, one-size-fits-all protocols, regardless of medication, according to Heather Bonome, PharmD, the director of pharmacy for URAC, the Washington, D.C.–based Continued on page 14

By Gina Shaw

Tips for preventing pharmacy benefit fraud and waste .............. 26

REVIEW ARTICLE

Harnessing the Potential of Therapy for MM See page 6.

By Karen Blum

POLICY

The scramble for supply amid a severe ambulatory pump shortage ..............................

Specialty Pharm Clinical Protocols: Tips for Success

he FDA and d state regulatory agenciess should investigate te unregulated direct irect access infusion b businesses, i according to a statement issued on Jan. 18 by the National Home Infusion Association (NHIA), ASHP, the American Society for Parenteral and Enteral Nutrition (ASPEN), and several allied organizations. The groups asked the regulators to assess the impact of direct access infusion businesses on critical drug shortages and for states to regulate such businesses in a manner comparable to medical, pharmacy and home health providers. The measures should be taken, they noted, to reduce shortages of critical parenteral products, ensure safety and protect the public. In October 2021, the FDA issued a public statement outlining concerns about compounding drug products by medical offices and clinics under unsanitary conditions. “FDA has also become aware of business models, such as intravenous (IV) hydration clinics, medical spas and mobile IV infusion services, that are compounding drugs that may not meet the conditions of section 503A of the FD&C [Federal Food, Drug, and Cosmetic] Act or comply with state regulations,” the statement noted. “Contaminated, or otherwise poor quality, compounded drug products can lead to serious patient illnesses, including death.”

Cost increases still a concern

IG Supplies Safe Despite Big Drop In Plasma/Blood By Gina Shaw

espite a recent critical blood shortage and an overall decline in plasma donations since the beginning of the COVID-19 pandemic, U.S. supplies of immune globulin (IG) products derived from plasma remain stable, market experts told Specialty Pharmacy Continuum. “This is the wrongest I’ve been in my career,” said Patrick M. Schmidt, the CEO of FFF Enterprises, a leading national wholesaler of plasma products, who had anticipated an IG supply

Continued on page 23

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g Bag n i uc lex d o r F Int

IN E T U B AL

NOW AVAILABLE

ALBUTEIN is more convenient than ever • Easy-to-open protective overwrap • No requirement for vented infusion sets or ﬁlters • Flexible container that allows ﬂexible storage • Easy-to-remove twist-off cap

• Both the ALBUTEIN FlexBag ﬂexible container and protective overwrap are latex-free and do not contain polyvinyl chloride (PVC), diethylhexyl phthalate (DEHP), or other plasticizers • Durable and easy-tospike port designed to avoid needle sticks

Please reach out to your local Grifols representative for additional details on ALBUTEIN FlexBag. For Grifols USA Customer Service contact 1-800-243-4153 and 1-888-325-8579, option 3.

25% SIZES

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Please see Important Safety Information and brief summaries of full Prescribing Information for ALBUTEIN FlexBag 5% and 25% on adjacent pages.

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

Trivalent Flu Shot Reduces Hospitalizations By Marie Rosenthal

ata from an independent study in Italy over 18 influenza seasons demonstrated that an adjuvanted trivalent vaccine (aTIV; Fluad, Seqirus) was associated with a 12% lower risk for hospitalization and a 37% lower risk for respiratory-related hospitalizations compared with standard-dose options. In addition, two studies demonstrated the cost-effectiveness of an adjuvanted quadrivalent influenza vaccine (aQIV;

Fluad Quadrivalent, Seqirus) in Spain and France, according to a presentation at the European Scientific Working Group on Influenza (ESWI) 2021 Virtual Conference. The relative effectiveness of aTIV compared with non-adjuvanted trivalent influenza vaccine (TIV) and standarddose quadrivalent influenza vaccine (QIV) against all-cause or respiratoryrelated hospitalization in adults 65 years of age and older was determined in an

independent study across 18 consecutive influenza seasons in Italy. A nested case–control analysis of older adults was conducted using an Italian data source of primary care called the Health Search Database. Conditional logistic regression was used to estimate outcomes in a cohort of 58,252 older adults vaccinated with aTIV or TIV/QIV. The use of aTIV was associated with a 12% lower risk for hospitalization (odds ratio [OR], 0.88; 95% CI,

0.80-0.98) and a 37% lower risk for respiratory-related hospitalizations (OR, 0.63; 95% CI, 0.44-0.91) compared with TIV/QIV in that period. A separate study presented at the conference estimated influenza-related costs and benefits of aQIV and high-dose quadrivalent influenza vaccine (QIV-HD) during one year of use in Spain. The researchers used the decision tree model with Spanish demography and costs

Important Safety Information ALBUTEIN® 25% (albumin [human] U.S.P.) is indicated for: hypovolemia, cardiopulmonary bypass procedures, acute nephrosis, hypoalbuminemia, ovarian hyperstimulation syndrome, neonatal hyperbilirubinemia, adult respiratory distress syndrome (ARDS), and prevention of central volume depletion after paracentesis due to cirrhotic ascites. ALBUTEIN® 5% (albumin [human] U.S.P.) is indicated for: hypovolemia, cardiopulmonary bypass procedures, hypoalbuminemia, and plasma exchange. ALBUTEIN 5% and 25% are contraindicated in patients with a history of hypersensitivity to albumin preparations or to any of the excipients, and in patients with severe anemia or cardiac failure with normal or increased intravascular volume. Allergic or anaphylactic reactions require immediate discontinuation of the infusion and implementation of appropriate medical treatment. Hypervolemia may occur if the dosage and rate of infusion are not adjusted to the patient’s volume status. At the first clinical signs of fluid overload, the infusion must be slowed or stopped immediately. Use albumin with caution in conditions where hypervolemia and its consequences or hemodilution could represent a special risk to the patient. The colloid-osmotic effect of human albumin 25% is approximately five times that of blood plasma. Therefore, when concentrated albumin is administered, care must be taken to assure adequate hydration of the patient. Patients should be monitored carefully to guard against circulatory overload and hyperhydration. Patients with marked dehydration require administration of additional fluids. Concentrated (20% - 25%) human albumin solutions are relatively low in electrolytes compared to 4% - 5% human albumin solutions. Regularly monitor the electrolyte status of the patient and take appropriate steps to restore or maintain the electrolyte balance when albumin is administered. Regular monitoring of coagulation and hematology parameters is necessary if comparatively large volumes are to be replaced. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes). Regularly monitor hemodynamic parameters during administration of ALBUTEIN® 5% and 25% (albumin [human] U.S.P.). ALBUTEIN 5% and 25% must not be diluted with sterile water for injection as this may cause hemolysis in recipients. Albumin is a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for ALBUTEIN 5% or 25%. The most serious adverse reactions with use of albumin are anaphylactic shock, heart failure and pulmonary edema. The most common adverse reactions are anaphylactoid type reactions. Adverse reactions to ALBUTEIN normally resolve when the infusion rate is slowed or the infusion is stopped. In case of severe reactions, the infusion should be stopped and appropriate treatment initiated. Please see brief summaries of full Prescribing Information for ALBUTEIN FlexBag 5% and 25%.

see TRIVALENT, page 4

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

TRIVALENT continued from page 3

extracted from Spanish and European published literature as well as Spanish tender prices for aQIV and QIV-HD. Results suggest that vaccination with aQIV in older adults helped prevent 5,406 symptomatic influenza cases, 760 office visits, 442 hospitalizations and 26 deaths annually, resulting in an increase of 206 quality-adjusted life-years and substantial cost savings compared with QIV-HD. From payor and societal

perspectives, about $72.59 million in vaccine costs alone were estimated in the model (Vaccines 2022;10[2]:176). “In Spain alone, nearly one-fifth of the population is aged 65 and older as of 2020, and this percentage can be expected to grow in the coming years,” said Sergio Marquez-Pelaez, of Pablo de Olavide University, in Seville, Spain, and study co-author. “The use of enhanced seasonal influenza vaccines, such as those that use an adjuvant, not only help to reduce influenza-related outpatient visits and hospitalizations in this population

but may also reduce the economic and societal burden associated with increased

outpatient medical encounters, as suggested by the data presented at ESWI.”

aQIV Budget Impact

ALBUTEIN

FlexBag 5% (albumin [human] U.S.P.) 5% solution These highlights do not include all the information needed to use ALBUTEIN FlexBag 5% safely and effectively. See full prescribing information for ALBUTEIN FlexBag 5%. ALBUTEIN FlexBag 5% (albumin [human] U.S.P.) 5% solution Initial U.S. Approval: 1978 ------------------------------------------INDICATIONS AND USAGE -----------------------------------------ALBUTEIN 5% is an albumin solution indicated for: • Hypovolemia. • Cardiopulmonary bypass procedures. • Hypoalbuminemia. • Plasma exchange. --------------------------------------DOSAGE AND ADMINISTRATION-------------------------------------For Intravenous Use Only Dosage and infusion rate should be adjusted to the patient’s individual requirements. Indication

Dose

Hypovolemia

Adults: Initial dose of 20 g (including renal dialysis). For acute liver failure: initial dose of 12 to 25 g.

Cardiopulmonary bypass procedures

Adults: Initial dose of 25 g.

Hypoalbuminemia

Adults: 50 to 75 g For pre- and post-operative hypoproteinemia: 50 to 75 g. For burn therapy after the first 24 h: initial dose of 25 g and dose adjustment to maintain plasma protein concentration of 2.5 g per 100 mL. Third space protein loss due to infection: initial dose of 50 to 100 g.

Plasma exchange

The dose required depends on the volume of plasma removed during the procedure.

ALBUTEIN

FlexBag 25% (albumin [human] U.S.P.) 25% solution These highlights do not include all the information needed to use ALBUTEIN FlexBag 25% safely and effectively. See full prescribing information for ALBUTEIN FlexBag 25%. ALBUTEIN FlexBag 25% (albumin [human] U.S.P.) 25% solution Initial U.S. Approval: 1978 ------------------------------------------INDICATIONS AND USAGE -----------------------------------------ALBUTEIN 25% is an albumin solution indicated for: • Hypovolemia. • Cardiopulmonary bypass procedures. • Acute nephrosis. • Hypoalbuminemia. • Ovarian hyperstimulation syndrome. • Neonatal hyperbilirubinemia. • Adult respiratory distress syndrome (ARDS). • Prevention of central volume depletion after paracentesis due to cirrhotic ascites. --------------------------------------DOSAGE AND ADMINISTRATION-------------------------------------For Intravenous Use Only Dosage and infusion rate should be adjusted to the patient’s individual requirements. Indication

Dose

Hypovolemia

Adults: Initial dose of 25 g (including renal dialysis). For acute liver failure: initial dose of 12 to 25 g.

Cardiopulmonary bypass procedures

Adults: Initial dose of 25 g.

Acute nephrosis

Adults: 25 g together with diuretic once a day for 7 - 10 days.

Hypoalbuminemia

Ovarian hyperstimulation syndrome

Adults: 50 g to 100 g over 4 hours and repeated at 4-12 hour intervals as necessary.

Do not dilute with sterile water for injection as this may cause hemolysis in recipients. ------------------------------------DOSAGE FORMS AND STRENGTHS -----------------------------------ALBUTEIN 5% is a solution containing 50 g per L of total protein of which at least 95% is human albumin. ---------------------------------------------CONTRAINDICATIONS--------------------------------------------• Hypersensitivity to albumin preparations or to any of the excipients. • Severe anemia or cardiac failure with normal or increased intravascular volume. --------------------------------------WARNINGS AND PRECAUTIONS-------------------------------------• Suspicion of allergic or anaphylactic reactions requires immediate discontinuation of the injection and implementation of appropriate medical treatment. • Hypervolemia may occur if the dosage and rate of infusion are not adjusted to the patient’s volume status. Use with caution in conditions where hypervolemia and its consequences or hemodilution could represent a special risk to the patient. • Monitor electrolytes, coagulation and hematology parameters, and hemodynamic status when albumin is given. • Do not dilute with sterile water for injection. • This product is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent. -------------------------------------------- ADVERSE REACTIONS -------------------------------------------The most common adverse reactions are anaphylactoid type reactions. To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals LLC at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------------- USE IN SPECIFIC POPULATIONS ------------------------------------• Pregnancy: No human or animal data. Use only if clearly needed. Revised: 07/2021

Manufactured by: Grifols Biologicals LLC 5555 Valley Boulevard Los Angeles, CA 90032, U.S.A. U.S. License No. 1694

3061038

Indication

Dose

Neonatal hyperbilirubinemia

1 g per kilogram body weight prior to or during exchange transfusion.

Adult respiratory distress syndrome (ARDS)

Adults: 25 g over 30 minutes and repeated at 8 hours for 3 days, if necessary.

Prevention of central volume depletion after Adults: 8 g for every 1000 mL of ascitic fluid removed. paracentesis due to cirrhotic ascites Do not dilute with sterile water for injection as this may cause hemolysis in recipients. ------------------------------------DOSAGE FORMS AND STRENGTHS -----------------------------------ALBUTEIN 25% is a solution containing 250 g per L of total protein of which at least 95% is human albumin. ---------------------------------------------CONTRAINDICATIONS--------------------------------------------• Hypersensitivity to albumin preparations or to any of the excipients. • Severe anemia or cardiac failure with normal or increased intravascular volume. --------------------------------------WARNINGS AND PRECAUTIONS-------------------------------------• Suspicion of allergic or anaphylactic reactions requires immediate discontinuation of the injection and implementation of appropriate medical treatment. • Hypervolemia may occur if the dosage and rate of infusion are not adjusted to the patient’s volume status. Use with caution in conditions where hypervolemia and its consequences or hemodilution could represent a special risk to the patient. • When concentrated albumin is administered, care must be taken to assure adequate hydration of the patient. • Monitor electrolytes, coagulation and hematology parameters, and hemodynamic status when albumin is administered. • Do not dilute with sterile water for injection. • This product is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent. -------------------------------------------- ADVERSE REACTIONS -------------------------------------------The most common adverse reactions are anaphylactoid type reactions. To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals LLC at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------------- USE IN SPECIFIC POPULATIONS ------------------------------------• Pregnancy: No human or animal data. Use only if clearly needed. Manufactured by: Grifols Biologicals LLC 5555 Valley Boulevard Los Angeles, CA 90032, U.S.A. U.S. License No. 1694

In the study presented at ESWI, researchers also evaluated the budget impact of a national immunization program in France that is based on the progressive use of aQIV instead of standard egg-based QIV (QIVe) or QIV-HD. The model forecasts influenza-related costs and benefits for the next three seasons, starting in 2021. Over three-years, it was estimated that 56,028 influenza cases, 13,449 medical care visits, 30,815 outpatient complications, 3,902 inpatient complications and 745 influenza-associated deaths may be prevented by switching from QIVe to aQIV vaccinations. Results suggest that progressively transitioning from QIVe to aQIV could potentially result in increased vaccination costs of about $102.2 million, with about $70.7 million in savings from fewer influenza events and complications, driven by avoidance of medical care visit costs ($529,000), outpatient complication costs ($887,00) and inpatient complication costs ($26.1 million). The MF59 adjuvant is designed to help boost the immune response to influenza vaccination in adults 65 years of age and older, who are more susceptible to flu complications. “Age-related immune decline can make it harder for the body to mount a sufficient immune response to flu vaccination in people aged 65 and older, who currently account for an estimated 727 million people globally—a number expected to double by 2050,” said Gregg Sylvester, MD, the chief medical officer for Seqirus. “The data presented at ESWI 2021 provide new evidence for the adjuvanted influenza vaccines in this population.” Estimates from the CDC report revealed that during the 2019-2020 influenza season, there were an estimated 380,000 influenza-related hospitalizations in the United States. The CDC recommends annual influenza vaccination for individuals 6 months of age and older who do not have any contraindications.

