40 minute read
A plan for predicting CAR T-Cell toxicity
Spotting Risk Factors Helps In CAR T-Cell Toxicity Fight
Chimeric antigen receptor (CAR) 4, as established by the American SociT-cell therapy is a rapidly expand- ety for Transplantation and Cellular ing, promising treatment for a variety Therapy (ASTCT), and includes antiof adult and pediatric cancers, but it pyretics, IV fluids and oxygen (Crit brings with it a number of significant Care Med 2020;48[1]:10-21). Additional toxicities, speakers said during the 2021 treatments include the anti–interleuCritical Care Congress Virtual Event. kin-6 (IL-6) receptor antibody tocili-
The good news is that researchers and zumab (Actemra, Genentech) for grade clinicians—including pharmacists—are 2 or greater CRS, and corticosteroids for starting to find characteristics that pre- those with grade 3 to 4 CRS. Siltuximab dict the risk for some severe toxicities, (Sylvant, EUSA Pharma), a monocloand several therapies are under inves- nal antibody to IL-6, and anakinra tigation that may eventually decrease (Kineret, Sobi), an IL-1 receptor antagtheir rate and severity, said Julie onist, may be used in refractory cases. Fitzgerald, MD, MACP, the co-director Clinicians also should consider infecof the pediatric sepsis program at Chil- tion and treat sepsis accordingly. dren’s Hospital of Philadelphia.
There are about six major toxici- Best Practices ties associated with CAR T-cell thera- Overall best practices include close py, said Stephen M. Pastores, MD, the observation of patients with regular, freprogram director of critical care medi- quent assessments; having a process for cine and vice chair of education at rapid treatment escalation and commuMemorial Sloan Kettering Memorial Sloan Kettering nication among ICU, oncology, nursing Cancer Center in New York City. The and pharmacy staff; having guidelines for most common are cytokine release management of complications; and consyndrome (CRS) and immune effec- ducting an infectious disease workup and tor cell–associated neurotoxicity syn- empirical broad antimicrobial coverage drome (ICANS). The incidence of grade in cases of concomitant infection, he said. 3 to 4 CRS is about 16%, and that of ICANS typically occurs four to five ICANS is about 35% (Cancers [Basel] days after infusion; previous severe CRS 2020;12[11]:3445). is the primary risk factor. Symptoms
CRS is a hyperinflammatory syndrome include encephalopathy, headache, tremmost commonly seen in patients with a or or seizures. The condition is marked high disease burden or after high CAR by elevated levels of cytokines such T-cell doses. Symptoms typically start as IL-6, interferon gamma and tumor two to three days after infusion. Toxicities necrosis factor-alpha, as well as elevated from CRS can affect every system of the C-reactive protein. ICANS grading also body, Pastores said, including fever, mal- is on a scale of 1 to 4, standardized by aise and fatigue (Blood 2016;127[26]:3321- the ASTCT (Crit Care Med 2020;48[1]: 3330). Fever, which is always present at 10-21). In addition, ICANS has an onset, can be accompanied by anything immune effector cell–associated encephfrom fatigue or diarrhea in mild cases to alopathy score, ranging from 0 to 10. hypotension and systemic inflammation To calculate this, clinicians give patients in more severe cases. cognitive tasks such as naming objects or
Management is guided by the grade writing a sentence. of CRS, with severity ranging from 1 to p nication among ICU, oncology, nursing
Chimeric antigen receptor (CAR) T-cell therapy uses T-cells gathered from the patient’s own blood. The T-cells are engineered and then infused back into the patient to target and attack cancer cells.
Q & A
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CAR T-CELL
continued from page 20
As for CRS, management of ICANS depends on the severity. Patients with grades 1 to 2 receive supportive care, brain imaging to rule out cerebral edema and electroencephalography to rule out seizures. Those with concurrent CRS should also receive tocilizumab. Patients with grades 3 to 4 also may benefit from corticosteroids, such as dexamethasone or methylprednisolone. Regardless of the toxicity, “the main tenets for treating all patients are rapid recognition, rapid transfer to the ICU, vigilant supportive care and [accounting for the effect] of therapies on the viability of the T cells,” said Fitzgerald, who is also an assistant professor of anesthesiology and critical care at the University of Pennsylvania Perelman School of Medicine, in Philadelphia. “We want to support our patients and reverse their shock and dysfunction while still maintaining efficacy of the antitumor treatment.”
The good news, she said, is that certain patient characteristics, such as cytokine profiles and the degree of tumor burden, may help predict the risk for severe CRS, potentially allowing the identification of patient populations who could be targeted with treatments to prevent CRS.
