infusion ; evaluate and treat promptly [ see Dosage and Administration ]. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [ see Patient Counseling Information ].
BREYANZI ( lisocabtagene maraleucel ) REMS
Because of the risk of CRS and neurologic toxicities , BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the BREYANZI REMS [ see Boxed Warning and Warnings and Precautions ]. The required components of the BREYANZI REMS are :
• Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements .
• Certified healthcare facilities must have on-site , immediate access to tocilizumab .
• Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion , if needed for treatment of CRS .
• Certified healthcare facilities must ensure that healthcare providers who prescribe , dispense , or administer BREYANZI are trained on the management of CRS and neurologic toxicities .
Further information is available at www . BreyanziREMS . com , or contact Bristol-Myers Squibb at 1-888-423-5436 .
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of BREYANZI . Serious hypersensitivity reactions , including anaphylaxis , may be due to dimethyl sulfoxide ( DMSO ).
Serious Infections
Severe infections , including life-threatening or fatal infections , have occurred in patients after BREYANZI infusion . Infections ( all grades ) occurred in 45 % ( 121 / 268 ) of patients . Grade 3 or higher infections occurred in 19 % of patients . Grade 3 or higher infections with an unspecified pathogen occurred in 16 % of patients , bacterial infections occurred in 5 %, and viral and fungal infections occurred in 1.5 % and 0.4 % of patients , respectively . Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately . Administer prophylactic antimicrobials according to standard institutional guidelines .
Febrile neutropenia has been observed in 9 % ( 24 / 268 ) of patients after BREYANZI infusion and may be concurrent with CRS . In the event of febrile neutropenia , evaluate for infection and manage with broad-spectrum antibiotics , fluids , and other supportive care as medically indicated .
Avoid administration of BREYANZI in patients with clinically significant active systemic infections . Viral Reactivation
Hepatitis B virus ( HBV ) reactivation , in some cases resulting in fulminant hepatitis , hepatic failure , and death , can occur in patients treated with drugs directed against B cells .
Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI .
Perform screening for HBV , HCV , and HIV in accordance with clinical guidelines before collection of cells for manufacturing .
Prolonged Cytopenias
Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion .
Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31 % ( 84 / 268 ) of patients , and included thrombocytopenia ( 26 %), neutropenia ( 14 %), and anemia ( 3.0 %). Monitor complete blood counts prior to and after BREYANZI administration .
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI . The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14 % ( 37 / 268 ) of patients ; laboratory IgG levels fell below 500 mg / dL after infusion in 21 % ( 56 / 268 ) of patients . Hypogammaglobulinemia , either as an adverse event or laboratory IgG level below 500 mg / dL after infusion , was reported in 32 % ( 85 / 268 ) of patients .
Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions , antibiotic prophylaxis , and immunoglobulin replacement as clinically indicated .
Live Vaccines
The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied . Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy , during BREYANZI treatment , and until immune recovery following treatment with BREYANZI .
Secondary Malignancies
Patients treated with BREYANZI may develop secondary malignancies . Monitor lifelong for secondary malignancies . In the event that a secondary malignancy occurs , contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing .
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events , including altered mental status or seizures , patients receiving BREYANZI are at risk for altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration . Advise patients to refrain from driving and engaging in hazardous occupations or activities , such as operating heavy or potentially dangerous machinery , during this initial period .
ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling :
• Cytokine Release Syndrome [ see Warnings and Precautions ]
• Neurologic Toxicities [ see Warnings and Precautions ]
• Hypersensitivity Reactions [ see Warnings and Precautions ]
• Serious Infections [ see Warnings and Precautions ]
• Prolonged Cytopenias [ see Warnings and Precautions ]
• Hypogammaglobulinemia [ see Warnings and Precautions ]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .
The safety data described in this section reflect exposure to BREYANZI in the TRANSCEND study , in which 268 adult patients with R / R large B-cell lymphoma received a flat dose of CAR-positive viable T cells [ see Clinical Studies ( 14 ) in full Prescribing Information ]. Patients with a history of CNS disorders ( such as seizures or cerebrovascular ischemia ) or autoimmune disease requiring systemic immunosuppression were ineligible . The median duration of follow-up was 9 months . The median age of the study population was 63 years ( range : 18 to 86 years ); 65 % were male . The Eastern Cooperative Oncology Group ( ECOG ) performance status at screening was 0 in 41 % of patients , 1 in 58 % of patients , and 2 in 1.5 % of patients .