Revised: 05/2019

Dr. Sergio Marquez-Pelaez disclosed a financial relationship with Seqirus. 3055225

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

Kimmtrak Takes a BiTE Out of Uveal Melanoma By Dave Doolittle

The FDA approved tebentafusp-tebn (Kimmtrak, Immunocore), a bispecific T-cell engager (BiTE) designed to redirect the immune system to recognize and kill cancerous cells, for the treatment of adults with unresectable or metastatic uveal melanoma. Tebentafusp-tebn is the first T-cell receptor (TCR) therapeutic to receive regulatory approval from the FDA and the first BiTE approved to treat a solid tumor, Immunocore said in a press release. It also is the only therapy approved to treat this rare form of ocular melanoma, the company said (bit.ly/3uaTXyt). “Uveal melanoma is a devastating disease that has historically resulted in death within a year of metastasis for our patients,” John Kirkwood, MD, the director of the Melanoma Center at the University of Pittsburgh Hillman Cancer Center, said in the press release. “The approval … represents a major paradigm shift in the treatment of metastatic uveal melanoma, and for the first time offers hope to those with this aggressive form of cancer.”

The approval was based on a phase 3 trial of 378 human leukocyte antigen (HLA)-A*02:01–positive adults who received tebentafusp-tebn or the investigator’s choice of therapy with single-agent dacarbazine, ipilimumab or pembrolizumab, according to results published in The New England Journal of Medicine (2021;385[13]:1196-1206). Overall survival at one year was 73% in the tebentafusp-tebn group and 59% in the control group (hazard ratio [HR] for death, 0.51; 95% CI, 0.37-0.71; P<0.001). Progression-free survival at six months was 31% in the tebentafusp-tebn group compared with 19% (HR for disease progression or death, 0.73; 95% CI, 0.58-0.94; P=0.01). Serious adverse reactions include cytokine release syndrome (CRS); skin reactions such as rash, pruritus and cutaneous edema; and elevations in liver enzymes, Immunocore said. Other common side effects include fatigue,

nausea, hypotension, dry skin, headache and vomiting.

Proprietary Technology Tebentafusp-tebn is a new class of BiTE therapy that specifically targets the lineage antigen glycoprotein 100 via an anti–cluster-of-differentiation 3 (CD3) immune-activating effector function, Immunocore said. The compound is an example of Immunocore’s proprietary TCR technology, which generates bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules, according to the company. “Based on the demonstrated mechanism of T-cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune ‘cold’ low mutation rate tumors,” Immunocore said.

Oncology Pharmacist’s Take “The approval of tebentafusp-tebn is very exciting, because it represents the first treatment for patients with unresectable or metastatic uveal melanoma, a devastating disease,” said Lisa Holle, PharmD, BCOP, a clinical professor of pharmacy practice in the Department of Pharmacy Practice,

EDITORIAL BOARD

University of Connecticut School of Medicine, in Storrs. “Incorporating this new medication, however, into patient care will require education of the healthcare team, especially for those who may not be familiar with BiTE therapies,” added Dr. Holle, a member of the Specialty Pharmacy Continuum editorial board. BiTE therapies can cause CRS, “which can be very serious and even life-threatening, requiring close monitoring for at least 16 hours the first three infusions,” Dr. Holle said. “This represents a challenge for infusion rooms, which typically are not operating for that length of time on a daily basis. Thus, observation in an inpatient setting may be needed.” She added that “a trained healthcare team should be available with access to the appropriate medications and equipment to manage CRS. Pharmacists should ensure that patients are euvolemic prior to starting therapy, as well.” Other potential toxicities, Dr. Holle noted, include skin reactions, “which are common but often can be managed with antihistamines and topical corticosteroids, and elevations in hepatic enzymes, which should be monitored closely during therapy.” Dr. Holle reported no relevant financial disclosures.

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Volume 11 • Number 1 • January/February 2022

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Specialty Pharmacy Continuum • January/February 2022

CLINICAL

Gene Therapy Series, Part 2:

Harnessing the Potential Of Therapy for MM RHONDA LETWIN, RN, BSN, OCN Clinical Program Manager AllianceRx Walgreens Prime Pittsburgh, Pennsylvania

MARCIE MORRIS, PHARMD, CSP Clinical Program Manager AllianceRx Walgreens Prime, Pittsburgh, Pennsylvania

ultiple myeloma (MM), which develops in plasma cells, can result in low blood counts and weakening of the immune

system.1 According to the National Cancer

Institute, MM accounted for approximately 1.8% of new cancer cases in the United States in 2020.2 The cause of MM is unknown, and there is no cure. Less than half of Americans diagnosed with MM die within 5 years.3

Despite advances in treatment over the last 20 years,4 MM remains an incurable disease characterized by periods of remission and relapse. Studies show that patients with relapsed or refractory MM who have been treated with the 3 major drug classes (immunomodulatory agent, proteasome inhibitor, and antiCD38 antibody) generally have low response rates (20%-30%), a short duration of response (2-4 months), and poor survival.5-8

Current Cell Therapies: CAR T-Cell Therapy Chimeric antigen receptor (CAR) T-cell therapy has been a major breakthrough in the treatment of specific types of leukemia and lymphoma, and now is approved for the treatment of relapsed or refractory MM. T cells collected from a patient’s blood are genetically modified to have CARs on their surface, giving the T cells the ability to bind to a specific protein expressed on a tumor cell, which, in turn, activates the immune system to destroy the tumors. After the new T cells multiply and reach a certain number in the laboratory (usually hundreds of millions to billions), they are sent back

Gene and Cell Therapy Defined Gene and cell therapy is an exciting new area of medicine offering the potential to treat, or even cure, diseases that previously may have had limited or no treatment options. These therapies treat or cure disease by introducing cells or DNA to address the underlying cause of a disease. Cell therapy involves removal of cells from either the patient (autologous) or a donor (allogeneic), modification of those cells outside the body, and reinfusion of the modified cells back into the patient to treat the disease.1 The type of cell used depends on the specific treatment. Gene therapy is the delivery of genetic material via a vector, usually viral in origin, to replace, deactivate, or repair faulty DNA that is causing a disease.1 Use of a viral vector allows the new genetic material to be inserted directly into a patient’s own DNA, thereby, enabling proper protein production to lessen the effects of or completely cure a disease. This is the part 1 of a series describing the potential of gene therapy for various disease states. 1. American Society of Gene and Cell Therapy. Gene and cell therapy FAQs. Accessed February 1, 2022. https://www.asgct.org/education/more-resources/gene-and-cell-therapy-faqs

for infusion into the patient. The process is detailed in the Figure.9-11 B-cell maturation antigen (BCMA) is a major target for CAR T-cell therapies. The targeted tumor cell protein normally is not expressed in healthy cells; thus, the CAR T cells bind to and destroy only tumor cells. Shortly before the CAR T-cell therapy infusion, a patient receives preparatory lymphodepleting chemotherapy to allow the new “superpotent” T cells to establish themselves. The infused cells then circulate throughout the body, attacking the patient’s cancer cells.10 CAR T-cell therapy is a onetime treatment, and if all goes well, the patient will achieve a complete remission and the CAR T cells will continue to proliferate and persist in the patient’s body. Like all treatments, CAR T-cell therapy carries risks. Approximately one-third of patients experience serious adverse effects (AEs) that require acute management in the hospital, occasionally in intensive care.10 Cytokine release syndrome (CRS) is the most frequent serious acute CAR T-cell–related toxicity, with an absolute incidence of 30% to 100% (10%-30% for CRS

grade ≥3).12,13 CRS causes shortness of breath, malaise, high fever, and a drop in blood pressure and oxygenation, among other symptoms. The inflammatory response also can cause neurotoxicity, resulting in difficulty speaking, drowsiness, disorientation, and even coma. Most patients will experience some AEs within the first 2 to 4 weeks of treatment, and the majority will completely recover. Due to the potential for serious AEs, CAR T-cell therapy is administered only in specialized centers and is reserved for patients who have no other options.10 BCMA-Targeted CAR T-Cell Therapy for MM There is one FDA-approved CAR T-cell therapy for the treatment of MM—idecabtagene vicleucel, or idecel (Abecma, Bristol Myers Squibb/ bluebird bio)—which is approved as a one-time infusion for the treatment of adults with relapsed or refractory MM after 4 or more lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.5,14,15 The safety and efficacy of ide-cel

were established in a multicenter study of 127 patients with relapsed or refractory MM who received at least 3 prior lines of therapy.15 Overall, 72% of the patients partially or completely responded to the treatment. Of those studied, 28% of patients showed a complete response (CR) to ide-cel, and 65% of this group remained in CR to the treatment for at least 12 months.15 Treatment with ide-cel has the potential to cause severe AEs. The labeling for ide-cel has a boxed warning about CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life-threatening.14 Because of the risk for CRS and neurologic toxicities, ide-cel is approved with a Risk Evaluation and Mitigation Strategy. The FDA also requires that hospitals and their associated clinics dispensing ide-cel be specially certified and that staff involved in prescribing, dispensing, or administering ide-cel be trained to recognize and manage CRS, nervous system toxicities, and other AEs associated with ide-cel. In addition, clinicians must inform patients about the potential

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

for serious AEs and of the importance of promptly seeking treatment if AEs develop.15

7. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221.

Future Cell and Gene Therapies

8. Jagannath S, Lin Y, Goldschmidt H, et al. KarMMa-RW: a study of real-world treatment patterns in heavily pretreated patients with relapsed and refractory multiple myeloma (RRMM) and comparison of outcomes to KarMMa. J Clin Oncol. 2020;38(15 suppl): abstract 8525.

BCMA-Based Cell Therapies Additional BCMA-targeted CAR T-cell therapies in development include JNJ-4528 (Janssen), which showed strong and durable responses in patients with relapsed or refractory disease in a phase 1b/2 trial,16 and bb21217, which uses the bb2121 CAR molecule with an additional manufacturing process.17 It is cultured with the PI3K inhibitor bb007 to improve CAR T-cell functional persistence. Overall, CAR T cells targeting BCMA on MM cells have shown high response rates.17 However, the question still remains whether these responses will be durable. Data released from a phase 1 study of bb21217 demonstrated that 6 of the 15 patients who achieved complete responses relapsed.18 Median progression-free survival among all patients was approximately 1 year.18 CD229-Based Cell Therapies Future approaches will have the goal of producing more durable responses. One such approach uses CD229, which is prevalent on the surface of both MM cells and stem cells, which can produce treatmentresistant tumor cells. A preclinical study found that CD229-targeted treatment produced a significant reduction in MM-propagating cells compared with the BCMA-targeted CAR T-cell therapies.19 The next step for researchers is to determine whether the CD229-targeted cells will be safe to use in human clinical trials. Dual-Targeted CAR T-Cell Therapy BM38 CAR T cells are the first dual-target CAR T cells that contain anti-BCMA and anti-CD38 in tandem for the treatment of MM. In a phase 1 trial, more than 90% of patients with relapsed or refractory MM responded to therapy with a bispecific CAR T-cell therapy targeting the CD38 protein and BCMA on myeloma cells.9 CRISPR Editing–Combined Gene And Cell Therapy An approach that uses the geneediting technique CRISPR has identified several pathways that MM cells use to evade immunotherapy, with the goal of enhancing the effectiveness of CAR T-cell therapy. The results could lead to therapeutic

9. Weaver CH. CAR-T cell therapy - advances in the management of multiple myeloma. Cancer Connect. Updated June 8, 2021. Accessed February 1, 2022. https://bit. ly/3pp5EPC 10. NewYork-Presbyterian. CAR T-cell therapy, a breakthrough treatment for cancer patients. Health Matters. Accessed February 1, 2022. https://bit.ly/3C8jJnZ 11. National Cancer Institute. CAR T-cell therapy. Accessed February 1, 2022. https://bit.ly/3Gaj1Jt 12. Frontiers in Oncology. CAR T-cells in multiple myeloma: state of the art and future directions. Accessed February 1, 2022. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC7399644/ Source: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy.

improvements, such as supplementing BCMA-targeted immunotherapy with a histone deacetylase inhibitor gene inhibitor to reduce resistance and potential relapses.20 Gene Inhibition Many patients with MM develop resistance to treatment due to the formation of cancer stem cells, which drive the disease. Some researchers are working to silence the IRF4 gene, which allows MM stem cells and tumor cells to proliferate and survive. They are using an engineered piece of DNA specifically designed to bind the genetic material coding for IRF4, causing it to degrade.21

The Specialty Pharmacist’s Role Although CAR T-cell therapy is a medication, neither specialty nor hospital pharmacists dispense this treatment. Due to the specialized nature of manufacturing and administering CAR T-cell therapy, these products are available only at certified treatment centers, where CAR T-cell therapy is treated in a similar manner as a stem cell infusion and less like traditional therapy. However, due to its potentially lifethreatening risks and monitoring requirements, it is critical that pharmacists be knowledgeable about the process of CAR T-cell therapy and toxicity management.22 Specialty pharmacists’ expertise and ability to manage limited distribution medications, including any relevant reporting, purchasing, or

dispensing requirements, may offer manufacturers added confidence as these products are given to patients. Research is seeking to uncover the next generation of CAR T-cell therapies, which are hoped to be off-the-shelf treatments that can be mass manufactured from a healthy donor’s cells and used for multiple patients. As CAR T-cell therapy enters mainstream cancer immunotherapy, pharmacists can play a fundamental role in the comprehensive care of patients receiving these treatments.

References 1.

Mayo Clinic. Multiple myeloma. Accessed February 1, 2022. https://www.mayoclinic. org/diseases-conditions/multiplemyeloma/symptoms-causes/syc-20353378

2. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Cancer stat facts: myeloma. Accessed February 1, 2022. https://seer.cancer.gov/ statfacts/html/mulmy.html 3. American Cancer Society. Survival rates by stage for multiple myeloma. Accessed February 1, 2022. https://www.cancer. org/cancer/multiple-myeloma/detectiondiagnosis-staging/survival-rates.html 4. Kumar S. Treatment of newly diagnosed multiple myeloma in transplanteligible patients. Curr Hematol Malig Rep. 2011;6(2):104-112. 5. U.S. Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma [press release]. Bristol Myers Squibb; March 26, 2021. Accessed February 1, 2022. https://bit.ly/3nmHQsO 6. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275.