High Tumor Burden a Red Flag
In a study of 213 patients, adolescents and young adults treated with CAR T-cell therapy for leukemia were found to a have a sixfold increased relative risk for ICU admission if they had a high tumor burden, defined as having at least 40% bone marrow blasts before treatment, noted Fitzgerald, whose team presented the results at the 2019 annual meeting of the American Society of Hematology; a manuscript is in progress. The risk for ICU admission was 68% in patients with a high tumor burden versus 11% in those with a low tumor burden.
Based on the identification of high tumor burden as a risk factor for severe CRS, Fitzgerald’s colleagues developed a separate clinical trial to study whether preemptive tocilizumab administered at the time of first sustained fever could reduce CRS development (J Clin Oncol 2021; in press). In the study, which included 70 children and young adults with relapsed refractory leukemia (55 with low tumor burden and 15 with high tumor burden), those with high tumor burden received one dose of tocilizumab after CAR T-cell therapy, then standard CRS care, while those with low tumor burden received just standard CRS care. Although all patients with high tumor burden still developed some degree of CRS, only 27 developed severe cases— about half the frequency of CRS in historical controls.
Use of preemptive tocilizumab had no impact on CAR T-cell expansion or persistence, or long-term outcomes, Fitzgerald noted. Comparing the 15 patients receiving tocilizumab with 26 historical controls, those receiving the drug were less likely to be admitted to the ICU (53% vs. 69%), had shorter ICU length of stay (median, nine vs. 11 days), and had fewer median days requiring mechanical ventilation (six vs. 10) or vasoactive support (four vs. six; P=0.05), she said.
More Refractory CRS Options
Additional treatments are being considered for refractory CRS, but they have limited data to support their use and are not yet included in guidelines, Fitzgerald noted. One such therapy is dasatinib (Sprycel, Bristol Myers Squibb), which may act as an on/off switch for CAR T cells and, therefore, for the cytokine storm that results from the expansion of these cells in the body after infusion, she said. CytoSorb (CytoSorbents Inc.), an external device that adsorbs cytokines and other molecules, is another, but it must be used in conjunction with continuous renal replacement therapy or extracorporeal membrane oxygenation.
In one case report, a critically ill teenager treated with CytoSorb was ultimately extubated and discharged from the ICU (Crit Care Expl 2020;2[1]:e0071). The device needs further study and is not yet FDA approved for this indication, Fitzgerald noted. (In April 2020, the FDA granted an emergency use authorization for CytoSorb in patients 18 years of age or older with confirmed COVID-19
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—Anne Rain Brown, PharmD
admitted to the ICU with confirmed or imminent respiratory failure; www.fda. gov/media/136867/download.)
Studies also are evaluating the use of anticytokine therapies for ICANS, she said. In one study, four of six adults with large B-cell lymphoma treated with anakinra had a clinical response (Blood Adv 2020;4[13]:3123-3127). Trials also are underway testing itacitinib (a Janus kinase1 inhibitor) for prevention of CRS and anakinra for prevention of ICANS.
A Rare but Life-Threatening Toxicity
Secondary hemophagocytic lymphohistiocytosis is another toxicity seen in patients undergoing CAR T-cell therapy, Pastores said. This life-threatening hyperinflammatory syndrome, which occurs in less than 5% of patients, also is seen with severe infections. Management depends on the level of organ toxicity, and can include anti–IL-6 therapy with tocilizumab and corticosteroids, similar to CRS regimens. Patients should be monitored closely and also can be treated with etoposide, IV immune globulin (IVIG), anakinra and other therapies (Nat Rev Clin Oncol 2018;15[1]:47-62).
Another toxicity related to CAR T-cell therapy that clinicians need to watch for is prolonged cytopenias, which occur in some 30% to 40% of patients, Pastores noted (Leuk Lymphoma 2020;61[4]:940-943). Additional toxicities include the rare tumor lysis syndrome, marked by the release of large amounts of potassium or other elements into the blood after cell death. (The condition can lead to cardiac or renal problems.) Supportive therapies for tumor lysis syndrome include IV hydration and allopurinol or rasburicase (Elitek, Sanofi-Aventis) in patients with elevated uric acid. B-cell aplasia and hypogammaglobulinemia, which can lead to recurrent infections, are expected side effects of CAR T-cell therapy but also need monitoring, Pastores said. IVIG supplementation may be used in adults with recurrent infections (Lancet Oncol 2019;20[1]:31-42).
CAR-ICU Multicenter Effort
Anne Rain Brown, PharmD, BCCCP, a clinical pharmacy specialist in critical care at The University of Texas MD Anderson Cancer Center, in Houston, has been part of a multicenter effort called CAR-ICU that has been researching these toxicities.