Serious adverse reactions occurred in 46 % of patients . The most common nonlaboratory , serious adverse reactions (> 2 %) were CRS , encephalopathy , sepsis , febrile neutropenia , aphasia , pneumonia , fever , hypotension , dizziness , and delirium . Fatal adverse reactions occurred in 4 % of patients .
Table 3 presents the adverse reactions reported in at least 10 % of patients treated with BREYANZI ( lisocabtagene maraleucel ), and Table 4 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10 % of patients .
The most common nonlaboratory adverse reactions of any grade ( ≥ 20 %) were fatigue , CRS , musculoskeletal pain , nausea , headache , encephalopathy , infections ( pathogen unspecified ), decreased appetite , diarrhea , hypotension , tachycardia , dizziness , cough , constipation , abdominal pain , vomiting , and edema .
Table 3 :
Summary of Adverse Reactions Observed in at Least 10 % of the Patients Treated with BREYANZI in the TRANSCEND Study ( N = 268 )
Adverse Reaction Any Grade (%) Grade 3 or Higher (%) Cardiac disorders Tachycardia a 25 0 Gastrointestinal disorders Nausea 33 1.5 Diarrhea 26 0.4 Constipation 23 0 Abdominal pain b 21 3.0 Vomiting 21 0.4 General disorders and administration site conditions Fatigue c 48 3.4 Edema d 21 1.1 Fever 16 0 Chills 12 0 Immune system disorders Cytokine release syndrome 46 4.1 Hypogammaglobulinemia e 32 0 Infections and infestations f Infections - pathogen unspecified g 29 16 Bacterial infectious disorders h 13 5 Upper respiratory tract infection i 13 0.7 Viral infectious disorders 10 1.5 Metabolism and nutrition disorders Decreased appetite 28 2.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain j 37 2.2 Motor dysfunction k 10 1.1 Nervous system disorders Headache l 30 1.1 Encephalopathy m 29 9 Dizziness n 24 2.6 Tremor o 16 0 Peripheral neuropathy p 11 0 Aphasia q 10 2.2 Psychiatric disorders Insomnia r 14 0.4 Anxiety s 10 0 Delirium t 10 2.2 Renal and urinary disorders Renal failure u 11 3.0 Respiratory , thoracic , and mediastinal disorders Cough v 23 0 Dyspnea w 16 2.6 Skin and subcutaneous tissue disorders Rash x 13 0.4 Vascular disorders Hypotension y 26 3.4 Hypertension 14 4.5 Hemorrhage z 10 1.5 a Tachycardia includes heart rate increased , sinus tachycardia , tachycardia . b Abdominal pain includes abdominal discomfort , abdominal pain , abdominal pain lower , abdominal pain upper , abdominal
tenderness . c Fatigue includes asthenia , fatigue , malaise .
d Edema includes edema , edema peripheral , fluid overload , fluid retention , generalized edema , hypervolemia , peripheral
swelling , pulmonary congestion , pulmonary edema , swelling . e Hypogammaglobulinemia includes subjects with adverse events of hypogammaglobulinemia ( 14 %) and / or laboratory
IgG levels that fell below 500 mg / dL after infusion ( 21 %). f Infections and infestations are grouped by pathogen type and selected clinical syndromes .
g Infections – pathogen unspecified contains febrile neutropenia ( 9 %). h Bacterial infection includes infections by pathogen type plus appendicitis , diverticulitis , peritonitis , skin infection , tooth
infection . i Upper respiratory tract infections includes nasopharyngitis , pharyngitis , rhinitis , rhinovirus infection , sinusitis , upper
respiratory tract congestion , upper respiratory tract infection . j Musculoskeletal pain includes arthralgia , back pain , bone pain , musculoskeletal chest pain , musculoskeletal discomfort ,
musculoskeletal pain , musculoskeletal stiffness , myalgia , neck pain , pain in extremity , spinal pain . k Motor dysfunction includes eyelid ptosis , motor dysfunction , muscle rigidity , muscle spasms , muscle spasticity , muscle
tightness , muscle twitching , muscular weakness , myoclonus , myopathy . l Headache includes headache , head discomfort , migraine , sinus headache .
( Continued )