13. Frey N, Porter D. Cytokine release syndrome with chimeric antigen receptor T cell therapy. Biol Blood Marrow Transplant. 2019;25(4):e123-e127. 14. ABECMA [prescribing information]. Bristol Myers Squibb; March 2021. Accessed February 1, 2022. https://packageinserts. bms.com/pi/pi_abecma.pdf 15. FDA. FDA approves first cell-based gene therapy for adult patients with multiple myeloma. Accessed February 1, 2022. https://www.fda.gov/news-events/ press-announcements/fda-approves-firstcell-based-gene-therapy-adult-patientsmultiple-myeloma 16. Johnson & Johnson. Janssen’s BCMA CAR-T therapy JNJ-4528 showed early, deep and durable responses in heavily pretreated patients with multiple myeloma. Accessed February 1, 2022. https://bit.ly/2XCgRAX 17. bluebird bio and Celgene Corporation present Initial data from ongoing phase 1 clinical study of next-generation antiBCMA CAR T cell therapy bb21217 in patients with relapsed/refractory multiple myeloma at ASH annual meeting [press release]. bluebird bio; December 2, 2018. Accessed February 1, 2022. https://investor. bluebirdbio.com/news-releases/newsrelease-details/bluebird-bio-and-celgenecorporation-present-initial-data 18. Weintraub A. Celgene reports ‘durable’ responses to multiple myeloma CAR-T in early trial despite relapses. Fierce Biotech. May 3, 2019. Accessed February 1, 2022. https://bit.ly/3B15dNr 19. Radhakrishnam SV, Leutkens T, Scherer SD, et al. CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide. Nat Commun. 2020;11(798). https://doi.org/10.1038/ s41467-020-14619-z13 20. Figueiredo M. CRISPR-edited T-cells safely, effectively target cancer cells in myeloma patients, early phase 1 data suggests. Myeloma Research News. November 13, 2019. Accessed February 1, 2022. https:// bit.ly/3C85fVi 21. Designer DNA therapeutic wipes out cancer stem cells, treats multiple myeloma in mice. Science Daily. January 20, 2021. Accessed February 1, 2022. https://bit.ly/3jsZrOS 22. Shaw G. Pharmacy’s role in managing CAR-T therapy. Specialty Pharmacy Continuum. Accessed February 1, 2022. https://www.specialtypharmacycontinuum. com/Clinical/Article/07-18/Pharmacy-sRole-in-Managing-CAR-T-Therapy/52309

For patients with cGVHD æÐÌ ɖǠǡ řÐīĮ åĴÐī åðăķīÐ ďå Ĵ ăÐĮĴ ǡ Ĩīðďī ăðĊÐĮ ďå ĮřĮĴÐĉðÆ ĴìÐīĨřș ìÐăĨ ĴìÐĉǠȭǢ

ROCK ON

INDICATION REZUROCK™ (belumosudil) is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

IMPORTANT SAFETY INFORMATION Warnings and Precautions • Embryo-Fetal Toxicity: ĮÐÌ ďĊ ť ĊÌðĊæĮ ðĊ ĊðĉăĮ ĊÌ ðĴĮ ĉÐÆìĊðĮĉ ďå ÆĴðďĊș t'¢ tZ N ÆĊ ÆķĮÐ åÐĴă ìīĉ œìÐĊ administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose Adverse Reactions • }ìÐ ĉďĮĴ ÆďĉĉďĊ ȧɖ ǡǟɦȨ ÌŒÐīĮÐ īÐÆĴðďĊĮș ðĊÆăķÌðĊæ ăÅďīĴďīř ÅĊďīĉăðĴðÐĮș œÐīÐ ðĊåÐÆĴðďĊĮș ĮĴìÐĊðș ĊķĮÐș ÌðīīìÐș ÌřĮĨĊÐș Æďķæìș ÐÌÐĉș ìÐĉďīīìæÐș ÅÌďĉðĊă ĨðĊș ĉķĮÆķăďĮāÐăÐĴă ĨðĊș ìÐÌÆìÐș ĨìďĮĨìĴÐ ÌÐÆīÐĮÐÌș æĉĉ æăķĴĉřă ĴīĊĮåÐīĮÐ ðĊÆīÐĮÐÌș ăřĉĨìďÆřĴÐĮ ÌÐÆīÐĮÐÌș ĊÌ ìřĨÐīĴÐĊĮðďĊ • qÐīĉĊÐĊĴ ÌðĮÆďĊĴðĊķĴðďĊ ďå t'¢ tZ N ÌķÐ Ĵď ÌŒÐīĮÐ īÐÆĴðďĊĮ ďÆÆķīīÐÌ ðĊ Ǡǧɦ ďå ĨĴðÐĊĴĮȘ }ìÐ ÌŒÐīĮÐ īÐÆĴðďĊĮ œìðÆì īÐĮķăĴÐÌ ðĊ ĨÐīĉĊÐĊĴ ÌðĮÆďĊĴðĊķĴðďĊ ďå t'¢ tZ N ðĊ ɔ Ǣɦ ďå ĨĴðÐĊĴĮ ðĊÆăķÌÐÌ ĊķĮÐ ȧǣɦȨȘ ÌŒÐīĮÐ īÐÆĴðďĊĮ ăÐÌðĊæ Ĵď ÌďĮÐ ðĊĴÐīīķĨĴðďĊ ďÆÆķīīÐÌ ðĊ ǡǨɦ ďå ĨĴðÐĊĴĮȘ }ìÐ ÌŒÐīĮÐ īÐÆĴðďĊĮ ăÐÌðĊæ Ĵď ÌďĮÐ ðĊĴÐīīķĨĴðďĊ ðĊ ɖ ǡɦ œÐīÐ ðĊåÐÆĴðďĊĮ ȧǠǠɦȨș ÌðīīìÐ ȧǣɦȨș ĊÌ ĮĴìÐĊðș ÌřĮĨĊÐș ìÐĉďīīìæÐș ìřĨďĴÐĊĮðďĊș ăðŒÐī åķĊÆĴðďĊ ĴÐĮĴ ÅĊďīĉăș ĊķĮÐș ĨřīÐŘðș ÐÌÐĉș ĊÌ īÐĊă åðăķīÐ œðĴì ȧǡɦ ÐÆìȨ • TďĊðĴďī ĴďĴă ÅðăðīķÅðĊș ĮĨīĴĴÐ ĉðĊďĴīĊĮåÐīĮÐ ȧ w}Ȩș ĊÌ ăĊðĊÐ ĉðĊďĴīĊĮåÐīĮÐ ȧ O}Ȩ Ĵ ăÐĮĴ ĉďĊĴìăř Drug Interactions • Strong CYP3A Inducers: Coadministration of REZUROCK with strong CYP3A inducers decreases belumosudil ÐŘĨďĮķīÐș œìðÆì ĉř īÐÌķÆÐ ĴìÐ ÐŨ ÆÆř ďå t'¢ tZ NȘ AĊÆīÐĮÐ ĴìÐ ÌďĮæÐ ďå t'¢ tZ N Ĵď ǡǟǟ ĉæ ĴœðÆÐ Ìðăř when coadministered with strong CYP3A inducers • Proton Pump Inhibitors: Coadministration of REZUROCK with proton pump inhibitors decreases belumosudil ÐŘĨďĮķīÐș œìðÆì ĉř īÐÌķÆÐ ĴìÐ ÐŨ ÆÆř ďå t'¢ tZ NȘ AĊÆīÐĮÐ ĴìÐ ÌďĮæÐ ďå t'¢ tZ N Ĵď ǡǟǟ ĉæ ĴœðÆÐ Ìðăř when coadministered with proton pump inhibitors

ORRa

75% (95% CI, 63-85; P<.0001) 1,4

REZUROCK achieved clinically and statistically ĮðæĊðť ÆĊĴ ÐŨ ÆÆř with the 200-mg once-daily dose in a real-world demographic of patients with cGVHD.1

• ZĊÆÐȭÌðăř ďīă ĉÐÌðÆĴðďĊ ĴìĴ ĴīæÐĴĮ ÅďĴì ðĊŦ ĉĉĴðďĊ ĊÌ ť ÅīďĮðĮ Ĵìīďķæì ĮÐăÐÆĴðŒÐ tZ Nǡ ðĊìðÅðĴðďĊ1-3 • CR was observed in all organsș ðĊÆăķÌðĊæ ĴìďĮÐ œðĴì ť ÅīďĴðÆ ĉĊðåÐĮĴĴðďĊĮ

• There was no death or new systemic therapy initiation in 62% (95% CI, 46-74) of the responder population at 12 months1 • Clinically meaningful improvements in QOL, with CS and CNI dose reductions and discontinuations ÆìðÐŒÐÌ ðĊ ÅďĴì īÐĮĨďĊÌÐīĮ and nonresponders5 • Well tolerated1

ASSIST

™

Enroll your patients with cGVHD in Kadmon ASSIST so our ĮĨÐÆðăðĮĴĮ ÆĊ ť ĊÌ ĴìÐ ÅÐĮĴ Ĩīďæīĉ Ĵď ť Ĵ řďķī ĨĴðÐĊĴĮȸ ÆďŒÐīæÐȘ Kadmon ASSIST ðĮ ŒðăÅăÐ Monday through Friday, 8ŬƢ-8ƲƢ ET, Åř ÆăăðĊæ 1-844-KADMON1 (523-6661).

VISIT REZUROCKhcp.com TO LEARN MORE cGVHD, chronic graft-versus-host disease; CNI, calcineurin inhibitor; CR, complete response; CS, corticosteroid; FDA, US Food and Drug Administration; NIH, National Institutes of Health; ORR, overall response rate; PR, partial response; QOL, quality of life; ROCK2, rho-associated coiled-coil–containing protein kinase-2. Proportion of patients who achieved CR or PR according to the 2014 NIH cGVHD Consensus Criteria in the 200-mg once-daily arm.1

IMPORTANT SAFETY INFORMATION (cont) ĮÐ ðĊ wĨÐÆðť Æ qďĨķăĴðďĊĮ • Pregnancy: ĮÐÌ ďĊ ť ĊÌðĊæĮ åīďĉ Ċðĉă ĮĴķÌðÐĮ ĊÌ ĴìÐ ĉÐÆìĊðĮĉ ďå ÆĴðďĊș t'¢ tZ N ÆĊ ÆķĮÐ åÐĴă ìīĉ œìÐĊ administered to pregnant women. There are no available human data on REZUROCK use in pregnant women to evaluate for a drug-associated risk. Advise pregnant women and females of reproductive potential of the potential risk to the fetus • Lactation: There are no data available on the presence of belumosudil or its metabolites in human milk or the effects on ĴìÐ ÅīÐĮĴåÐÌ ÆìðăÌș ďī ĉðăā ĨīďÌķÆĴðďĊȘ ÐÆķĮÐ ďå ĴìÐ ĨďĴÐĊĴðă åďī ĮÐīðďķĮ ÌŒÐīĮÐ īÐÆĴðďĊĮ åīďĉ ÅÐăķĉďĮķÌðă ðĊ ĴìÐ ÅīÐĮĴåÐÌ ÆìðăÌș ÌŒðĮÐ ăÆĴĴðĊæ œďĉÐĊ ĊďĴ Ĵď ÅīÐĮĴåÐÐÌ ÌķīðĊæ ĴīÐĴĉÐĊĴ œðĴì t'¢ tZ N ĊÌ åďī Ĵ ăÐĮĴ ďĊÐ œÐÐā after the last dose • Pediatric Use: The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older. The safety and effectiveness of REZUROCK in pediatric patients less than 12 years old have not been established • Geriatric Use: Zå ĴìÐ Ǡǧǥ ĨĴðÐĊĴĮ œðĴì ÆìīďĊðÆ : ># ðĊ ÆăðĊðÆă ĮĴķÌðÐĮ ďå t'¢ tZ Nș ǡǥɦ œÐīÐ ǥǤ řÐīĮ ĊÌ ďăÌÐīȘ Uď clinically meaningful differences in safety or effectiveness of REZUROCK were observed in comparison to younger patients • Renal and Hepatic Impairment: Treatment with REZUROCK has not been studied in patients with pre-existing severe īÐĊă ďī ìÐĨĴðÆ ðĉĨðīĉÐĊĴȘ 9ďī ĨĴðÐĊĴĮ œðĴì ĨīÐȭÐŘðĮĴðĊæ ĮÐŒÐīÐ īÐĊă ďī ìÐĨĴðÆ ðĉĨðīĉÐĊĴș ÆďĊĮðÌÐī ĴìÐ īðĮāĮ ĊÌ ĨďĴÐĊĴðă ÅÐĊÐť ĴĮ ÅÐåďīÐ ðĊðĴðĴðĊæ ĴīÐĴĉÐĊĴ œðĴì t'¢ tZ N You are encouraged to report side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call Ǡȭǧǟǟȭ9# ȭǠǟǧǧȘ ďķ ĉř ăĮď ÆďĊĴÆĴ NÌĉďĊ qìīĉÆÐķĴðÆăĮș OO ș Ĵ ǠȭǧǦǦȭǢǦǦȭǦǧǥǡ Ĵď īÐĨďīĴ ĮðÌÐ ÐååÐÆĴĮȘ References: 1. REZUROCK. Package insert. Kadmon Pharmaceuticals, LLC; 2021. 2. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA. 2014;111(47):16814-16819. doi:10.1073/pnas.1414189111 3. Flynn R, Paz K, Du J, et al. Targeted rho associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144-2154. doi:10.1182/blood-2015-10-678706 4. #Ĵ ďĊ ť ăÐȘ NÌĉďĊ qìīĉÆÐķĴðÆăĮș OO ț ǡǟǡǠȘ 5. Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study. Blood. 2021;blood.2021012021. doi:10.1182/blood.2021012021

Please see Brief Summary of full Prescribing Information on adjacent pages.

REZUROCK™ (belumosudil) tablets, for oral use Initial U.S. Approval: 2021 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE REZUROCK is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versushost disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, REZUROCK can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits during the period organogenesis caused adverse developmental outcomes including embryo-fetal mortality and malformations at maternal exposures (AUC) less than those in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1) in the full prescribing information]. 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Chronic Graft versus Host Disease In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Studies (14.1) in the full prescribing information]. The median duration of treatment was 9.2 months (range 0.5 to 44.7 months). Fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea and multi-organ failure. Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. The adverse reactions which resulted in permanent discontinuation of REZUROCK in > 3% of patients included nausea (4%). Adverse reactions leading to dose interruption occurred in 29% of patients. The adverse reactions leading to dose interruption in ≥ 2% were infections (11%), diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, liver function test abnormal, nausea, pyrexia, edema, and renal failure with (2% each). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension. Table 2 summarizes the nonlaboratory adverse reactions. Table 2: Nonlaboratory Adverse Reactions in ≥ 10% Patients with Chronic GVHD Treated with REZUROCK REZUROCK 200 mg once daily (N=83) Adverse Reaction

Table 3 summarizes the laboratory abnormalities in REZUROCK. Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK REZUROCK 200 mg once daily

Parameter

Grade 0-1 Baseline

Grade 2-4 Max Post

Grade 3-4 Max Post

(N)

(%)

Chemistry Phosphate Decreased

Gamma Glutamyl Transferase Increased

Calcium Decreased

Alkaline Phosphatase Increased

Potassium Increased

Alanine Aminotransferase Increased

Creatinine Increased

Lymphocytes Decreased

Hemoglobin Decreased

Platelets Decreased

Neutrophil Count Decreased

Hematology

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on REZUROCK Strong CYP3A Inducers Coadministration of REZUROCK with strong CYP3A inducers decreases belumosudil exposure [see Clinical Pharmacology (12.3) in the full prescribing information], which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK when coadministered with strong CYP3A inducers [see Dosage and Administration (2.3) in the full prescribing information].

All Grades (%)

Grades 3-4 (%)

Infection (pathogen not speciﬁed)a

Viral infectionb

Bacterial infectionc

Astheniad

Edemae

Pyrexia Gastrointestinal

Nauseaf

Diarrhea

Abdominal paing

Dysphagia

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1) in the full prescribing information], REZUROCK can cause fetal harm when administered to pregnant women. There are no available human data on REZUROCK use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including alterations to growth, embryo-fetal mortality, and embryo-fetal malformations at maternal exposures (AUC) approximately ≥ 3- (rat) and ≥ 0.07 (rabbit) times the human exposure (AUC) at the recommended dose (see Animal Data). Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

Dyspneah

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Coughi

Nasal congestion

Hemorrhagej

Hypertension

Musculoskeletal paink

Muscle spasm

Arthralgia

Decreased appetite

Skin and subcutaneous Rashm

Pruritusn

Infections and infestations

General disorders and administration site conditions

Respiratory, thoracic and mediastinal

Vascular

Musculoskeletal and connective tissue

Nervous system Headachel Metabolism and nutrition

includes edema peripheral, generalized edema, face edema, localized edema, edema. includes nausea, vomiting. g includes abdominal pain, abdominal pain upper, abdominal pain lower. h includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome. i includes cough, productive cough. j includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura. k includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. l includes headache, migraine. m includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative. n includes pruritus, pruritus generalized. f

infection with an unspecified pathogen includes acute sinusitis, device related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, tooth infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, septic shock. b includes influenza, rhinovirus infection, gastroenteritis viral, viral upper respiratory tract infection, bronchitis viral, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenzae virus infection, Varicella zoster virus infection, viral infection. c includes cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastroenteritis Escherichia coli, Pseudomonas infection, urinary tract infection bacterial. d includes fatigue, asthenia, malaise.