“As pharmacists, we really look to make sure people are familiar with the grading of these patients and when we need to escalate therapies and add on [other agents],” she said. “A lot of discussions center on when to initiate steroids, which patients are appropriate for tocilizumab, and if patients are refractory, when do we increase steroids or consider additional treatments like anakinra.”
Some CAR T-cell therapies have “safety switch” products that clinicians can give to shut off the treatment, Brown said, but that involves detailed discussions with the treatment team and patient’s family, and generally is a last resort because patients won’t get the benefit of the therapy. “We have to really weigh all the treatments and how they will affect the overall efficacy of the CAR-Ts in curing their disease.”
Despite the toxicities, she said, CAR T-cell therapy is considered a groundbreaking treatment offering relapsed patients who would have had no chance of survival up to 50% to 80% cure rates. —Karen Blum
The sources reported no relevant fi nancial disclosures.
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Glucardipase Keeps CNS Lymphoma Rx on Track
Anew outpatient treatment regimen allowed patients with central nervous system (CNS) lymphoma to continue infusions during the height of the COVID-19 pandemic, and could change the way patients receive care after the current crisis subsides.
Researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City found methotrexate could be coupled with repeated doses of glucarpidase (Voraxaze, BTG International), and patients could safely receive the two treatments in an outpatient setting, according to a study presented at the 2020 Society for Neuro-Oncology virtual annual meeting.
While the pandemic was surging in New York in the spring 2020, many patients with CNS lymphoma canceled treatments because they were afraid to come to the hospital, missing potentially curative infusions, said Lauren Schaff, MD, a neuro-oncologist and neurologist at MSKCC and lead investigator on the research. “We just felt like that was not in the best interest of our patients and really not acceptable,” she said.
Before the pandemic began, the investigators had started examining the safety and efficacy of low-dose glucarpidase to clear methotrexate from patients who received both medications in the hospital (abstract CTNI-61). Schaff and her team wanted to see whether glucarpidase could be given multiple times and stay effective for patients with new or recurrent CNS lymphoma without systemic involvement and renal failure.
Encouraging Data
In the study, 12 patients received a total of 65 doses of methotrexate (28 doses of 3 g/m2, 26 doses of 6 g/m2 and 11 doses of 8 g/m2). Twenty-four hours after each methotrexate infusion, patients received glucarpidase, at 1,000 (20 doses) and 2,000 units (45 doses). The researchers found that glucarpidase led to a more than 95% reduction in serum methotrexate levels within 15 minutes 97.7% of the time after administration of 2,000 units of glucarpidase and 75% of the time after administration of 1,000 units.
Four of 11 analyzed patients had anti-glucarpidase antibodies that were associated with reduced methotrexate clearance and methotrexate rebound. The researchers also analyzed the cerebrospinal fluid of seven patients and found potentially cytotoxic methotrexate concentrations remained in the fluid one hour and six hours after patients received glucarpidase. Glucarpidase was not detected in the cerebrospinal fluid of the seven patients tested.
To Schaff and her team, these findings demonstrated the glucarpidase treatment was safe and did not cross the blood–brain barrier to interfere with the methotrexate response. They also noticed that patients who received glucarpidase could go home earlier than they would have been able to otherwise, Schaff said.
—Lisa Holle, PharmD, BCOP
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aze, and eive n outding to he 2020 logy virwas surge spring ith CNS
Glucarpidase yielded 95%+
reduction in serum methotrexate 97.7%
of time after dose of 2,000 units and 75%
after 1,000 units
Source: MSKCC —Jillian Mock
Holle reported no relevant fi nancial disclosures. Schaff has her name on a patent pending for a lower dose of glucarpidase. BTG Specialty Pharmaceuticals provided the glucarpidase for this study.
When COVID-19 hit in March and April 2020, Schaff and her team quickly reconceived a follow-up study already in the works to accommodate patients who were unable to continue their inpatient treatment because of the pandemic. They opened the study to patients who had isolated CNS lymphoma and previously tolerated high-dose methotrexate. The study enrolled four patients who received a total of 10 methotrexate treatments (3.5 g/m2) in the outpatient setting with hydration. Patients came back 24 hours later for 2,000 units of glucarpidase and additional hydration.
None of the patients required hospitalization, and in each case, methotrexate levels dropped to less than 100 nmol/L 48 hours after the dose. Two patients experienced grade 1 elevation of aspartate aminotransferase/ alanine aminotransferase levels over three treatments, and one had a grade 2 creatinine increase that was remedied with additional hydration.
