39 minute read
hospitalizations
Trivalent Flu Shot Reduces Hospitalizations
By Marie Rosenthal
Data 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
see TRIVALENT, page 4
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%.
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
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.
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
Cardiopulmonary bypass procedures Adults: Initial dose of 20 g (including renal dialysis). For acute liver failure: initial dose of 12 to 25 g.
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. 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
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
Cardiopulmonary bypass procedures Adults: Initial dose of 25 g (including renal dialysis). For acute liver failure: initial dose of 12 to 25 g.
Adults: Initial dose of 25 g.
Acute nephrosis Adults: 25 g together with diuretic once a day for 7 - 10 days. 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. Adults: 50 g to 100 g over 4 hours and repeated at 4-12 hour intervals as necessary.
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 paracentesis due to cirrhotic ascites Adults: 8 g for every 1000 mL of ascitic fluid removed. 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.
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 TheNew 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, 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 fi nancial disclosures.
EDITORIAL BOARD
HOME INFUSION
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PBMs
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SPECIALTY PHARMACY
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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
Multiple 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
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
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 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
for serious AEs and of the importance of promptly seeking treatment if AEs develop.15
Future Cell and Gene Therapies
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 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
Source: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy.
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 fi rst 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. 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. 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. 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/
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 fi rst cell-based gene therapy for adult patients with multiple myeloma. Accessed February 1, 2022. https://www.fda.gov/news-events/ press-announcements/fda-approves-fi rstcell-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 anti-
BCMA 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.
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Role-in-Managing-CAR-T-Therapy/52309
For patients with cGVHD ROCK ON
INDICATION
IMPORTANT SAFETY INFORMATION
Warningsand Precautions
• Embryo-Fetal Toxicity: 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
Adverse Reactions
• • •
Drug Interactions
• Strong CYP3A Inducers: Coadministration of REZUROCK with strong CYP3A inducers decreases belumosudil when coadministered with strong CYP3A inducers • Proton Pump Inhibitors: Coadministration of REZUROCK with proton pump inhibitors decreases belumosudil when coadministered with proton pump inhibitors
ORRa 75%
(95% CI, 63-85; P<.0001)1,4
REZUROCK achieved clinically and statistically with the 200-mg once-daily dose in a real-world demographic of patients with cGVHD.1
• 1-3 • CR was observed in all organs 5
• 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 and nonresponders5
• Well tolerated1
ASSIST ™
Enroll your patients with cGVHD in Kadmon ASSIST so our Kadmon ASSIST Monday through Friday, 8 -8 ET, 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. aProportion 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)
• Pregnancy: 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 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: 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 You are encouraged to report side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call
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. 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.
a 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. e includes edema peripheral, generalized edema, face edema, localized edema, edema. f 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. Table 3 summarizes the laboratory abnormalities in REZUROCK.
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]. 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].
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. 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. 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 embryo- fetal 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.
Table 2: Nonlaboratory Adverse Reactions in ≥ 10% Patients with Chronic GVHD Treated with REZUROCK
Adverse Reaction REZUROCK 200 mg once daily (N=83) All Grades (%) Grades 3-4 (%)
Infections and infestations
Infection (pathogen not specified)a Viral infectionb Bacterial infectionc
General disorders and administration site conditions
Astheniad 53 16 19 4 16 4
46 4 Edemae 27 1 Pyrexia 18 1
Gastrointestinal
Nauseaf 42 4 Diarrhea 35 5 Abdominal paing 22 1 Dysphagia 16 0
Respiratory, thoracic and mediastinal
Dyspneah 33 5 Coughi 30 0 Nasal congestion 12 0
Vascular
Hemorrhagej 23 5 Hypertension 21 7
Musculoskeletal and connective tissue
Musculoskeletal paink 22 4 Muscle spasm 17 0 Arthralgia 15 2
Nervous system
Headachel 21 0
Metabolism and nutrition
Decreased appetite 17 1
Skin and subcutaneous
Rashm 12 0 Pruritusn 11 0
Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK REZUROCK 200 mg once daily
Grade 0-1 Baseline Grade 2-4 Max Post
Grade 3-4 Max Post Parameter (N) (%) (%) Chemistry
Phosphate Decreased 76 28 7 Gamma Glutamyl Transferase Increased 47 21 11 Calcium Decreased 82 12 1 Alkaline Phosphatase Increased 80 9 0 Potassium Increased 82 7 1 Alanine Aminotransferase Increased 83 7 2 Creatinine Increased 83 4 0
Hematology
Lymphocytes Decreased 62 29 13 Hemoglobin Decreased 79 11 1 Platelets Decreased 82 10 5 Neutrophil Count Decreased 83 8 4
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