Proton Pump Inhibitors Coadministration of REZUROCK with proton pump inhibitors decreases belumosudil exposure [see Clinical Pharmacology (12.3) in the full prescribing information], which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK when coadministered with proton pump inhibitors [see Dosage and Administration (2.3) in the full prescribing information].

Data Animal Data Embryo-fetal development studies were conducted in rats with administration of belumosudil to pregnant animals during the period of organogenesis at oral doses of 25, 50, 150, and 300 mg/kg/day in a pilot study and doses of 15, 50, and 150 mg/kg/day in a pivotal study. In the pilot study, maternal toxicity and embryofetal developmental effects were observed. Maternal toxicity (reduced body weight gain) occurred at 150 and 300 mg/kg/day doses. Increased post-implantation loss occurred at 50 and 300 mg/kg/day. Fetal-malformations were observed at ≥ 50 mg/kg/day and included absence of anus and tail, omphalocele, and dome shaped head. The exposure (AUC) at 50 mg/kg/day in rats is approximately 3 times the human exposure at the recommended dose of 200 mg. In an embryo-fetal developmental study in rabbits, pregnant animals administered oral doses of belumosudil at 50, 125, and 225 mg/kg/day during the period of organogenesis resulted in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (body weight loss and mortality) was observed at doses ≥ 125 mg/kg/day. Embryo-fetal effects were observed at doses ≥ 50 mg/kg/day and included spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, malformations, and decreased fetal body weight. Malformations included those in the tail (short), ribs (branched, fused or deformed), sternebrae (fused), and neural arches (fused, misaligned, and deformed). The exposure (AUC) at 50 mg/kg/day in rabbits is approximately 0.07 times the human exposure at the recommended dose of 200 mg. 8.2 Lactation Risk Summary There are no data available on the presence of belumosudil or its metabolites in human milk or the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions from belumosudil in the breastfed child, advise lactating women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose. 8.3 Females and Males of Reproductive Potential REZUROCK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with REZUROCK.

Contraception Females Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. Infertility Females Based on findings from rats, REZUROCK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1) in the full prescribing information]. Males Based on findings from rats and dogs, REZUROCK may impair male fertility. The effects on fertility are reversible [see Nonclinical Toxicology (13.1) in the full prescribing information]. 8.4 Pediatric Use The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older. Use of REZUROCK in this age group is supported by evidence from adequate and well-controlled studies of REZUROCK in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of drug substance, that the exposure of drug substance is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The safety and effectiveness of REZUROCK in pediatric patients less than 12 years old have not been established. 8.5 Geriatric Use Of the 186 patients with chronic GVHD in clinical studies of REZUROCK, 26% were 65 years and older. No clinically meaningful differences in safety or effectiveness of REZUROCK were observed in comparison to younger patients. Active ingredient made in India. Distributed and marketed by: Kadmon Pharmaceuticals, LLC Warrendale, PA 15086 1-877-377-7862 REZUROCK™ is a trademark of Kadmon Pharmaceuticals, LLC. © 2021 Kadmon Pharmaceuticals, LLC, Warrendale, PA 15086. All rights reserved. KAD25000266 10/21

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

Data: What Works in HIV Prevention By Sarah Michienzi, PharmD, BCPS, AAHIVP, and Eric Wenzler, PharmD, BCPS, BCIDP, AAHIVP

omparisons have been made between the public health response to COVID-19 and the early days of the HIV epidemic.1 As with COVID-19, messaging regarding HIV risk and severity is of utmost importance. Many people do not believe they will contract the viruses; or if they do, they will not develop severe illness. Additionally, there is

not a one-size-fits-all approach to preventing infection with either virus. We know masking, handwashing, and physical distancing help prevent the spread of COVID-19.2 However, not all people are able to adequately physically distance due to factors such as crowded living environments and performing essential job functions. Similarly, we

know correct and consistent condom use and adherence to oral pre-exposure prophylaxis (PrEP) with emtricitabinetenofovir disoproxil fumarate (FTC/ TDF) or FTC-tenofovir alafenamide (FTC/TAF; Descovy, Gilead) are both highly effective in preventing HIV.3 However, not all people are willing to use condoms or able to negotiate for

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their use successfully. Additionally, not all people are able to adhere to daily medication, and some have contraindications to FTC/TDF and FTC/TAF. Achieving the goal of a 75% reduction in new HIV infections by 2025 and at least a 90% reduction by 2030, as set forth in the federal program “Ending the HIV Epidemic: A Plan for America,” requires a multifaceted approach that targets the highest-risk populations.4 The initiative calls for ramping up diagnosis, treatment, prevention, and outbreak response efforts. It is estimated that fewer than 25% of people who could benefit from PrEP are using it. Solutions to increase PrEP uptake and adherence/persistence are many. For example, data presented at the AIDS 2020 virtual meeting showed that a California Pre-Exposure Prophylaxis Assistance Program contributed to PrEP expansion by removing financial and structural barriers.5 Developing additional pharmacotherapeutic options for PrEP to meet the diverse needs of patients represents another potential solution.

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One such agent is the long-acting injectable integrase strand transfer inhibitor (INSTI), cabotegravir and rilpivirine (CAB/RPV; Cabenuva, ViiV Healthcare/ Janssen). The treatment was recently evaluated in the HPTN 083 trial (ClinicalTrials.gov Identifier: NCT02720094). The primary efficacy end point of this phase 2b/3, randomized, double-blind trial was incident HIV infections with CAB/RPV or oral FTC/TDF.6 The study was terminated early in May 2020 after reaching the prespecified stopping bound of accruing 25% of the end points in an interim analysis, which allowed for the final results to be presented at the AIDS 2020 meeting. The study continued unblinded, and all participants were offered CAB/RPV. To be eligible for inclusion in HPTN 083, subjects had to be cisgender men and transgender women who have sex

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

the FTC/TDF arm. Only 5 of the 13 HIV infections in the CAB arm occurred despite continuous on-time CAB/RPV injections. The others occurred after prolonged nonadherence to CAB/RPV (n=5) and during the oral lead-in phase (n=3). Of note, the pooled HIV incidence of 0.81 (95% CI, 0.61-1.07) per 100 person-years observed in the study was considerably lower than the target background HIV incidence of about 4.5%. Although designed as a noninferiority trial, CAB/RPV met the criteria for superiority, with a 66% reduction

in HIV acquisition risk compared with FTC/TDF. Similarly, as noted, CAB/ RPV was shown to be superior to FTC/ TDF in women in HPTN 084.7 Overall, CAB/RPV was well tolerated in the HPTN 083 trial. Injection site reactions (ISRs) were the primary adverse event (AE), with 80.9% of participants in the CAB arm reporting an ISR. Most were classified as mild (grade 1) or moderate (grade 2), and lasted a median of 3 days (IQR, 2-5 days). There was a strong association

A multifaceted approach is needed to reach the US goal of a

75% reduction in new HIV cases by 2025, and at least a

90% reduction by 2030.

see HIV PREVENTION, page 21

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with men, at least 18 years of age who met criteria for HIV risk, generally in good health, not diagnosed with hepatitis, and tolerant of gluteal injections. (Of note, cisgender women were not included in HPTN 083 despite the large number of heterosexual women in the United States who could benefit from PrEP. Safety and efficacy of CAB/RPV among cisgender women of sub-Saharan Africa were investigated in a similar study, HPTN 084,7 which showed that the treatment was superior to oral FTC/TDF for the prevention of HIV. Data on adolescents are forthcoming from HPTN substudies 08301 and 084-01.8) Participants in the HPTN 083 trial were randomized 1:1 to a CAB/RPV or FTC/ TDF arm. In step 1, participants received daily oral CAB or FTC/TDF. This oral lead-in is required before administering the long-acting injectable CAB to ensure tolerability, because it has a long half-life once injected. Injections began in step 2. Participants received injections of CAB/ RPV (CAB arm) or matching placebo (FTC/TDF arm) at weeks 5 and 9 and every 2 months after that as well as oral FTC/TDF (FTC/TDF arm) or matching placebo (CAB arm) daily. The study planned for step 2 to last approximately 3 years, at which time injections would be discontinued. Participants in the CAB/RPV arm would receive oral daily FTC/TDF for 1 year in step 3 to reduce the risk for HIV acquisition in the presence of subtherapeutic levels of CAB/RPV. The primary efficacy cohort included 2,243 and 2,247 participants in the CAB/ RPV and FTC/TDF arms, respectively. Transgender women represented 12.4% of the total study population. There were study sites in the United States, Latin America, Asia, and Africa, and nearly 50% of the US participants were Black. In 6,389 person-years of follow-up, with a median per-participant followup time of 1.4 years (interquartile range [IQR], 0.8-1.9), there were 52 HIV infections: 13 in the CAB arm and 39 in

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Making Patients Special continued from page 1

accrediting organization. However, URAC changed its standard requirements in 2019, and programs now must be specific to disease states or medications, said Dr. Bonome, who was one of several pharmacy experts who presented best tips for successful clinical protocol programs at the ASHP 2021 Midyear Clinical Meeting and Exhibition, held virtually. It turns out the best practices outlined during the ASHP session are the same ones that make any therapy successful, the speakers said: proper planning, thorough education, consistency, occasional reassessment and the ability to adjust when necessary. Protocols also should be specific to the disease or therapy, incorporate all members of the patient care team, and track outcome measures to demonstrate value, Dr. Bonome said. “At the end of the day, specialty patients are special because of the disease state that they’re dealing with and because of the drugs that they’re taking,” she said. “Their unique needs need to be addressed.”

component and should be provided prior to the patient taking the medication, Dr. Richards said. Topics should include information about medication use and safety, side effects, and what to do in case of missed doses, she said. It’s also important to boost patient literacy via education and counseling, Dr. Jessee said. Some of those discussions should focus on safety, including at-home medication storage, because many specialty medications need to be refrigerated or frozen, he continued. Other conversations may need to

patient health, she said. “Get to a place where you have covered a majority of the issues that can occur with these drugs, and how you’re going to handle that,” she said. Interventions should be evidencebased, Dr. Richards continued. Documenting and reporting on interventions can ensure the entire care team has access to the data, and it supports the value of having pharmacists involved in treatment, she said. However, clinical interventions are a newer metric from URAC, and technology systems may not have an easy way to track them, Dr. Jessee cautioned. It’s important to determine a workflow to show this information, he said.

design methods for evaluating clinical protocols and decide which measures are needed to evaluate their effectiveness, Dr. Richards said. In doing so, think what would be needed to determine whether the program is effective, how the data can best be captured, and define inclusion and exclusion criteria, she said. Metrics to be measured can be divided into clinical outcomes, such as laboratory values; financial outcomes, including projected savings from avoided hospitalizations; or quality-of-life outcomes. Make sure everything is clearly documented and that you outline a plan for how to analyze data and how often, she said.

8 Best Protocol Practices 1. Do an initial assessment to identify appropriate clinical services and touch points. 2. Use digital engagement tools to connect with patients. 3. Boost patient health literacy, with a focus on safety and compliance. 4. Reassess patients during refills, lab tests and other points of contact.

A Solid Start

5. Document all clinical interventions and outcomes.

The first step in establishing good protocols is identifying services and touch points to be provided, said Jenn Richards, PharmD, JD, CSP, the product development principal at URAC. An initial assessment is essential to determine the appropriateness of the therapy, based on factors such as diagnosis, comorbidities and medical history, Dr. Richards said. Assessments can be done by phone/video or in person, or information can be collected from the prescriber’s office through notes or a conversation, she noted. Specifically, URAC accreditors look for key measures during the initial assessment, such as patient diagnosis, medication lists and prior allergies, Quintin Jessee, RPh, DPh, the vice president of specialty services and accreditation for D2 Pharma Consulting, told Specialty Pharmacy Continuum. Understanding what makes these patients unique—as well as what is different about a particular disease state or drug—will help when deciding how to customize protocols, Dr. Richards said. Consider what information will ensure a medication is appropriate, such as other drugs the patient is taking, whether patients are comfortable injecting at home by themselves, or whether they have a caregiver at home, she continued. Digital engagement technologies, such as text messaging, can help improve communications and patient outreach while taking some burden off staff during a challenging time, Dr. Jessee said. Education is another important

6. Collaborate on decisions affecting provider roles and optimal site of care. 7. Share plan with internal and external stakeholders to ensure buy-in. 8. Work with IT department to avoid tracking and documentation pain points.

address patient requests or preferences for certain types of medications or formulations. Discussions over whether those requests are appropriate can be supported by reading material or demonstrations with medication in hand, Dr. Richards said. “The goal is to help the patient understand the nuances of the medication and overall health safety.”

Regular Checkups Reassessments should be done regularly, such as during refills, lab tests and changes to patient health, Dr. Richards continued. “The goal here is to touch base with the patient enough to ensure you remain confident the medication continues to be appropriate and safe.” Reassessment points may vary based on each drug or disease state, and pharmacies should rely on industry best practices or guidance from drug manufacturers, Dr. Jessee said. Some drugs with Risk Evaluation and Mitigation Strategy programs also include elements to ensure safe use, which will include specific touch points, he added. Clinical interventions also are necessary and may arise because of issues for which you can prepare, such as particular disease states or drugs, Dr. Richards advised. Others may arise for unexpected reasons, such as changes in

Working Together Next, team collaborations should be planned, Dr. Richards said. Where will services be provided—in a pharmacy, clinic or other location, such as a longterm care facility or patient’s home with nursing support? What roles will the pharmacist, nurse, provider and others have? Also consider who will administer the medication, she said. All of this should be documented in each step of the clinical protocol, Dr. Richards said. Consider resources such as time required for each patient, the number of people required to service all patients, and the use of clinicians and nonclinicians, she said. Doing so can minimize duplication of work and allow individuals to work at the top of their licensure, she added.

Avoid PA Pitfalls One issue specialty pharmacy medications can run into is getting stuck in a prior authorization, step therapy or failed claim scenario, Dr. Jessee said. Electronic benefit tools and collaborations with insurers can speed up the resolution of these issues. Remember that infused products may require additional collaborations with provider offices, he continued. Once these steps are completed,

Then, share the plan with internal and external stakeholders, including current or prospective clients and payors, Dr. Richards said. Before implementation, protocols should be approved by a clinical oversight body, she said, and plan to review and update the protocol at least annually.

A Transparent Launch During implementation, ensure processes are documented, educate and train all members of the team, and communicate your launch to all stakeholders, Dr. Bonome said. During ongoing evaluations, check whether your measures are meeting goals or whether a change in protocol is required based on its effectiveness or any new clinical guidelines. Pharmacists should note that some clinical management software systems are not accreditation-specific, and may be more challenging to extract reports about patient interactions, Dr. Jessee said. You may have to work with your information technology department or the software manufacturer to determine the best process to do this, he said. “Tracking and documenting interactions has been the pain point.” The sources reported no relevant financial disclosures.

OūŞĚ TŠĲƭƙĿūŠɫƙ ǷîĳƙĺĿƎ ĚǄĚŠƥ ČūŞĚƙ ƥū s sîƙĺǄĿŕŕĚ Did you know....