Patients really appreciated the outpatient option, Schaff said. “Every patient who received this treatment opted to continue the outpatient treatment as long as feasible.”
Some Centers Likely To Face Logistical Hurdles
“It’s very interesting and exciting to see what researchers and clinicians are doing to try to move patients from an inpatient setting to an outpatient setting in a way that’s safe,” said Lisa Holle, PharmD, BCOP, an associate clinical professor at the University of Connecticut School of Pharmacy, in Storrs.
However, moving these treatments to an outpatient setting likely will involve surmounting some logistical hurdles, Holle said. Many smaller institutions don’t have the laboratory capacity to process their own methotrexate, she noted. In addition, a new treatment like this could require additional training for infusion center staff, and the costs and cost-effectiveness of the treatment also need to be determined, she added.
For now, the MSKCC researchers are continuing to study the safety and efficacy of this approach. They are treating patients who need access to outpatient treatment as a result of the continuing pandemic and have started enrolling patients into a prospective study of this treatment approach in the outpatient setting. Schaff predicted, “I think certainly there’s going to be a place for this post-pandemic.”
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New Guidance for Managing DOAC-Related Bleeding
Anew resource from the Anticoagulation Forum provides guidance on bleeding related to direct oral anticoagulants (DOACs), highlighting areas where pharmacists and other clinicians can promote stewardship of these agents and develop systematic approaches to facilitate ordering, delivery, administration and management of reversal agents. The resource “provides distilled, evidence-based guidance on appropriately identifying patients [who] might need reversal, and how to effectively manage those patients depending on which anticoagulant they take,” said
Allison Burnett, PharmD, CACP, an antithrombosis stewardship pharmacist at the University of New Mexico Health Sciences Center, in Albuquerque, and the president-elect of the Anticoagulation Forum, a group of anticoagulant service providers in North America.
Although DOACs are associated with improved safety compared with vitamin K antagonists, 2.1% to 3.6% of patients who took these agents in phase 3 clinical trials experienced major bleeding (Blood 2014;124[15]:2450-2458; Lancet 2014;383[9921]:955-962), noted Scott Kaatz, DO, MSc, one of the authors of the guidance document, during a webinar sponsored by the Anticoagulation Forum.
The rate of major bleeding in atrial fibrillation/venous thromboembolism trials is about 2.0 per 100 patient-years (Blood 2019;133[5]:425-435), with the distribution being predominantly gastrointestinal bleeding versus intracranial hemorrhage (ICH), said Kaatz, a senior staff hospitalist at Henry Ford Health System, in Detroit.
Pointing out the importance of 30-day mortality rates in DOAC-associated hemorrhages, Kaatz said between 9% and 20% of patients who bleed on anticoagulant therapy die within 30 days (Eur Heart J 2015;36[20]:12641272). With intracranial hemorrhage (ICH), that percentage increases to 36% to 48%. Withholding anticoagulant reversal in DOAC-associated ICH leads to a 1.5-fold increased risk for death and poor outcomes (Front Neurol 2020;11:760), he noted.
Thus, Kaatz stressed, patients should not leave the hospital after a bleeding event without a plan in place to restart anticoagulation through medication or other options, such as a Watchman device for stroke prevention.
Stopping a Bleeding Event
The Anticoagulation Forum m resource can be used to inform m aatz advised h these th fully com things ov u
Table. Bottom-Line Recommended Actions
Do Do Not Consider Be Cautious About
• Determine timing of the last anticoagulant dose.
Depending on this, there may not be a lot of drug left circulating, so reversal may not be needed • Reverse life-threatening or uncontrolled bleeding with andexanet alfa (Andexxa, Alexion), if available, in patients taking apixaban or rivaroxaban (Xarelto,
Janssen) and with idarucizumab (Praxbind, Boehringer
Ingelheim), if available, in patients taking dabigatran • Form an anticoagulation restart plan or at least a stroke prevention plan • Give FFP for DOAC reversal • Delay administration of reversal agents for life-threatening bleeding while awaiting lab results • Reversing life-threatening or uncontrolled bleeding with PCC or activated PCC if a specific reversal agent is unavailable • Activated charcoal to absorb any anticoagulant drug taken within the previous 2 to 4 hours • Hemodialysis for dabigatran removal if the drug was taken recently and idarucizumab is unavailable • Lab measurements of DOACs if you can get them rapidly • Potential thromboembolic risks with reversal • Reversal agent redosing due to limited safety and efficacy data
DOAC, direct oral anticoagulant; D FFP, fresh frozen plasma; PCC, prothrombin complex concentrate Source: S Anticoagulation Forum.
