Safety data were collected from CARTITUDE-1 and other ongoing trials.

Safety Boxed warning

BOXED WARNING1

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, and PROLONGED and RECURRENT CYTOPENIA

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI™. Do not administer CARVYKTI™ to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids
  • Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI™, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI™. Provide supportive care and/or corticosteroids as needed
  • Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI™
  • Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI™
  • Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI™
  • CARVYKTI™ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI™ REMS Program

CARVYKTI REMS Program1

CARVYKTI™ is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called CARVYKTI™ REMS. The FDA has determined that a REMS is necessary to ensure that the benefits of CARVYKTI™ outweigh the risks of cytokine release syndrome and neurological toxicities. One of the goals of the CARVYKTI™ REMS is to ensure that healthcare professionals that prescribe, dispense, or administer CARVYKTI™ at the CARVYKTI™ Certified Treatment Centers are aware of how to manage the risks of CRS and neurological toxicities.

For more information, visit www.CARVYKTIrems.com

aSafety data were collected from CARTITUDE-1 and other ongoing trials.

Cytokine release syndrome (CRS)1,2

CRS, including fatal or life-threatening reactions, occurred after ciltacabtagene autoleucel infusion

Any grade GRADE 3-4 Grade 5
95%(n=92/97) 4%(n=4/97) 1%(n=1/97)
  • Median time to onset of cytokine release syndrome (CRS): 7 days (range, 1-12 days)
  • Median duration of CRS: 4 days (range, 1-40 days) with one patient extending out to 97 days
  • Some patients required tocilizumab, corticosteroids, and/or anakinra for management of CRS
  • Sixty-nine of 97 patients (71%) received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four patients (45%) received only tocilizumab; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids
  • Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after CARVYKTI™ (ciltacabtagene autoleucel) infusion, if needed for treatment of CRS
  • In patients with early onset of fever (if onset less than 72 hours after infusion), early tocilizumab should be considered
  • At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids, depending on CRS grade (See Table 1 in Prescribing Information)
  • Evaluation for hemophagocytic lymphohistiocytosis should be considered in patients with severe or unresponsive CRS

aSafety data were collected from CARTITUDE-1 and other ongoing trials.

NEUROLOGIC TOXICITIES1

Neurologic toxicities, which may be severe, life-threatening, or fatal, occurred following treatment with ciltacabtagene autoleucel

Any grade GRADE 3 OR HIGHER
26%(n=25/97) 11%(n=11/97)

Immune effector cell–associated neurotoxicity syndrome (ICANS)1

Any grade GRADE 3-4 GRADE 5
23%(n=22/97) 3%(n=3/97) 2%(n=2/97)
  • The onset of ICANS occurred during CRS in 16 patients, before the onset of CRS in 3 patients, and after the CRS event in 3 patients
  • Median time to first onset of ICANS: 8 days (range 1-28 days)
  • Median duration of ICANS in all patients―including those with fatal ICANS, ICANS ongoing at time of death from other causes, or ongoing at last known alive date―was 7.5 days (range, 2-927 days)
  • ICANS resolved in 17 of 22 patients (77%), and the median time to resolution was 6 days (range, 2-143 days)
  • All 22 patients with ICANS had CRS
  • Counsel patients to seek immediate medical attention should signs and symptoms of neurotoxicity occur after recovery from CRS and/or ICANS
  • Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities

Parkinsonism

  • Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS)
  • Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs
  • The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel
  • Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI™ treatment

Guillain-Barré syndrome (GBS)

  • A fatal outcome following GBS has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis
  • Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS

Peripheral neuropathy

  • Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel

Cranial nerve palsies

  • Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel
  • Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms

CRS=cytokine release syndrome.

aSafety data were collected from CARTITUDE-1 and other ongoing trials.

Hemophagocytic lymphohistiocytosis (HLH)1

HLH is a potentially life-threatening complication

  • In the CARTITUDE-1 study, one patient (1%) had a duration of CRS of 97 days which was complicated by secondary HLH with a subsequent fatal outcome that occurred 99 days after infusion
  • HLH/MAS can occur with CRS or neurologic toxicities
  • Other monoclonal antibodies targeting cytokines (for example, anti-IL1, and/or anti-TNFα) or therapy directed at reduction and elimination of CAR-T cells may be considered for patients who develop high-grade CRS and HLH that remains severe or life-threatening following prior administration of tocilizumab and corticosteroids

CAR-T=chimeric antigen receptor T cell; CRS=cytokine release syndrome; IL1=interleukin1; MAS=Macrophage Activation Syndrome; TNF-α= tumor necrosis factor-alpha.

aSafety data were collected from CARTITUDE-1 and other ongoing trials.

PROLONGED AND/OR RECURRENT CYTOPENIAS1

  • Prolonged Grade 3 or 4 neutropenia was experienced by 30% (n=29) of patients
  • Forty-one percent (n=40) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion
  • Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were seen in 63% (n=61), 18% (n=17), 60% (n=58), and 37% (n=36) after recovery from initial Grade 3 or 4 cytopenia following ciltacabtagene autoleucel infusion
  • After Day 60 following ciltacabtagene autoleucel, 31%, 12%, and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia, and thrombocytopenia, respectively, after initial recovery from their Grade 3 or 4 cytopenia

Hematologic Adverse Events1

Grade 3-4 hematologic laboratory abnormalities occurring in ≥10% of patients in CARTITUDE-1 (N=97)

Laboratory abnormality Grade 3-4 (%)
Lymphopenia 99
Neutropenia 98
White blood cells decreased 98
Anemia 72
Thrombocytopenia 63
Aspartate aminotransferase increased 21

asafety data were collected from CARTITUDE-1 and other ongoing trials.

ADVERSE REACTIONS (≥10%) (N=97)1

ADVERSE REACTIONS ALL GRADES (%) GRADE ≥3 (%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Coagulopathy 22 2.1
Febrile neutropenia 10 10
Cardiac disorders
Tachycardia 27 1
Gastrointestinal disorders
Diarrhea 33 1
Nausea 31 1
Constipation 22 0
Vomiting 20 0
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS
Pyrexia 96 5
Fatigue 47 7
Chills 33 0
Edema 23 0
Immune system disorders
Cytokine release syndrome 95 5
Hypogammaglobulinemia 94 2
INFECTIONS AND INFESTATIONS
Infections-pathogen unspecified 41 17
Upper respiratory tract infection 28 3
Viral infection 23 7
Pneumonia 12 11
Sepsis 10 7
Bacterial infections 10 3
Metabolism and nutrition disorders
Decreased appetite 29 1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain 48 2
Nervous system disorders
Encephalopathy 30 6
Headache 27 0
Dizziness 23 1
Motor dysfunction 16 3
Psychiatric disorders
Insomnia 13 0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough 39 0
Dyspnea 23 3
Nasal congestion 15 0
Hypoxia 12 4
Vascular Disorders
Hypotension 51 10
Hypertension 19 6
Hemorrhage 15 4

asafety data were collected from CARTITUDE-1 and other ongoing trials.

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