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Specialty Pharmacy Continuum • January/February 2022

CLINICAL

IG Supply Still Safe continued from page 1

shortage. “But one of the things we say internally is, ‘if we’re wrong about this, then patient care is still OK.’” In early January, the Red Cross said it had experienced a 10% decline in donations since the beginning of the pandemic, and has had to limit blood distributions to hospitals in recent weeks. “In fact, on certain days, some hospitals may not receive as much as one-quarter of the blood products requested,” the organization said in a media release (rdcrss. org/3fWZSyG). Similarly, blood plasma donations at U.S. donation centers remain below 2019 donation levels, despite recovering somewhat in 2021 from their 2020 lows, said Matthew Hotchko, PhD, the president of the Marketing Research Bureau, which supplies market data and intelligence on the global blood and plasma industry. “For all of 2021, I would estimate that donations were down approximately 15% on a same-center basis compared to 2019. But the Mexican border centers have dropped much more, skewing the average [somewhat],” said Dr. Hotchko, who added that the omicron variant put a damper in what was expected to be a strong fourth quarter. “Donations were up compared with 2020, but that’s not a great achievement.” However, Dr. Hotchko said he did not anticipate a reduction in the availability of IG in the United States, partly because it is the leading supplier and consumer of IG, and Americans pay by far the most for the products. “In fact, the challenge

right now is boosting demand for IG in the U.S. market,” he said. People might be avoiding healthcare settings out of concern about COVID-19, and staffing shortages mean fewer procedures and treatments have been completed than before the pandemic, Dr. Hotchko noted. “We saw shrinking demand in the third quarter of 2021 and that didn’t really bounce back over the fourth quarter,” he said. “Overall, I would say there was a decline in sales between 2020 and 2021 in the low single digits, although I don’t have final numbers yet.”

Climbing Costs The decline in plasma collections has raised the cost of doing business for plasma manufacturers and fractionators, Mr. Schmidt noted. “Those costs have been passed on in the form of price increases, which over the past two years have been in excess of what we were experiencing earlier,” he said. “It’s hard to pass on that cost because a lot of payors have adopted Medicare reimbursement rates, and there is a six-month lag time in adjusting those rates. As a result, many healthcare providers are upside down on IG, and there are very few products to choose from in both subcutaneous and intravenous IG that are profitable.” Smaller suppliers might be having a difficult time, Mr. Schmidt said, because each infusion pharmacy makes its own decision on how much cost to pass on to buyers. “Unfortunately, I think what happens is that the big

‘Many healthcare providers are upside down on IG [due to price increases not covered by Medicare], and there are very few products to choose from in both subcutaneous and intravenous IG that are profitable.’ —Patrick M. Schmidt players get bigger because they potentially have more purchasing power.” FFF Enterprises has increased its IG supply in anticipation of supply constraints, Mr. Schmidt said. “If they don’t materialize, yes, it has cost us money, but we’ve protected patients.”

More Centers Built Hoping to reach more donors, blood plasma companies, such as CSL, Octapharma and Takeda, have been building more donation centers over the past few years. “There were more than 100 new FDA-licensed centers opened in 2020, and again over 100 added in 2021,”

Dr. Hotchko said, adding that the newer centers might be more evenly distributed geographically than the footprint that existed before 2020. “The companies aren’t building many new centers at the U.S.–Mexico border, where many were concentrated before, because of COVID travel restrictions,” Dr. Hotchko said. “They’re building more in suburbia and large metro areas, sometimes even within five or 10 miles of the next-closest donation center.” The sources reported no relevant financial disclosures other than their stated employment.

Navigating COVID-19 and Other IG Challenges Las Vegas—A patient with primary immunodeficiency on immune globulin (IG) therapy receives the first and second doses of a messenger RNA COVID-19 vaccine as well as a booster dose, but no COVID-19 antibodies develop. Is the patient protected against the SARS-CoV-2 virus? This isn’t a hypothetical situation; it’s a real case described by a clinician looking for answers at the IgNS 2021 Conference. He posed the question to Vivian Hernandez-Trujillo, MD, the director of the Division of Allergy and Immunology at Nicklaus Children’s Hospital, in Miami. Dr. Hernandez-Trujillo had just finished the formal portion of her Vaccination in Immunodeficiency presentation and was fielding questions from the live and virtual audiences. The clinician concerned about his patient’s

antibody failure followed with a general question about immunodeficient patients: “What if they never develop the COVID-19 antibody?” “I know,” Dr. Hernandez-Trujillo said. “This is the case for some of my antibody-deficient patients.” But she added: “The hope is that they have some cellular protection.” Earlier she had emphasized the value of the cellular response. “In many patients,” she said, “it can be as important as the antibody response. Even patients with agammaglobulinemia can receive

the flu vaccine because we’re looking for a T-cell response to protect them.” Inactivated flu and COVID-19 vaccines also can be given to patients with common variable immunodeficiency (CVID) and agammaglobulinemia, she said, adding, “these patients should obviously be on immune globulin therapy. For these patients, this immune globulin treatment is lifelong.” (Dr. Hernandez-Trujillo mentioned that more definitive answers on COVID-19 vaccine responses in patients with immune deficiencies may be forthcoming from a National Institutes of Health ongoing study [ClinicalTrials. gov Identifier: NCT04852276].) COVID-19 immunity aside, Dr. Hernandez-Trujillo focused on vaccines and immune deficiencies for which clinical evidence is solidly grounded, including the safe delivery of inactivated

(killed) and live-attenuated vaccines. Correctly timing vaccines is vitally important, Dr. Hernandez-Trujillo said. “It’s OK to give vaccines that are not live, including inactivated flu and COVID-19 vaccines, during therapy, but it’s best to wait a month after the last dose if the patient is on intravenous IG.” On the other hand, she said, “live-attenuated vaccines such as measles, mumps, rubella and varicella are contraindicated during IG therapy. They may be dangerous, and IG therapy will neutralize the effect of the vaccines.” But immunodeficient patients at risk for developing clinical disease from weakened viruses should never receive live vaccines, Dr. Hernandez-Trujillo said. The proscribed conditions include: • agammaglobulinemia; • CVID;

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

Additional Sources Consensus document on common variable immune deficiency (CVID). J Allergy Clin Immunol Pract. 2016;4(1):38-59. Pneumococcal vaccination in adults. UpToDate. Updated July 30, 2021. Accessed January 31, 2022. bit.ly/3GiupSq. Vaccination & Immunoprophylaxis: General Recommendations. CDC Yellow Book. Updated August 10, 2021. Accessed January 31, 2022. bit. ly/34nzpHW.

‘Live-attenuated vaccines such as measles, mumps, rubella and varicella are contraindicated during IG therapy. They may be dangerous, and IG therapy will neutralize the effect of the vaccines.’ —Vivian Hernandez-Trujillo, MD after treatment has started.” As for checking laboratory values, she said, “I can’t tell you how many times

I’ll get a lymphocyte subset back and the numbers don’t add up. All of the decisions we make as clinicians are based on

comparing laboratory results to ‘normal’ values. We need to have very specific, valid information, because, if not, we may be incorrectly diagnosing or, more than likely, underdiagnosing patients with immunodeficiency.” Dr. Hernandez-Trujillo reported that she is an advisory board member of and a consultant to CSL Behring and Takeda, and a speaker for Takeda. She also is a member of the Clinical Immunology Society Advocacy Committee and Immune Deficiency Foundation Medical Advisory Committee.

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• severe combined immunodeficiency (SCID); • poor or severely impaired T-cell function; and • DiGeorge syndrome, with significant hypogammaglobulinemia or very low T cells. Dr. Hernandez-Trujillo also said the rotavirus vaccine, another live vaccine, is contraindicated in patients with SCID. “That’s hard,” she said, “because infants get rotavirus. This is why I’m passionate about newborn screening because we can identify babies [with SCID] at birth. Now, thankfully, all 50 states for the first time are screening for patients with T-cell deficiencies. That’s good news because rotavirus can kill a baby with SCID or cause very debilitating disease.”

2 Key Strategies For Reliable Lab Results Dr. Hernandez-Trujillo had two pieces of advice for clinicians who regularly see patients with immunodeficiency diseases. One is to draw blood samples for immune studies before starting IG treatment, whenever possible. The other is to vigorously check laboratory results for calculation errors and compare with age-matching flaws. She said when a patient without a diagnosis of immunodeficiency needs gamma globulin, the medical team can consider drawing blood and setting it aside, so it’s available for testing after treatment has started. “Knowing the baseline can really help decrease the delay in diagnosis,” she stressed, “because you never know what tests you’re going to need

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CLINICAL

Pediatric OCD May Respond to IG Therapy By Bruce Buckley

Las Vegas—Timely treatment with IV immune globulin (IVIG) therapy may help children who develop obsessive-compulsive disorder (OCD) and other severe psychiatric or neurologic symptoms in the aftermath of streptococcal or other infections, according to new data presented at the IgNS 2021 Conference. At the University of Arizona (UA)/ Banner Health Children’s Postinfectious Autoimmune Encephalopathy (CPAE) Center of Excellence, in Tucson, a tiered treatment strategy is designed to counter the constellation of symptoms that can arise after an infection triggers an autoimmune reaction targeting the brain’s basal ganglia, said Sydney Rice, MD, a professor of pediatrics at the UA College of Medicine and co-director of the CPAE clinic. The regimen involves a three-step strategy, starting with an antibiotic to clear any infection that may be present, followed by an anti-inflammatory to suppress the immune system: either a nonsteroidal medication such as ibu-

profen/naproxen or a cortiicosteroid such as prednisone. e. The final step, Dr. Rice said, d, involves the use of IVIG. About out 10% or fewer of CPAE clinic patients advance to IVIG therapy, she added. Dr. Rice said Stanford University researchers have done “a lot of work showing that treatment with just nonsteroidal medications will abate symptoms and may even be curative. It’s really quite striking” (J Child Adolesc Psychopharmacol 2017;27[7]:574-593). However, “the important issue is that you need to treat quickly,” she said. “The sooner you do, the more likely that there will be a cure for your child. But if that doesn’t go well and symptoms persist, we move on to prednisone,” and finally, she said, to IVIG. Michael Daines, MD, an associate professor of pediatric allergy and immunology at the UA College of Medicine

and the other CPAE clinic co-director, elaborated on the use of IVIG, but first discussed the risks of anti-inflammatories for immunosuppression. “The problem is that we can’t just suppress that immune problem,” he said, referring to the adverse psychiatric and neurologic effects of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS).

‘Suppress Everything’ “We suppress everything in the immune system,” he said, and while that will prevent symptoms related to PANDAS and PANS, “it will also suppress response to

the parainfluenza virus and everything else out there. So, we use them, but they have to be temporary solutions. “The last thing we do is block antibodies,” Dr. Daines said. “So, we use IVIG in immunomodulatory doses to try to stop these antibodies from doing what they do.” He added, “There are multiple mechanisms [through which] immunomodulatory IVIG works, which means we don’t completely understand how. But it does work; it’s been clinically proven.” The cost, however, can be challenging. “It’s not hard to get authorization for amoxicillin,” Dr. Daines noted. “But once you move up into IVIG therapy, which can cost thousands of dollars a month, insurance companies raise concerns. And as an immunologist, I also

have concerns. IVIG has risks associated with its use. It’s a human blood product, and its quantity is finite. We have run out before. And it is terrifying to an immunologist to be out of something that is keeping some of your very immune-deficient patients from having life-threatening infections. So, we do need to be good stewards of IVIG, especially for off-label purposes.” Dr. Daines said the CPAE clinic has had success in obtaining IVIG authorization from insurance companies, with a prior approval rate of about 90%. One reason, he said, was the use of neurocognitive testing to demonstrate therapy success or failure. “What we try to

conditions. “What we see are dramatic onset of OCD, severe obsessive-compulsive behavior where children can’t be touched,” she said. “They quit eating. This is not body dysmorphia, but it’s because they’re afraid their food is going to kill them. They’re afraid they’re going to choke, or their food is contaminated, and they just quit eating.” The onset of these extreme symptoms, she said, is within 72 hours. “So, a child is completely neurotypical and 72 hours later extremely mentally ill.”

Addressing Food Refusal Dr. Daines noted that food refusal also can trigger an issue with hydration,

‘We have different ways to work through their anticipatory anxiety and to pharmacologically and nonpharmacologically treat these problems so we can safely administer these medications.’ —Michael Daines, MD

do,” Dr. Daines explained, “is get authod rrization for three rounds of treatment, with a limited neuropsychiatric testing w rrun before and after, so we have objective evidence of whether this worked.” If it does work and the patient is completely better, he said, “there is no need to continue treatment. If it didn’t work at all, there is no reason to continue treatment because it is futile at that stage. If it worked with a statistically significant improvement, but incomplete, then we would consider doing an extension of the treatment and retesting at a later date to see if we continue to get an improvement, and if not, we stop.”

Pinning Down PANDAS and PANS Dr. Rice described some of the challenges to diagnosing PANDAS and PANS, whose neuropsychiatric symptoms can resemble those of other

which can make treatment challenging. “When we’re giving IVIG to these children, we try to ensure that they’re well hydrated prior to administration of it to prevent many of the complications” that can come with IVIG therapy. In addition, he said, children can have anxieties that make it difficult to sit still for six hours in a chair with a needle in their arms. “So, we have different ways to work through their anticipatory anxiety and to pharmacologically and nonpharmacologically treat these problems so we can safely administer these medications,” Dr. Daines said. “This includes heavy sedation for children who are unable to tolerate these IG infusions in any other way. So, you just have to be flexible.”

More Evidence of Efficacy The CPAE clinic is not the only example of clinicians having success using IVIG to treat young patients with postinfection neuropsychiatric disorders. In a case series of 12 youths with PANDAS/ PANS, several experienced significant symptom relief after IVIG infusions. In one representative patient, partial remission of symptoms occurred about two weeks after the infusion, and a complete remission was achieved by one month post-IVIG (J Child Adolesc Psychopharmacol 2015;25[1]:65-69). Both Drs. Daines and Rice have grant funding from the Arizona Biomedical Research Centre for research on PANDAS/ PANS. Dr. Daines is a site principal investigator on the Octapharma IVIG PANDAS/PANS international trial.

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Specialty Pharmacy Continuum • January/February 2022

CLINICAL

‘Off-the-Shelf’ CAR-T Therapy Shows Promise By Gina Shaw

A novel allogeneic chimeric antigen receptor (CAR) T-cell therapy, herapy, ALLO-501A, showed encouraging safety and efficacy in a small mall single-arm, open-label, phase 1/2 trial in heavily pretreated patients with advanced relapsed/refractory large B-cell lymphophoma, with signs of increased efficacy for consolidation dosing. g. If the results are replicated in larger clinical trials, “off-the-shelf” CAR T-cell therapy would be a major step toward simplifying this complex treatment, avoiding the complicated individualized process of leukapheresis, freezing and reprogramming currently required for autologous CAR T-cell therapies, experts noted. “Overall it’s pretty promising, with efficacy results that were comparable to the approved [autologous] CAR-T products

continued to have ongoing CR at nine and 12 months and later.