9% and 20% of patients who bleed on the lab result isnt going to come back BCPS, BCCCP, a neurocritical care clini anticoagulant therapy die within 30 right away and the patient is having seri- cal pharmacy specialist with Massachudays ( (Eur Heart J 2015;36[20]:1264- ous bleeding, don’t wait before making a setts General Hospital, in Boston. 1272). With intracranial hemorrhage decision whether to use a reversal agent.” She said it is helpful to restart anti(ICH), that percentage increases to In the setting of bleeding with hemo- coagulation when a patient is in the dynamic compromise, Kaatz said, standard supportive care and resuscita- hospital, “so you can slowly escalate the tive measures always should be applied. intensity and get a repeat scan to ensure Besides holding anticoagulation, consid- tolerability.” But she said that’s not er mechanical intervention to stop bleed- always possible, especially for patients ing events, the use of topical hemostatic who have short hospital stays. agents, and replacing losses through Restarting therapy also is a good time transfusions or supplemental oxygen. for reeducation of patients, noted Kelly The document divides its bottom-line Rudd, PharmD, BCPS, the director of recommendations into four actions: do, network pharmacy operations for Basdo not do, consider, or proceed with sett Healthcare Network, a health system caution (Table). in New York. “Often patients may not be Regardless of the situation, Kaatz fully compliant or [are] doing advised clinicians to be cautious with things or taking additional these reversal strategies because over-the-counter prodthere are no comparison trials ucts that may have systematic approaches, such as DOAC in this setting. Be aware of the c contributed to [the bleeding],” reversal protocols to manage bleeding potential thromboembolic risk Rudd said. events, Burnett said. As agents are used, with reversal, and be cautious about Panelists addressed whethshe added, the document recommends reversal agent redosing due to limited er size of the ICH should dictracking and documenting efficacy and safety and efficacy data. tate treatment. Large intracereany adverse events. bral hemorrhages are the ones with The guidance lists reversal strategies Restarting Anticoagulation the highest risk for hematoma expansion, for dabigatran, rivaroxaban (Xarelto, In a panel discussion during the webi- Barra said, and for which anticoagulant Janssen), apixaban and edoxaban (Savay- nar, Kaatz, Cuker and other authors of reversal might not be enough to improve sa, Daiichi Sankyo), including timing and the guidance document noted that cli- functional outcome and mortality rates. other considerations. It also discusses the nicians commonly ask when it is safe However, expansion also can occur role of laboratory tests to measure “clini- to restart anticoagulation therapy after with small hemorrhages and could have cally significant” DOAC levels that may treatment of a bleeding event. “The anti- a large impact on long-term functional contribute to bleeding. coagulation indication did not go away, so outcomes, she said, stressing that it needs Such tests include assays to determine we need to do something about that,” said “to be an individualized approach.” the concentration of DOAC in plasma, Ronni Nemeth, PharmD, CACP, DPLA, —Karen Blum such as diluted thrombin time for dabiga- the manager of the anticoagulation clintran, and assays that can identify wheth- ics at Confluence Health, a health syser a clinically significant amount of drug tem in Washington. “We defer to speis present, such as the DOAC Dipstick cialists, especially for ICH. We find out (DOASENSE), said guidance co-author why bleeds happen, do some diagnostic Adam Cuker, MD, an associate professor testing and imaging, hopefully stop the of medicine and of pathology and labora- bleeding, and then restart therapy.” tory medicine at the Perelman School of For most indications, such as gastroMedicine at the University of Pennsylva- intestinal bleeding, a two-week waiting nia, in Philadelphia. period is appropriate before restarting, But Cuker emphasized the importance the panelists said. However, for very large of monitoring and treating the patient ICHs, some clinicians wait up to four to if and when it becomes indicated. “If six weeks, said Megan Barra, PharmD, the lab result isn’t going to come back BCPS, BCCCP, a neurocritical care cliniright away and the patient is having seri- cal pharmacy specialist with Massachuous bleeding, don’t wait before making a setts General Hospital, in Boston. decision whether to use a reversal agent.” She said it is helpful to restart antiIn the setting of bleeding with hemo- coagulation when a patient is in the dynamic compromise, Kaatz said, e isk s about to limited e tat
The guidance document project was supported by Alexion. Kaatz reported relationships with Bristol Myers Squibb, Janssen, Novartis, Osmosis, Pfi zer and Portola/Alexion. Cuker reported relationships with Alexion, Novartis, Novo Nordisk, Pfi zer, Sanofi , Spark Therapeutics and Synergy. The other speakers reported no relevant fi nancial disclosures.
