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Cytokine Release Syndrome (CRS): IMDELLTRA® can cause CRS
including life-threatening or fatal reactions. In the pooled safety population, CRS occurred in 57%
(268/473)
of patients who received IMDELLTRA®, including 39% Grade 1, 15% Grade 2, 1.7%
Grade 3 and 0.2% Grade 4.
Recurrent CRS occurred in 24% of IMDELLTRA®-treated patients including 20%
Grade 1 and 3.4% Grade 2; one
patient experienced recurrent Grade 3.
Among the 268 patients who experienced CRS, 73% had CRS after the first dose, 60% had CRS after the second dose, and 15% had CRS following the third or later dose. Following the Cycle 1 Day 1, Day 8, Day 15 infusions, 24%, 8%, and 1% of patients experienced Grade ≥ 2 CRS, respectively. From Cycle 2 onwards, 1.5% of patients experienced Grade ≥ 2 CRS. Of the patients who experienced CRS, 31% received steroids and 10% required tocilizumab. The median time to onset of all grade CRS from most recent dose of IMDELLTRA® was 16 hours (range: start of infusion to 15 days). The median time to onset of Grade ≥ 2 CRS from most recent dose of IMDELLTRA® was 15 hours (range: start of infusion to 15 days).
Clinical signs and symptoms of CRS included pyrexia, hypotension, fatigue, tachycardia, headache,
hypoxia, nausea, and vomiting. Potentially life-threatening complications of CRS may include cardiac
dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and
disseminated intravascular coagulation (DIC).
Administer IMDELLTRA® following the recommended step-up dosing and
administer concomitant medications before
and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA® infusions as described
in Table 3 of the Prescribing
Information (PI) to reduce the risk of CRS. Administer IMDELLTRA® in an
appropriate healthcare facility
equipped to monitor and manage CRS. Ensure patients are well hydrated prior to administration of
IMDELLTRA®.
Closely monitor patients for signs and symptoms of CRS during treatment with IMDELLTRA®. At the first
sign of CRS, immediately discontinue IMDELLTRA® infusion, evaluate the
patient for hospitalization and
institute supportive care based on severity. Withhold or permanently discontinue IMDELLTRA® based on
severity. Counsel patients and caregivers to seek medical attention should signs or symptoms of CRS occur.
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Neurologic Toxicity, Including ICANS: IMDELLTRA® can cause
life-threatening or fatal neurologic toxicity, including ICANS. In the pooled safety population, neurologic
toxicity occurred in 65% of patients who received IMDELLTRA®, with Grade 3 or
higher events in 7% of patients
including fatal events in 0.2%. The most frequent neurologic toxicities were dysgeusia (34%), headache
(17%), peripheral neuropathy (9%), dizziness (9%), and insomnia (8%).
The incidence of signs and symptoms consistent with ICANS was 10% in IMDELLTRA®-treated patients, including events with the preferred terms: ICANS (4.7%), muscular weakness (3.2%), cognitive disorder (0.6%), aphasia (0.6%), depressed level of consciousness (0.4%), seizures (0.4%), encephalopathy (0.4%), and leukoencephalopathy (0.2%). There was one fatal reaction of ICANS. Recurrent ICANS occurred in 1.5% of patients. Of the patients who experienced ICANS, most experienced the event following Cycle 1 Day 1 (2.5%) and Cycle 1 Day 8 (3.6%). Following Day 1, Day 8, and Day 15 infusions, 1.3%, 1.3% and 0.4% of patients experienced Grade ≥ 2 ICANS, respectively. ICANS can occur several weeks following administration of IMDELLTRA®. The median time to onset of ICANS from the first dose of IMDELLTRA® was 16 days (range: 1 to 862 days). The median time to resolution of ICANS was 4 days (range: 1 to 40 days).
The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level
of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.
Patients receiving IMDELLTRA® are at risk of neurologic adverse reactions
and ICANS resulting in depressed
level of consciousness. Advise patients to refrain from driving and engaging in hazardous occupations or
activities, such as operating heavy or potentially dangerous machinery, until neurologic symptoms resolve.
Closely monitor patients for signs and symptoms of neurologic toxicity and ICANS during treatment with
IMDELLTRA®. At the first sign of ICANS, immediately discontinue the infusion,
evaluate the patient and
provide supportive therapy based on severity. Withhold IMDELLTRA® or
permanently discontinue based on
severity.
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Cytopenias: IMDELLTRA® can cause cytopenias including
neutropenia, thrombocytopenia, and anemia. In the pooled safety population, based on laboratory data,
decreased neutrophils occurred in 16% of patients, including 9% Grade 3 or 4. The median time to onset for
Grade 3 or 4 decreased neutrophil count was 41 days (range: 2 to 306 days). Decreased platelets occurred in
30% including 2.2% Grade 3 or 4. The median time to onset for Grade 3 or 4 decreased platelets was 67 days
(range: 3 to 420 days). Decreased hemoglobin occurred in 56% of patients, including 4.7% Grade 3 or 4.
Febrile neutropenia was reported as an adverse event in 1.5% of patients treated with IMDELLTRA®.
Monitor patients for signs and symptoms of cytopenias. Perform complete blood counts prior to treatment
with all doses of IMDELLTRA®, up through Cycle 5 Day 15 and then prior to
administration on Day 1 of each
cycle starting with Cycle 6. Based on the severity of cytopenias, temporarily withhold, or permanently
discontinue IMDELLTRA®.
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Infections: IMDELLTRA® can cause serious infections,
including life-threatening and fatal infections.
In the pooled safety population, infections, including opportunistic infections, occurred in 43% of
patients
who received IMDELLTRA®, including 14% Grade 3 or 4. The most frequent
infections were pneumonia (11%),
urinary tract infection (9%), COVID-19 (6%), upper respiratory tract infection (4.7%), respiratory tract
infection (4%), candida infection (2.1%), oral candidiasis (2.1%), and nasopharyngitis (2.1%).
Monitor patients for signs and symptoms of infection prior to and during treatment with IMDELLTRA® and
treat as clinically indicated. Withhold or permanently discontinue IMDELLTRA®
based on severity.
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Hepatotoxicity: IMDELLTRA® can cause hepatotoxicity. In the
pooled safety population, based on laboratory data, elevated ALT occurred in 39% of patients who received IMDELLTRA®, including 2.5% with Grade
3 or 4 ALT. Elevated AST occurred in 43%
of patients, including 3.2%
Grade 3 or 4. Elevated bilirubin also occurred in 16% of patients, including 1.3% Grade 3 or 4. Liver enzyme
elevation can occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin prior to treatment with IMDELLTRA®, and
as clinically indicated.
Withhold IMDELLTRA® or permanently discontinue based on severity.
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Hypersensitivity: IMDELLTRA® can cause severe
hypersensitivity reactions. Clinical signs and symptoms of hypersensitivity may include, but are not limited
to, rash and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity during treatment with
IMDELLTRA® and manage as clinically indicated. Withhold or consider permanent
discontinuation of IMDELLTRA®
based on severity.
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Embryo-Fetal Toxicity: Based on its mechanism of action, IMDELLTRA® may cause fetal harm
when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during treatment with IMDELLTRA® and for 2 months
after the last dose.