Boosting Cellular Responses nses “What’s unique to this regimen n is that not only is it off the shelf, but it included two doses,” Dr. Scappaticci said. “I always thought that perhaps the persistence istence of autologous CAR-T cells may bee limited because, in some instances, disease ease burden may be very high and immunotheraunothera-

‘Overall it’s pretty promising, with efficacy results that were comparable to the approved [autologous] CAR-T products indicated for lymphomas.’ —Gianni Bruno Scappaticci, PharmD indicated for lymphomas,” Gianni Bruno Scappaticci, PharmD, BCOP, a clinical specialist for inpatient BMT/cellular therapies at Michigan Medicine in Northville, told Specialty Pharmacy Continuum. Following a lymphodepletion regimen combining the monoclonal antibody ALLO-647 and fludarabine-cyclophosphamide chemotherapy, patients received either a single dose, or a first dose and an additional consolidation dose, of ALLO-501A. The consolidation dose was given at day 28. The abstract (649), presented at the 2021 annual meeting of the American Society of Hematology (ASH) meeting (bit.ly/3AMwN2J), included 12 evaluable patients of 20 initially enrolled in the study. Of these patients, six were assigned to the single-dose group and the remainder to the consolidation group. In both groups, the overall response rate (ORR) and complete response (CR) after the first dose were 50% (95% CI, 21.1%-78.9%). In the consolidation group, both ORR and CR rate after the consolidation dose were 66.7% (95% CI, 22.3%95.7%), with all three patients who had had a partial response (PR) after the first dose converting to CR after consolidation, the investigators reported. One patient in this group had CR at days 28 and 56 after consolidation, and two patients had progressive disease at month 1 and did not receive consolidation treatment. In the single-dose group, two patients

pies take time to work. Here, they used a boost, and it does seem to improve cellular expansion and response. With an off-the-shelf therapy, there would theoretically be no limit to how many times you could administer the cells.”

GvHD Risk Reduced The safety profile was manageable in both groups, the investigators reported. ALLO-501A has been genetically modified to reduce the risk for graft-versushost disease (GvHD)—a significant concern with CAR T-cell therapy, occurring in up to 93% of patients, depending on the specific CAR T-cell regimen given (Hemasphere 2019;3(2):e186). No cases of GvHD were seen in either group, the investigators said. In the single-dose group, the most common adverse events were anemia, leukopenia, neutropenia and thrombocytopenia (73%), and lymphopenia (64%), as previously reported at the American Society for Clinical Oncology annual meeting in 2021 (bit.ly/3gfemtZ). Cytokine release syndrome (CRS) developed in two patients (18%), both grade less than 3. Infusionrelated reactions, all grade less than 3, were observed in four patients (36%). In the consolidation group, no cases of CRS or immune effector cell–associated neurotoxicity syndrome were reported, nor were there any dose-limiting toxicities, dose reductions, grade 3 or higher infections, and serious adverse events. “ALLO-501A with consolidation dosing demonstrated comparable safety and

an improved efficacy profile compared with single dosing, with all four patients who received consolidation remaining in CR,” concluded the authors, led by Lazaros Lekakis, MD, an associate professor of clinical medicine at the University of Miami Health System. “Additional follow-up is needed to determine whether consolidation also improves the durability of response. Consolidation was well tolerated and, given the generally favorable overall safety profile, ALLO-501A may have the potential to be given in the outpatient setting.” They added that, given its safety profile to date, the consolidation dose could be given even in the outpatient setting.

Data Gap for Serious Infections? However, Dr. Scappaticci expressed concern about the lack of reported serious

infections. “You’re giving this treatment with an anti-CD52 monoclonal antibody, so you are essentially making all of these patients pancytopenic,” he said. “Cytopenias are very common post CAR-T, and they can persist for months afterward, posing an ongoing infection risk. I see this in patients after undergoing CAR T-cell therapy with current available treatments. “I would be concerned about the risk of viral reactivations, fungal infections and other serious infections that can occur in neutropenic patients,” he added. “I would like to see more data as to how long patients were followed for cytopenias and infections, as well as long-term efficacy follow-up.” Dr. Scappaticci reported no relevant financial disclosures. Disclosures for the ALLO-501A investigators are reported on the ASH abstracts page at bit.ly/3AMwN2J.

More on the Web From SPC Managing Asparaginase Hypersensitivity Reactions bit.ly/3sb5on9-SPC

Next-Generation Sequencing Helps Risk-Stratify Pediatric Leukemia Patients bit.ly/3Hninby-SPC Studies Point to Optimal Dosing in Acute Leukemia And Lymphoma bit.ly/34lMn9g-SPC

Specialty Pharmacy Continuum • January/February 2022

CLINICAL

HIV PREVENTION continued from page 13

between ISR severity and odds of permanent discontinuation, with 27 participants (2.2%) in the CAB arm permanently discontinuing the injection due to an injection-related AE. Grade 2 or higher AEs reported in at least 5% of participants and more frequently in the CAB arm were nasopharyngitis (19.3%), increased blood glucose (9.0%), and pyrexia (5.4%). In contrast, grade 2 or higher decreased creatinine clearance occurred more frequently in the FTC/ TDF arm (72.0%), which is an expected result of TDF therapy.

References 1. Dunleavy BP. Fauci sees similarities between HIV, COVID-19 in public health response. UPI. Accessed February 1, 2022. http://bit.ly/3uHstOF-IDSE 2. CDC. COVID-19 vaccination. Accessed February 1, 2022. https://www.cdc.gov/vaccines/ covid-19/index.html 3. CDC. HIV prevention. Accessed February 1, 2022. http://bit.ly/3r8KALl-idse 4. CDC. Ending the HIV Epidemic: A Plan for America. Accessed February 1, 2022. https:// www.cdc.gov/endhiv/index.html 5. Peters P, Nakamur A, Barraza A, et al. The California pre-exposure prophylaxis assistance program: lessons learned during an

initial expansion of services. Presented at: AIDS 2020: Virtual; July 6-10, 2020. Abstract PEC0622. Accessed February 1, 2022. http://bit.ly/3uKj3Cc-IDSE 6. Landovitz R, Donnell D, Clement M, et al. HPTN083 interim results: pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB-LA) is safe and highly effective for cisgender men and transgender women who have sex with men (MSM, TGW). Presented at: AIDS 2020: Virtual; July 6-10, 2020. Abstract OAXLB01010. Accessed February 1, 2022. http://bit.ly/30kOJjL-idse 7.

HIV Prevention Trials Network. HPTN 084 study demonstrates superiority of CAB LA to oral FTC/TDF for the prevention of HIV. Accessed February 1, 2022. http://bit.

ly/2OEK6hu-IDSE 8. HIV Prevention Trials Network. HPTN studies. Accessed February 1, 2022. https://www.hptn. org/index.php/research/studies 9. Patel M, Zang X, Youfang C, et al. Islatravir (ISL) PK threshold & dose selection for monthly (QM) oral HIV-1 PrEP. CROI 2021 Virtual. March 6-10. Presentation 1167. 10. Merck. Merck announces clinical holds on studies evaluating islatravir for the treatment and prevention of HIV-1 infection. Accessed February 3, 2022. https://bit.ly/3ggtXcG-PPN

The authors reported no relevant financial disclosures.

A Superior Dosing Regimen Results of HPTN 083 demonstrated the superiority of a novel long-acting injectable INSTI, CAB/RPV, given every 2 months after the initial 2 injections compared with the standard combination of 2 nucleotide reverse transcriptase inhibitors, FTC/TDF, taken orally once daily. However, FTC/TDF still performed well in this study and remains a highly effective means of HIV prevention.

Implantable Device At CROI 2021, Merck presented some exciting, but early results from a phase 1, double-blind, placebo-controlled study of an investigational islatravir subdermal implant for PrEP.9 Twelve people received the implant with 48, 52, or 56 mg of islatravir, a nucleoside reverse transcriptase translocation inhibitor, for 12 weeks. After 12 weeks, the patients were evaluated for an additional 8 weeks. The implant demonstrated a prespecified pharmacokinetic threshhold at 12 weeks across all 3 drug concentrations. However, the company placed a clinical hold on the studies in December 2021 based on FDA observations of decreases in total lymphocyte and CD4+ T-cell counts in some participants.10

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About the authors: Sarah Michienzi, PharmD, BCPS, AAHIVP, is a clinical assistant professor and clinical infectious disease pharmacist in the Pharmacotherapy Section, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois. Eric Wenzler, PharmD, BCPS, BCIDP, AAHIVP, is an assistant professor in the Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.

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Specialty Pharmacy Continuum • January/February 2022

POLICY

Conserve supplies, prioritize needs, NHIA advises

Taming Ambulatory Infusion Pump Shortage By Dave Doolittle

As a nationwide shortage of ambulatory infusion pump administration sets continues, pharmacists should take steps to conserve supplies while prioritizing patients with specific delivery needs, according to the National Home Infusion Association (NHIA). The shortage “is specific to the administration sets commonly used by home infusion providers to administer continuous infusions to patients on therapies such as parenteral nutrition,” NHIA president and CEO Connie Sullivan, BSPharm, told Specialty Pharmacy Continuum. “NHIA was first made aware of the challenges by members in early December 2021.” The NHIA issued a guidance (bit.ly/ 3G1bBa4) that recommends ways pharmacists can navigate the shortage, such as rationing supplies and considering nonpump options for administering medications. It also advises against stockpiling inventory “in the interest of fair allocation to all patients nationally.” According to the guidance, pharmacists should consider: • assessing or reassessing each patient for the indication and requirement for an ambulatory infusion pump; • reserving pumps for situations in which flow accuracy is critical to patient response and safety; and • using non-pump options for administering antibiotics, hydration, monoclonal antibodies and more. Several non-pump options are recommended in the guidelines, including using gravity administration and flow regulators for medications not at risk for free-flow complications; converting all nurse-administered therapies to gravity infusions; and prioritizing elastomeric infusion and syringes whenever possible. “As a last resort, consider extending the time between bag and/or set changes,” the guidance says. Pharmacists also should work with patients and physicians to determine whether it is possible to prescribe equally effective medications that do not require ambulatory infusion pumps, the guidance notes. The NHIA also recommends pharmacists take time to understand each patient’s learning needs and home situation to create an effective learning plan if changing medication administration, including assessing fall risk if using pole-mounted pumps. Smiths Medical, the Minneapolisbased specialty medical device manufacturer that supplies the majority of sets, said it is once again producing at full capacity—“with normal levels of supply

arriving at our distribution center in mid-January.” However, the shortage is still ongoing, caused by backorders and “unprecedented demand which is likely a market reaction to inventory concerns associated with global supply chain challenges,” the company said in a Dec. 21, 2021, letter (bit.ly/3H8k10R). The continuing shortage has begun to negatively affect pharmacy businesses as well as patient care, Ms. Sullivan said. Some companies have had to spend extra capital to buy new pumps, while others are not accepting new patients whose therapies require such pump sets.

Steering Clear of Shortages However, some companies have been able to navigate the shortage, such as New York–based Upstate HomeInfusion. CEO Greg LoPresti said the firm began taking steps early to avoid delivery interruptions, based on watching other supplychain issues throughout the COVID-19 pandemic. “The old standard is changing. Before it used to be ‘just in time,’ now it’s ‘expanding your inventory,’” Mr. LoPresti said. “Nobody wanted to have dead-head inventory on your shelves, but you have to now, or else it’s going to impact future revenue, because you will not be able to meet sales demand, and more importantly, serve your patients.” In addition, Upstate HomeInfusion has taken several steps to conserve infusion pump sets for critical-access patients, including those needing pain control and total parenteral nutrition when precise flows are needed. The company also has been using rate-flow sets to deliver antibiotics, hydration or monoclonal antibodies that require their own tubing set, he said. “You have to have multiple different delivery channels—and this is mainly done by our pharmacy—for delivering medication just as the NHIA guidance states, and that’s exactly what we’ve done,” Mr. LoPresti said. “It’s a multipronged operational effort that requires your purchasing department, pharmacy and nurses all to be in lockstep. It’s not something you can do in hindsight.” The sources reported no relevant financial disclosures.

Specialty Pharmacy Continuum • January/February 2022

POLICY

Battling Bad Infusors continued from page 1

These IV therapy businesses advertise IV “treatments” for everything from hangovers to migraines to altitude sickness and COVID-19. “These businesses promote IV services to the general public without a medical assessment or prescriber order,” said the statement from the NHIA, ASHP, ASPEN and allied groups. “The situations being treated can usually be resolved with oral medications or through other means—making IV treatment unnecessary. The result is the diversion of scarce resources—many of which appear on the FDA’s drug shortage list—from patients who have legitimate medical needs.” Direct access infusion companies have been growing rapidly within the last cou-

operate on a cash basis rather than through medical insurance plans. Because these centers may not be registered with the FDA, the extent to which adverse events are associated with direct access infusion is likely underreported, the agency noted. But a number of cases of unsanitary compounding and/or complications associated with these services have been documented. In February 2021, for instance, the FDA received a report about a California woman who was hospitalized and treated for suspected septic shock with multi-organ failure after reportedly receiving a home IV vitamin infusion compounded by Age Management Institute Santa Barbara, a

‘As licensed home infusion pharmacies are struggling to get the components we need to do the most basic pharmacy operations, … how are [direct access infusion businesses] getting the supplies to make these vitamin infusions?’ —Connie Sullivan, BSPharm ple of years, said NHIA president and CEO Connie Sullivan, BSPharm. “Today, you can find one in almost every major metropolitan area. They are particularly common in California, and there are many in Colorado as well. They seem to be all over.” A Google search for direct access infusion brought up multiple ads for such providers, including “Mobile IV Drips New Jersey” offering a 10% coupon; “The Cure IV,” which claims locations throughout California and says it is soon expanding to Dallas-Fort Worth, New York, Seattle and Washington, D.C.; and “LEAA Home IV Drips,” with locations in New York, New Jersey, Miami and Texas. “These kinds of clinics have been operating a little under the radar, and that’s one of our questions. How are they doing that? Do they have a legitimate licensed clinician behind them that makes it possible for them to get the licenses that they need?” Ms. Sullivan asked. “It’s time for [federal and state officials] to start taking these clinics seriously and understand what they’re doing. If they are owned by physicians or nurses, we need to understand their scope of practice. Are they compounding? Do they have the expertise to compound safely? Do they adhere to USP <797> standards?” In many cases, the NHIA and other organizations noted in their statement, these clinics may escape the licensure and accreditation requirements that traditional pharmacy and home health providers must abide by, since they often

wellness clinic providing services including IV therapies and vitamin injectables, sexual health products, hormone replacement therapy, weight loss/management products and diagnostic laboratory assays. “The patient’s blood cultures grew Pseudomonas fluorescens, a gram-negative bacterium,” the FDA said in a statement (bit.ly/3L284vX). A cooperative investigation involving the FDA and state regulators revealed unsanitary conditions at the clinic, including lack of a certified ISO 5 classified area for sterile compounding, visible contamination in the compounding area, difficult-to-clean equipment and surfaces such as carpeting in the IV storage and mixing room, standing water in a refrigerated storage area for sterile vials, and use of expired active pharmaceutical ingredients, the FDA reported (bit.ly/ 3AUIjcc-PPN). The previous year, the clinic had received a warning letter in October 2020 from the Federal Trade Commission about advertising COVID-19 cures. Advertising products, such as electrolyte infusions, containing ingredients that are in short supply, is of particular concern. “As licensed home infusion pharmacies and other providers are struggling to get the components we need, particularly for parenteral nutrition, with a severe shortage of even sterile water for injection to do the most basic pharmacy operations, how are they getting the supplies to make these vitamin infusions?” Ms. Sullivan asked.

4 Steps to Better Federal And State Oversight 1. Investigate and assess the extent to which direct access infusion businesses are contributing to the ongoing national shortages of parenteral drugs, nutrition components and diluents/ solutions. 2. Require all businesses that sell direct access infusion therapies to the general public to comply with licensure and regulations applicable to the services offered. 3. Investigate claims of health benefit, treatment or cure, and require businesses that sell direct access infusion therapies to disclose the lack of evidence and unique risks of administering compounded IV products that are not medically necessary. 4. Establish a licensure category for businesses that sell direct access infusions. Source: NHIA, ASHP, ASPEN and allied groups.