The Anticoagulation Forum produces 12 rapid resource guides. For more information, go to https://acforum-excellence.org/ Resource-Center/index.php.
Polypill Reduces Cardiovascular Risk
Global implications, but less likely to affect U.S. patients
Daily use of a polypill composed of a statin, a beta-blocker, an angiotensin-converting enzyme inhibitor and hydrochlorothiazide reduced the incidence of cardiovascular disease (CVD) in TIPS-3 (International Polycap Study-3).
In the trial, investigators randomly assigned 5,713 patients in a 1:1 fashion to receive either a daily capsule composed of simvastatin (40 mg), atenolol (100 mg), ramipril (10 mg) and hydrochlorothiazide (2 mg) or placebo, then further randomized them in a 2×2 fashion to receive daily aspirin (75 mg) or placebo. The trial included patients who had an intermediate risk for CVD (>1% per year) but no vascular disease. Men ages 50 years and older and women 55 years and older with an INTERHEART Risk Score (IHRS) of at least 10, and men and women older than 65 years with an IHRS of at least 5, were included in the trial. The majority of the patients were from India and the Philippines. The patients had an average age of 53.9 years; 53% were women.
After a follow-up of 4.6 years, the polypill was associated with a 21% reduced incidence of the primary outcome of cardiovascular death, myocardial infarction, stroke, heart failure, cardiac arrest or revascularization (4.4% vs. 5.5%; hazard ratio [HR], 0.79; 95% CI, 0.63-1.00; P=0.05). The combination of polypill and aspirin also was associated with a reduced incidence of the primary outcome relative to placebo (4.1% vs. 5.8%; HR, 0.69; 95% CI, 0.50-0.97; P=0.031).
The polypill resulted in a higher incidence of side effects, including hypotension or dizziness, than placebo (2.7% vs. 1.1%), but nonadherence to the polypill and placebo was similar: 19% at two years, 32% at four years and 43% at the end of the study.
The polypill resulted in a 21% reduc-
tion in CVD, and the polypill and aspirin together resulted in a 31% reduction in CVD, according to the results of the study, which were presented at the American Heart Association (AHA) Scientific Sessions 2020 and published in The New England Journal of Medicine (2021;384[3]:216-218). The researchers noted that the benefits of the polypill and aspirin combined are greater (approximately 40%) in patients who did not discontinue treatment for nonmedical reasons and underscored that aspirin “contributes importantly” to these benefits.
‘Enormous’ Potential Public Health Benefits
“If half of eligible people use a polypill with aspirin,” the authors estimated, 3 million to 5 million CVD events could be “avoided each year globally.”
During an American College of Cardiology podcast highlighting top papers presented at the AHA meeting, Deepak L. Bhatt, MD, MPH, called TIPS-3 “a terrific study,” noting that “for certain health care systems, in certain regions of the world, it could make an enormous difference.”
The reductions in risk seen in the study population “are believable because if you’re treating multiple risk factors at once, that’s sort of the effect sizes you’d expect to see,” said Bhatt, the executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, in Boston. “So, I think there’s really merit in this approach.”
C. Michael White, PharmD, the department head and a distinguished professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs, agreed that the TIPS-3 findings have “important implications for developing countries where their access to medications, ability to fully monitor for cardiac risk factors and to titrate therapies to goals is reduced.”
But “in the U.S., this polycap would likely not provide the same benefits as using the best drugs for each individual patient and titrating the drugs to effect. For instance, they used atenolol once daily, which is not the most effective way to use that beta-blocker, and simvastatin instead of the more potent atorvastatin,” White told Pharmacy Practice News.
Beyond that, combining aspirin with the polypill “led to greater reductions in
cardiovascular risk than the drugs alone,” White said, which “adds to the confusion surrounding the role of aspirin for primary prevention.”
CV Risk Reduction
Polypill >21%
Polypill + aspirin >31%
—C. Michael White, PharmD
—Sarah Tilyou
The TIPS-3 investigators reported fi nancial relationships with Cadila Pharmaceuticals and the Wellcome Trust. White and Bhatt reported no relevant fi nancial disclosures.
340B Restrictions
continued from page 1
The manufacturer restrictions “began with Eli Lilly and have expanded to five other drug companies that have either stopped offering 340B discounts through community and retail contract pharmacies, or have placed restrictions on providing those discounts,” said Ted Slafsky, the former CEO of 340B Health, a membership organization representing nonprofit hospitals participating in the 340B drug pricing program. (The other manufacturers are AstraZeneca, Merck, Novartis, Sanofi and United Therapeutics.)
As noted, one of the biggest areas affected is diabetes care because all three manufacturers of insulin are no longer providing 340B discounts at contract pharmacies. “Our hospitals’ Community Benefit Program allows us as a 340B-covered entity to pass 340B pricing directly on to eligible patients, who can get the drug at their pharmacy at the 340B price,” said Jahred Washington, PharmD, the 340B program coordinator at UCSF Medical Center, in San Francisco. “But because of this pricing being removed at the contract pharmacy level, we have had dozens of patients with diabetes who have either had to pay much more or change to potentially less effective regimens from other manufacturers that do not have these restrictions. The patients are very upset and feel like they are at the mercy of the manufacturers.”
“We’ve been talking with groups representing people with type 1 diabetes, and their patients are telling us that they saw dramatic price increases on their insulin beginning at the end of last year,” said Peggy Tighe, JD, a prin-
cipal at Powers, Pyles, Sutter and Verville and legislative counsel to the Ryan White Clinics for 340B Access.
Meanwhile, she noted that Eli Lilly’s announcement that its U.S. fourth-quarter revenue for 2020 increased 31%, to $4.598 billion, attributed some of that increase to “lower utilization in the 340B segment,” primarily for two diabetes medications, dulaglutide (Trulicity) and insulin lispro (Humalog). “You’re making millions off the backs of people not getting a targeted discount anymore, and you’re proud of that?” Tighe asked.
Washington and other pharmacy leaders from UCSF have met with the manufacturers, and the companies “held their ground,” he said. “They believe that what they are doing is equitable, and they do not believe that they need to participate with the 340B pricing program at contract pharmacies.”
“Their take is that the 340B program has grown out of proportion and has gone unchecked, and that the savings don’t actually go to the patients,” UCSF Medical Center’s Galens said. “But the intent of the 340B program is very clear: to provide savings to covered entities that are providing care to these patients. In some instances, we do pass on dollar-fordollar savings to the patients in a direct manner, but even when we don’t, we use those savings to be able to expand care to our vulnerable patients and to all patients in an equitable way.”
Tarsis Lopez, a spokesperson for Eli Lilly, disputed the 340B-covered entities’ claims. “Unfortunately, there continues to be a lot of misinformation circulating about 340B and some of the details have obfuscated the truth,” Lopez told Pharmacy Practice News. “The 340B program, which was meant to help underserved and low-income populations, has become a major source of profit to forprofit pharmacies, which obtain insulins at deep discounts and then sell them to patients at egregious markups,” Lopez said. “If a patient doesn’t receive 340B pricing, Lilly offers multiple affordability solutions through the Lilly Diabetes Solution Center so that anyone, regardless of their insurance status, can purchase their monthly insulin prescription for $35. Further, we also offer solutions that address numerous circumstances—such as donations to charities where people struggling financially can get their insulin for free.”
Lopez added that although “the statute does not require manufacturers to offer 340B discounts to contract pharmacies, Lilly nevertheless will voluntarily sell to a contract pharmacy when its covered entity either does not have an in-house pharmacy or that contract pharmacy is wholly owned by the entity. We have crafted our policy to explicitly provide 340B pennypriced insulin to any contract pharmacy
—Jessica Galens, PharmD
Helping you deliver better medicine to more people.
Leiters is an FDA registered and inspected 503B outsourcing provider of high-quality compounded sterile preparations and services including: Pre-filled syringes, IV bags and vials Opioid-free surgical pain services medications ON-Q* Pain Relief System fill services Ophthalmology medications including FDA-compliant repackaged Avastin®
In 2017, tax-exempt hospitals participating in the 340B drug discount program provided $64.3 billion
in total benefits to their communities.a
Source: American Hospital Association. a The most recent year for which this information is available.
that passes the discounts on to patients at cost—which is 15 cents for a 5-pack of 3-mL pens of Lilly’s most prescribed insulin and would cost most patients less than $1 for their monthly prescription.”
Washington responded by noting that Lilly “will allow the covered entity to have one contract pharmacy with 340B pricing. Is it reasonable to expect all patients of a covered entity to use a single pharmacy? And their insulin policy sounds great at face value, but is difficult to operationalize. If Lilly wanted to provide this medication for less than $1, they would offer coupon cards to patients directly and wouldn’t make covered entities jump through hoops to gain access.”