The groups’ statement calls for federal and state regulators to take a fourpronged approach to boosting regulatory oversight of these infusion providers (box). The actions are a critical first step in protecting legitimate infusion providers and their patients, Ms. Sullivan noted. “As organizations invested in the safe and effective administration of infused medications to patients with acute and chronic medical conditions, we are highly devoted to ensuring the availability of these products and their safe

administration to patients with legitimate medical needs,” she said. “Unlicensed and unregulated businesses administering medically unnecessary therapies with no adherence to industry and professional standards introduces unwarranted risks. We urge state regulatory agencies and the FDA to assess the impact of these operations and establish an appropriate licensing requirement.” Ms. Sullivan reported no relevant financial disclosures.

Specialty Pharmacy Continuum • January/February 2022

POLICY

$4.1 billion savings from just 3 entrants

A Windfall From Biosimilars By Gina Shaw

enver—Biosimilars initially had only a moderate uptake in the U.S. market, but more recently, these products have begun to take off—a trend that will only continue, according to several industry analysts. Even the modest levels of biosimilar adoption to date have served to drive prices down for many branded products. At the annual AMCP Nexus 2021 conference, Leslie Fish, RPh, PharmD, the vice president of clinical pharmacy for IPD Analytics, shared tracking information on several leading biosimilar launches. He obtained the information from third-party sales data from IPD Analytics over eight quarters, beginning in the third quarter of 2019 and ending with the second quarter of 2021. However, other biosimilars have begun to claim a much more significant share of the market against their originator competitors. In the third quarter of 2019, bevacizumab (Avastin, Genentech) had 96% of the market, with its first biosimilar, bevacizumab-awwb (Mvasi, Amgen), claiming the remaining 4%. By the second quarter of 2021, that had dropped to just 32%, compared with 49% for bevacizumab-awwb and 19% for bevacizumab-bvzr (Zirabev, Pfizer). Infliximab (Remicade, Janssen) had 89% of the market share compared with 11% for two biosimilars—infliximab-abda (Renflexis, Organon) and infliximab-dyyb (Inflectra, Pfizer)—in the first quarter tracked. By the second quarter of 2021, that had dropped to about 75%, while infliximab-dyyb had 16%, infliximab-abda had 7% and infliximab-axxq (Avsola, Amgen), the latest to launch in 2019, had 1%. Consider also the fate of two more originator products: Trastuzumab (Herceptin, Genentech) went from 96% of the market against one biosimilar in the third quarter of 2019 to 32% of the market against five biosimilars in the second quarter of 2021. Rituximab (Rituxan, Biogen/Genentech) went from a 100% market share in 2019 to 47% in the second quarter of 2021 against two

biosimilars: rituximab-pvvr (Ruxience, Pfizer) and rituximab-abbs (Truxima, Celltrion). “That’s remarkable,” Dr. Fish said during the AMCP Nexus meeting. “We estimate that the savings during this time period on just these three drugs alone was approximately $4.1 billion.” But it’s not just biosimilar adoption that’s driving down costs, Dr. Fish said;

IPD’s vice president of clinical pharmacy. (An interchangeable biosimilar product may be substituted for the reference product without the intervention of the prescriber.) “Interchangeability can help promote the use of a biosimilar, but the price must be competitive. From an ease-of-switching standpoint for a biosimilar, if you’re in a hospital or clinic facility and the drug is under

How ASP Plays Out • On July 1, 2019, when Amgen’s trastuzumab-anns (Kanjinti)—the first trastuzumab biosimilar—launched, the branded product’s ASP was $100.92 per unit. As of July 1, 2021, with 5 biosimilars on the market, the ASP had dropped by 15% to $85.83. • On April 1, 2018, when there were 2 biosimilars for infliximab (Pfizer’s infliximab-dyyb and Organon’s infliximab-abda), the branded product’s ASP was $78.57 per unit. By July 2021, with 3 biosimilars available (including Amgen’s infliximab-axxq), the ASP had decreased by 50% to $38.98. • On Oct. 1, 2018, when pegfilgrastim-jmdb (Fulphila, Mylan), the first biosimilar for pegfilgrastim (Neulasta Onpro, Amgen) launched, the originator ASP was $4,422.37 per unit. As of July 1, 2021, with 4 biosimilars on the market, the ASP had dropped by 47% to $2,329.58. ASP, average sales price

it’s also the pressure that those biosimilars are putting on the average sales price (ASP) of originator products (box). Brand responses to biosimilar launches have taken several forms, Dr. Fish noted. “They have pursued aggressive rebating on branded medications, thus the lower ASPs. They have also increased marketing and rebating for medications with the same ingredient but a different dosage form, such as subcutaneous versus intravenous. They have increased marketing for branded medications with a different mechanism of action that are used for the same indication. And they’ve pushed antibiosimilar messaging, such as concerns about the patients being stable on their current medication.”

Interchangeability “The ever-elusive interchangeability factor may be a tiebreaker in formulary management if cost and clinical aspects are equal,” said Jeff Casberg, MS, RPh,

the medical benefit, there are already policies that guide which products you can interchange. But in the specialty setting, on the pharmacy benefit side, with more self-administered products, interchangeability can have more importance.” IPD Analytics tracks several products that are close to market with an interchangeability designation, Dr. Casberg said. Described by the FDA as the first true interchangeable biosimilar, insulin glargine-yfgn (Semglee, Viatris) received biosimilar and interchangeable status in July 2021 (bit.ly/3IatKod). According to a report in Healthline, Viatris is marketing Semglee as two-thirds less expensive than the list price of the reference product, Sanofi’s Lantus (bit.ly/3Gk1VaM). MYL-1601D, Viatris’ biosimilar to insulin aspart (Novolog, Novo Nordisk), also could receive FDA approval before the end of the year, Dr. Casberg said. Other potential interchangeables for Novo Nordisk’s insulin

aspart include SAR341402, a Sanofi potential interchangeable, which does not yet have an FDA application. Dr. Casberg noted that if MYL-1601D insulin is approved, one-year interchangeability exclusivity attaches, meaning that Sanofi couldn’t launch its product until a full year after MYL-1601D hits the market.

A Robust Pipeline Dr. Casberg also pointed to dozens of additional biosimilar products in the pipeline to watch, including ranibizumab-nuna (Byooviz, Samsung Bioepis/ Biogen), which will be a biosimilar version of Genentech’s Lucentis, for the treatment of adults with neovascular age-related macular degeneration, macular edema after retinal vein occlusion and myopic choroidal neovascularization. The first ophthalmology biosimilar, it was approved in September 2021 but will not come to market until June 2022 because of a licensing agreement between the biosimilar developers and the originator company. At least a dozen other biosimilars are either pending approval or in stage 2 to 3 development, seeking indications for ophthalmology, inflammatory disease, respiratory/ allergic disease, multiple sclerosis and inflammatory bowel disease, etc. Another factor that is likely to influence the market is the advent of authorized biologics—nonbranded versions of the innovator drugs, marketed by the original manufacturer. They aren’t interchangeables because there’s nothing to interchange, Dr. Casberg noted, adding, “they’re the same drug.” So far, no true authorized biologics have hit the market, but that is likely to change soon, as manufacturers attempt to hold the line against loss of market share and revenue to biosimilars. “Today, we haven’t really seen brand companies have the motivation to bring these authorized products to market,” he said. “But I think you’ll start to see a few in the future.” The sources reported no relevant financial disclosures.

Specialty Pharmacy Continuum • January/February 2022

POLICY

Generics, Biosimilars Remain a Moving Target By Bruce Buckley

For decades, the introduction of generic medicines has kept a lid on rising drug prices. More recently, biosimilar launches have been adding to those savings. But challenges in uptake and utilization persist for both drug classes.

Drug

Price, $

Amphetamine salt combo XR

190

Celecoxib

210

Diclofenac sodium

277

Estradiol

252

Levetiracetam

186

Paroxetine

188

Sildenafil

248

Tadalafil

518

Valacyclovir

192

organizations are moving to overo come them. For example: • Civica Rx’s new retail/outpatient en nt operating unit, CivicaScript, plans ans a 2022 launch of its first two to three commonly prescribed, but expensive, generics that lack the market competition needed to drive down their price. • Vizient Inc. is working with key pharmaceutical suppliers to build sufficient supplies of essential generic medications through its Novaplus Enhanced Supply Program to meet the needs of its health-system and hospital members as well as for future pandemics or other disasters. • Fresenius Kabi USA has formed an alliance with Phlow Corp., a generic pharmaceutical manufacturer, to increase the supply of essential medicines for U.S. patients. (Phlow also has been working with Civica Rx to produce generic injectable drugs for Civica’s health-system and hospital members [bit.ly/3nMA3WH-PPN].)

Zolpidem

296

CivicaScript Debuts

In 2020, generics and biosimilars combined to drive savings of more than $338 billion, according to IQVIA’s December 2020 National Sales Perspectives, published in the most recent report of the Association for Accessible Medicines.

Table. The Top 10 Most Expensive, and Popular, U.S. Generic Drugsa

Based on average monthly retail cash prescription prices for the year ended June 30, 2021.

Source: GoodRx (bit.ly/3HT9t6z).

Over the last 10 years, savings amounted to nearly $2.4 trillion, according to the report (bit.ly/3cKJS1b). Still, the cost of many commonly prescribed generic medicines remains stubbornly high, often impeding patient access to crucial treatments. In addition, chronic shortages of relatively inexpensive but vital injectable medications are often an obstacle to therapy—one that’s been exacerbated by the COVID-19 pandemic. These challenges are shared across the retail, health-system, specialty pharmacy and managed care spectrum, and some stakeholder

Civica’s plan to expand from its hospital inpatient roots into the retail/outpatient arena began last year. In June, the company put a name on the new venture—CivicaScript—and announced that Gina Guinasso, a senior vice president for commercial and Medicare formulary contracting strategy at UnitedHealth Group’s OptumRx subsidiary, would head the new unit’s operations as president. Ms. Guinasso said the company’s first generic drug launches would consist of solid dosage forms, but added, “we will consider all types of outpatient drugs that patients are struggling to afford.” What’s more, she said, “the savings will be available to both hospital outpatient and retail pharmacy patients. With CivicaScript’s transparent, cost-plus pricing platform,

U.S. Healthcare System Savingsa • 2020 generic and biosimilar drug savings: $338 billion • Generic 10-year savings: nearly $2.4 trillion • 2020 savings to Medicare: $109.6 billion • 2020 savings to Medicaid: $53.8 billion • Nearly 4 billion generic and biosimilar prescriptions dispensed • Generics represent 90% of prescriptions filled, yet account for only 18.1% of prescription drug spending • Generics represent only 3% of all healthcare spending a

Generic and brand drug share of prescription drug spending was calculated using an analysis of the 2018 Medical Expenditure Panel Survey. Total drug spending was segmented into generics and brands. Those percentages were then applied to the Peterson-KFF Health System Tracker analysis of spending by type of expenditure in the U.S. healthcare system.

Source: Peterson-KFF Health System Tracker. “What drives health spending in the US compared to other countries.” September 25, 2020.

patients can benefit from lower prices at hospital outpatient pharmacies in the same way they would at a traditional retail pharmacy.” Civica also announced that Catalent, the global pharmaceutical manufacturer, had been selected to develop “a range of CivicaScript-owned generic Abbreviated New Drug Applications” and produce them at Catalent’s oral solids facilities. “We are not yet disclosing the medicines we will produce,” Ms. Guinasso said, adding that the company would announce the names before making the first products available in 2022. (A recent GoodRx analysis of the 10 most expensive common generic medications suggests some potential targets [Table].)

CVS Health’s Formulary Strategy

t CVS Health, promoting the use of generic medicines and biosimilars for the treatment of complicated chronic conditions is a prioriy, according to Joshua Fredell, PharmD, the company’s vice president of specialty product development. Dr. Fredell described the use of the company’s formulary to reduce the cost of expensive therapies, a process that factors in market dynamics and makes selections based on clinical and financial benefits to clients and patients. The choices are not always generics and biosimilars. CVS Health, he noted, takes “a lowest-net-cost approach to formulary placement, while ensuring

clinical appropriateness. Particularly in the case of specialty medications, the lowest-net-cost product can be either the reference brand or the biosimilar. Of biosimilars that have launched, we have many preferred biosimilars on our commercial template formularies.” Equivalency is another important consideration. “Biosimilars and generics are clinically equivalent alternatives to brand-name drugs and biologics and can be cost-effective,” Dr. Fredell told Specialty Pharmacy Continuum. Competition within a category also is key. “Whether between brand and generic drugs or biosimilars and a reference brand,” competition “can

Vizient Focuses on Shortages As noted, generics have, at times, been subject to shortages. At Vizient, coping with shortages and gearing up to meet future supply disruptions are central to its strategic approach. “Drug shortages have been an issue over the last two decades,” said Steven Lucio, PharmD, BCPS, a senior principal for pharmacy solutions at Vizient. “But the pandemic really crystallized the attention of the market. “There’s been a lot of work done recently, especially around medications that you absolutely have to have to keep your doors open,” Dr. Lucio added. “They span the spectrum from critical care drugs to those needed to treat chronic diseases.” see 2 DRUG CLASSES, page 26

reduce costs, while increasing patient access and quality of care,” he said. Payor relations also have to be factored into the equation, Dr. Fredell continued. “As approvals, regulation and network acceptance gain momentum under the medical benefit, we help health plans utilize biosimilars.” As for future formulary trends, its important to keep an eye on the drug pipeline, Dr. Fredell noted. “As more biosimilars launch and [account for] a larger portion of the pharmaceutical landscape, market competition will continue to increase, and drug costs will start to lower,” he said. “At the same time, a balance between brand biologics and biosimilars is necessary to ensure patient acces to the lowest cost appropriate therapy.” —B.B.

Specialty Pharmacy Continuum • January/February 2022

POLICY

The $80+ Billion Price Tag of Healthcare Fraud By Bruce Buckley

Each year, healthcare fraud and abuse drains off tens of billions of dollars that might have gone to lower medical insurance premiums and expanded prevention and treatment services for patients. Although countering these schemes can be difficult, data mining and other interventions may help to defray at least some of the damage, experts noted during a recent webinar. One reason why anti-fraud measures can be a huge challenge is the fast-paced nature of pharmacy claims processing, said Carrie Aiken, CHC, the vice president and corporate compliance and privacy officer at Navitus Health Solutions, a Pharmacy Benefit Manager (PBM) owned jointly by SSM Health and Costco Wholesale Corp., and the

exploited from a fraud, waste and abuse perspective, or if the number of claims from a pharmacy or associated with a prescriber are proportionately higher than others, “it’s something we need to take a look at,” she said. The interventions produce results. Ms. Aiken said Navitus has collaborated with plan sponsors on claims investiga-

‘Fraud, waste and abuse in the pharmacy space [is] a crime of opportunity because it’s rapid. As a result, it requires rapid intervention to make sure we’re protecting those dollars for our plan sponsors and protecting beneficiaries.’ —Carrie Aiken, CHC sponsor of the webinar. “Pharmacy services are processed in real time,” Ms. Aiken explained. “That makes fraud, waste and abuse in the pharmacy space a crime of opportunity because it’s rapid. As a result, it requires rapid intervention to make sure we’re protecting those dollars for our plan sponsors and protecting beneficiaries.” Navitus uses a variety of tools to identify fraud, waste and abuse cases. “We have several mechanisms, including internal systems that allow for data mining on our plan sponsor’s claims to detect anomalies and outliers,” Ms. Aiken said. “We have the ability to look at these claims on a monthly and quarterly basis and see deviations.” If a higher proportion of claims turn up for a drug that has been previously

2 DRUG CLASSES continued from page 25

Dr. Lucio said Vizient has been working with key pharmaceutical suppliers not only to meet members’ existing supply needs but also to build enough redundancy to meet future needs, “because we don’t know when the next pandemic or hurricane will occur.” This means, he added, “building not just what members traditionally use but adding another three to six months of capacity.” He said Vizient “is now at the

tions that have resulted in the recovery of “hundreds of thousands of dollars for our plan sponsors.”