Federal Efforts to Thwart Restrictions Fail
As the debate over the 340B program continues, efforts to rein in the manufacturers’ 340B restrictions by the Department of Health and Human Services (HHS) and the Health Resources and Services Administration (HRSA) have so far been unsuccessful. Last December, HHS finalized the long-awaited 340B Administrative Dispute Resolution (ADR) rule setting up a process for challenging the restrictions. Then, on Dec. 30, 2020, the agency issued an advisory opinion that held the restrictions to be unlawful. “We conclude that to the extent contract pharmacies are acting as agents of a covered entity, a drug manufacturer in the 340B Program is obligated to deliver its covered outpatient drugs to those contract pharmacies and to charge the covered entity no more than the 340B ceiling price for those drugs,” wrote then–HHS General Counsel Robert Charrow.
Despite this opinion, as well as bipartisan letters from nearly 250 members of the House of Representatives and 28 senators, the manufacturers refused to yield. Eli Lilly, AstraZeneca and Sanofi filed complaints challenging the advisory opinion and ADR rule in Indiana, Delaware and New Jersey district courts, respectively. This year, on March 30, the U.S. District Court for the Southern District of Indiana granted Lilly’s request for an injunction against the ADR, noting that HHS and HRSA had not reopened a required comment period before issuing the ADR rule. “[The] agency’s message regarding the ongoing rulemaking related to the ADR Rule was ambiguous, confusing, duplicitous and misleading—the antithesis of fair notice under the APA [Administrative Procedure Act],” Judge Sarah Evans Barker wrote.
So what’s next? It’s unclear whether HHS and HRSA will appeal the ruling, or reissue the ADR with a notice and comment period. In the meantime, experts say it’s unlikely that the six manufacturers that have placed contract pharmacy restrictions on 340B-covered entities will reverse their positions.
HHS Secretary Xavier Becerra has yet to take any specific action on the 340B contract pharmacy restrictions in his new role, but as California’s attorney general, he spearheaded a bipartisan coalition of attorneys general who urged HHS to require drug manufacturers to provide the 340B discounts to contract pharmacies. “While Americans grapple with COVID-19, it is critical that we protect access to affordable care,” Becerra said in a statement (bit.ly/3seRFK1).“Discounts afforded under the 340B Drug Pricing Program are more critical now than ever. They ensure that low-income and uninsured patients have access to affordable medication as they deal with the substantial impact of [COVID-19]. We call on HHS to hold these non-compliant drug manufacturers accountable and provide immediate relief for health care centers and the Americans they serve.”
Becerra’s stance is good news for covered entities, but it doesn’t mean an overnight resolution, noted Slafsky, who is now the publisher and CEO of 340B Report, a news service that focuses specifically on the 340B program. “It’s very likely that the court cases will have to play out. However, in the meantime, no additional manufacturers have moved toward restricting access, and I think if some of these advocacy efforts had not occurred, others would possibly have felt emboldened to restrict 340B discounts.”
Even if the manufacturers are forced to reverse course, many of the losses experienced by covered entities and their patients will be impossible to recoup. “These restrictions have already been in place for more than six months, and even if this were to be reversed, manufacturers don’t let you do a credit rebill for such a long time frame,” said Kristin Smith, a senior vice president for the Hospital & Health System Services Division at Visante, Inc. “We’re outside the window where [a credit] would even be feasible.”
Ryan White Clinics Vulnerable
Ryan White 340B providers, such as the Damien Center, in Albany, N.Y., have been particularly hard hit. The center provides housing, food, mental health counseling and access to support services—including 340B drug discounts—for their clients, people living with HIV and AIDS. “We can purchase the medications our patients are refilling for them, and then capture the savings between the 340B discount and what the insurance companies pay in order to expand and create services for people who are underserved, which is what the federal law was intended to do,” said Perry Junjulas, the executive director.
The center lost $80,000 in savings over just a three-month period as a result of manufacturers not honoring 340B pricing, Junjulas told Pharmacy Practice News. “Our overall budget is only $3 million, so that’s enormous to us,” he said. “Those are funds that we were planning to spend on meals, housing, mental health counseling, transportation and medication adherence services. We’ve had to cut staff and reduce the amount of services we can provide. I can’t even tell you what this agency is going to look like in a year. I can tell you what the need will be, though: There will still be people walking up to my door, homeless and hungry and in need. That’s going to continue.”
“We’re doing all we can to guide our patients through this very difficult health care environment,” UCSF Medical Center’s Washingon said. “We have a coordinator who does the legwork to help them find alternative therapies and set up appointments with providers to get their regimen changed. We will continue to care for our patients; we will not let them suffer. If we have to pay for their medications, we will do so, because it’s not about the money—it’s about the patients and their needs.”
—Gina Shaw
Tighe reported that she represents 340B providers/groups participating as covered entities in the 340B program and 340B service providers with whom they work. The remaining sources reported no relevant fi nancial disclosures other than stated employment.