Billions Still Out There Although such successes should be applauded, the vast majority of healthcare fraud remains to be tackled, according to Louis Saccoccio, the CEO of the National Health Care AntiFraud Association (NHCAA). One study cited by Mr. Saccoccio estimated fraud and abuse losses between $58.5 billion and $83.9 billion per year. Nearly one-third—$22.8 billion to $30.8 billion—could have been saved by timely interventions from managed care payors, PBMs and law enforcement agencies, according to the investigators (JAMA 2019;322[15]:1501-1509).

threshold of bringing 100 million units into existence” to support its member health systems and hospitals. In early November, Vizient launched the End Drug Shortages Alliance, an initiative to bring together organizations from all parts of the supply chain to find enduring solutions of the long-standing challenge of drug shortages. In announcing the launch, Dan Kistner, PharmD, Vizient’s group senior vice president, pharmacy solutions, said the shortages were “too big to tackle as individual organizations. It will take

The impact of fraud and abuse can be particularly damaging if it involves fraudulent billing for unnecessary or even harmful treatments, noted Mr. Saccoccio, who was not part of the Navitus webinar. He pointed to the case of a Detroit-area oncologist who in 2015 pleaded guilty to 13 counts of Medicare fraud after ordering chemotherapy for more than 550 patients who didn’t need treatment, including some who didn’t have cancer. How much of the lost billions results from pharmacy fraud and abuse? “I can’t tell you that,” Mr. Saccoccio told Specialty Pharmacy Continuum. But he did suggest one potential marker found in the massive database NHCAA maintains on fraud investigations initiated by private and public health insurers and government investigative agencies. “Each year we summarize the types of providers based upon the number of cases that were entered,” he said, “and for pharmacies, it’s been about 20% of the cases over the last two years. That’s a significant number; it’s like the second or third highest.”

Looking for Outliers Spotting database outliers is also a key to the work of Michael Devine, PhD, the director of the Special Investigations Unit at L.A. Care, the country’s largest publicly operated health plan, which has more than 2.4 million Los Angeles County members. L.A. Care also is one of Navitus’ plan sponsors. Dr. Devine, a former investigator for

all stakeholders working collectively to achieve real and effective change.”

Fresenius Kabi Collaboration For Fresenius Kabi, the Phlow collaboration “will further advance our efforts to make essential injectable medicines more accessible to more U.S. patients,” said Matt Kuhn, the senior director, external communication, at Fresenius Kabi. He said the company plans to “more than double” its sterile injectable supply capacity “in the next few years to support America’s efforts to strengthen its

the Naval Criminal Investigative Service and Anthem Health, oversees a team of 12 analysts and investigators that last year saved or recovered more than $10 million in fraud, waste and abuse cases. “That’s a lot of flu shots,” he said. “If we can cut down on fraud and make those dollars go to help people who actually need these services, it’s a rewarding job.” Dr. Devine, who was not part of the webinar, said investigative leads come from a variety of sources, including a fraud hotline and emails to L.A. Care’s website. Employees also contribute tips, he said, and “we’ll also get calls from the Department of Justice or the FBI saying they have a case and want to know if we have exposure.” In one such instance, a call from a law enforcement agent led to the exposure of a “pill mill” doctor who was writing oxycodone prescriptions without any supporting office visits. Dr. Devine said the analysis of billing data showed 321 prescriptions written for the narcotic by the doctor “without a single documented member visit.” Not all outlier data indicate fraud or abuse, he said. Often there’s a “reason somebody is billing a code at three times the amount that anybody else is doing. It might be a specialist. You never really know until you kick the tires whether you have a good case or not.” The sources reported no relevant financial disclosures.

domestic pharmaceutical supply chain.” Mr. Kuhn said Fresenius Kabi already works with its customers and the FDA to ensure “a reliable supply of essential medicines.” The new alliance, he added, will combine the company’s “expertise in developing, filling and finishing injected and infused medicines with Phlow’s support for the domestic production of active pharmaceutical ingredients.” The sources reported no relevant financial disclosures beyond their stated employment.

FLUAD® QUADRIVALENT (Influenza Vaccine, Adjuvanted) Injectable Emulsion for Intramuscular Use 2021-2022 Formula

Unsolicited adverse events (AEs) were collected for all subjects for 21 days after vaccination. Related unsolicited AEs were reported by 303 (9.0%) and by 261 (7.7%) of the subjects for FLUAD QUADRIVALENT and Boostrix, respectively. For FLUAD QUADRIVALENT, injection site pain and influenza-like illness were the only unsolicited adverse reactions reported in ≥ 1% of subjects (1.7% and 1.5%, respectively).

BRIEF SUMMARY OF PRESCRIBING INFORMATION Consult the full US Prescribing Information for complete product information. INDICATIONS AND USAGE FLUAD QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. For intramuscular injection only. CONTRAINDICATIONS Do not administer FLUAD QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein, or to a previous influenza vaccine. WARNINGS AND PRECAUTIONS Guillain-Barré Syndrome: If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated risk of GBS. [see Reference (1)] Evidence for a causal relationship of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. Preventing and Managing Allergic Reactions: Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. Altered Immunocompetence: The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Syncope: Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope. Limitations of Vaccine Effectiveness: Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against influenza disease. ADVERSE REACTIONS The most common (≥10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect rates observed in clinical practice. The safety of FLUAD QUADRIVALENT was evaluated in two clinical studies in 4269 elderly subjects 65 years of age and older. Study 1 (NCT02587221) was a multi-center, randomized, observer-blind, non-influenza comparator-controlled efficacy and safety study conducted in 12 countries during the 2016-2017 Northern Hemisphere and 2017 Southern Hemisphere seasons. In this study, 3381 subjects received FLUAD QUADRIVALENT and 3380 subjects received a US-licensed non-influenza comparator vaccine (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® [GlaxoSmithKline Biologicals]). The mean age of subjects at enrollment was 72 years, 62% were female, 48% White, 34% Asian, 16% Other, 2% American Indian/Alaska Native, and 18% of Hispanic/Latino ethnicity. Solicited local and systemic adverse reactions were collected for 7 days after vaccination in a subset of 665 subjects who received FLUAD QUADRIVALENT and 667 subjects who received the comparator vaccine. The percentages of subjects reporting solicited local adverse reactions are presented in Table 1a and systemic adverse reactions are presented in Table 1b. Onset usually occurred within the first 2 days after vaccination. The majority of solicited reactions resolved within 3 days. Table 1a. Percentages of Subjects Reporting Solicited Local Adverse Reactionsa in the Solicited Safety Populationb within 7 Days of Vaccination (Study 1) Local (Injection site) Reactionsc Injection site pain Erythema ≥25mm Induration ≥25mm Ecchymosis ≥25mm

FLUAD QUADRIVALENT N=595-659 16.3 3.8 4.0 0.5

Non-Influenza Comparator Vaccine N=607-664 11.2 1.8 2.6 0.7

Study 1: NCT02587221 Abbreviation: N=number of subjects with solicited safety data Non-Influenza Comparator Vaccine = combined Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® (GlaxoSmithKline Biologicals) a All solicited local adverse events reported within 7 days of vaccination are included b Solicited Safety Population: all subjects in the exposed population who received a study vaccine and provided post-vaccination solicited safety data c Severe reactions of each type were reported in 1.1% or fewer subjects receiving FLUAD QUADRIVALENT; severe reactions of each type were also reported in the comparator group at similar percentages. Severe definitions: Erythema, Induration and Ecchymosis = >100 mm diameter; Injection site pain = prevents daily activity.

Table 1b. Percentages of Subjects Reporting Solicited Systemic Adverse Reactionsa in the Solicited Safety Populationb within 7 Days of Vaccination (Study 1) Systemic Reactionsc Headache Fatigue Myalgia Arthralgia Chills Diarrhea Nausea Loss of appetite Fever ≥100.4°F (38°C) Vomiting

FLUAD QUADRIVALENT N=595-659 10.8 10.5 7.7 7.3 5.0 4.1 3.8 3.6 1.7 0.8

Non-Influenza Comparator Vaccine N=607-664 8.3 8.8 6.1 6.6 3.9 3.0 2.3 3.6 1.2 1.1

Study 1: NCT02587221 Abbreviation: N=number of subjects with solicited safety data Non-Influenza Comparator Vaccine = combined Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® (GlaxoSmithKline Biologicals) a All solicited systemic adverse events reported within 7 days of vaccination are included b Solicited Safety Population: all subjects in the exposed population who received a study vaccine and provided post-vaccination solicited safety data c Severe reactions of each type were reported in 1.1% or fewer subjects receiving FLUAD QUADRIVALENT; severe reactions of each type were also reported in the comparator group at similar percentages. Severe definitions: Nausea, Fatigue, Myalgia, Arthralgia, Headache, and Chills = prevents daily activity; Loss of appetite = not eating at all; Vomiting = 6 or more times in 24 hours or requires intravenous hydration; Diarrhea = 6 or more loose stools in 24 hours or requires intravenous hydration; Fever = ≥102.2°F (39°C).

Serious adverse events (SAEs) and potentially immune-mediated adverse events of special interest (AESIs) were collected up to 366 days after vaccination. SAEs were reported by 238 (7.0%) FLUAD QUADRIVALENT recipients and 234 (6.9%) comparator recipients. There were no SAEs, AESIs or deaths in this study that were related to FLUAD QUADRIVALENT. Study 2 (NCT03314662) was a multicenter, randomized, double-blind, comparator-controlled study conducted during the 201718 Northern Hemisphere influenza season. In this study, 888 subjects received FLUAD QUADRIVALENT, 444 subjects received the licensed adjuvanted trivalent vaccine (aTIV-1 - FLUAD® (trivalent formulation)) and 444 subjects received an adjuvanted trivalent influenza vaccine with an alternate B strain (aTIV-2). The mean age of subjects at enrollment who received FLUAD QUADRIVALENT was 72.5 years. Female subjects represented 56.6% of the study population and the racial distribution of subjects was 91.6% Caucasian, 7.0% Black or African American, and ≤ 1% each for Asian, Native Hawaiian or Pacific Islander, American Indian or Alaska Native or Other. Solicited local and systemic adverse reactions reported within 7 days after vaccination were similar to those reported for Study 1. Unsolicited AEs were collected for 21 days after vaccination. Related unsolicited AEs were reported by 39 (4.4%) and by 17-19 (3.8%-4.3%) of subjects administered FLUAD QUADRIVALENT or aTIV, respectively. For FLUAD QUADRIVALENT, injection site bruising (1.0%) was the only unsolicited adverse reaction reported in ≥ 1% of subjects. Serious AEs and AESIs were collected up to 181 days after vaccination. Within 6 months after vaccination, 37 (4.2%) FLUAD QUADRIVALENT recipients and 18-28 (4.1%-6.3%) aTIV recipients experienced an SAE. There were no SAEs, AESIs or deaths in this study that were related to the study vaccine. There were no AEs leading to withdrawal from the study. Postmarketing Experience: There are no postmarketing data available for FLUAD QUADRIVALENT. However, the postmarketing experience with FLUAD (trivalent formulation) is relevant to FLUAD QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Blood and lymphatic system disorders: Thrombocytopenia (some cases were severe with platelet counts less than 5,000 per mm3), lymphadenopathy General disorders and administration site conditions: Extensive swelling of injected limb lasting more than one week, injection site cellulitis-like reactions (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week) Immune system disorders: Allergic reactions including anaphylactic shock, anaphylaxis, and angioedema Musculoskeletal and connective tissue disorders: Muscular weakness Nervous systems disorders: Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, neuralgia, parasthesia, syncope, presyncope Skin and subcutaneous tissue disorders: Generalized skin reactions including erythema multiforme, urticaria, pruritus or nonspecific rash Vascular disorders: Vasculitis, renal vasculitis DRUG INTERACTIONS Concomitant Use With Other Vaccines: No clinical data on concomitant administration of FLUAD QUADRIVALENT with other vaccines is available. If FLUAD QUADRIVALENT is given at the same time as other injectable vaccine(s), the vaccine(s) should be administered at different injection sites. Do not mix FLUAD QUADRIVALENT with any other vaccine in the same syringe. Concurrent Use With Immunosuppressive Therapies: Immunosuppressive or corticosteroid therapies may reduce the immune response to FLUAD QUADRIVALENT. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. There are insufficient human data to establish whether there is a vaccine-associated risk with use of FLUAD QUADRIVALENT in pregnancy. There were no developmental toxicity studies of FLUAD QUADRIVALENT performed in animals. A developmental toxicity study has been performed in female rabbits administered FLUAD (trivalent formulation) prior to mating and during gestation. A 0.5 mL dose was injected on each occasion (a single human dose is 0.5 mL). Lactation Risk Summary FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. No human or animal data are available to assess the effects of FLUAD QUADRIVALENT on the breastfed infant or on milk production/excretion. Pediatric Use Safety and effectiveness of FLUAD and FLUAD QUADRIVALENT (same manufacturing process and overlapping composition with FLUAD) were evaluated in clinical trials conducted in children 6 months to <72 months of age. Data from these trials are inconclusive to demonstrate the safety and effectiveness of FLUAD QUADRIVALENT in children 6 months to <72 months of age. The safety and effectiveness of FLUAD QUADRIVALENT in infants less than 6 months of age and in children older than 72 months of age have not been evaluated. Geriatric Use Safety and immunogenicity of FLUAD QUADRIVALENT have been evaluated in adults 65 years of age and older. REFERENCE 1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998; 339(25):1797-1802. To report SUSPECTED ADVERSE REACTIONS, contact Seqirus at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

FLUAD QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates. Seqirus USA Inc., 25 Deforest Avenue, Summit, NJ 07901, USA US License No. 2049 ©2021 Seqirus USA Inc. December 2021 USA-aQIV-21-0072

Adjuvanted to help prevent seasonal inﬂuenza in adults 65+1 gned to strrengtthen, broaden, Desig and length hen th he du uration of the une re espon nse2-4 immu

Learn more at ﬂuad.com For more information, please see Important Safety Information below and the Brief Summary on adjacent page.

INDICATION and IMPORTANT SAFETY INFORMATION INDICATION AND USAGE FLUAD® QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not administer FLUAD QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein, or to a previous inﬂuenza vaccine.

WARNINGS AND PRECAUTIONS If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior inﬂuenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential beneﬁts and risks. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope. Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against inﬂuenza disease.

ADVERSE REACTIONS The most common ( 10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). To report SUSPECTED ADVERSE REACTIONS, contact Seqirus USA Inc. at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. Before administration, please see the full US Prescribing Information for FLUAD QUADRIVALENT. FLUAD® QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates.

REFERENCES: 1. FLUAD QUADRIVALENT. Package insert. Seqirus Inc; 2021. 2. O’Hagan DT, Ott GS, De Gregorio E, Seubert A. The mechanism of action of MF59—an innately attractive adjuvant formulation. Vaccine. 2012;30(29):4341-4348. doi:10.1016/j.vaccine.2011.09.061 3. O’Hagan DT, Ott GS, Nest GV, Rappuoli R, Del Giudice G. The history of MF59® adjuvant: a phoenix that arose from the ashes. Expert Rev Vaccines. 2013;12(1):13-30. doi:10.1586/erv.12.140 4. Banzhoff A, Pellegrini M, Del Giudice G, Fragapane E, Groth N, Podda A. MF59-adjuvanted vaccines for seasonal and pandemic inﬂuenza prophylaxis. Inﬂuenza Other Respir Viruses. 2008;2(6):243-249. doi:10.1111/j.1750-2659.2008.00059.x