Cytokine Release Syndrome and Neurologic Toxicity

Cytokine Release Syndrome

• IMDELLTRA can cause cytokine release syndrome (CRS) including serious or lifethreatening reactions.
• In the pooled safety population [see Adverse Reactions (6.1)], CRS occurred in 55% ofpatients who received IMDELLTRA, including 34% Grade 1, 19% Grade 2, 1.1% Grade 3 and 0.5% Grade 4. Recurrent CRS occurred in 24% of IMDELLTRA-treated patients including 18% Grade 1 and 6% Grade 2.
• Most events (43%) of CRS occurred after the first dose with 29% of patients experiencing any grade CRS after the second dose and 9% of patients experiencing CRS following the third dose or later. Following the Day 1, Day 8, Day 15 infusions, 16%, 4.3%, and 2.1% of patients experienced ≥ Grade 2 CRS, respectively. The median time to onset of all grade CRS from most recent dose of IMDELLTRA was 13.5 hours (range: 1 to 268 hours). The median time to onset of ≥ Grade 2 CRS from most recent dose of IMDELLTRA was 14.6 hours (range: 2 to 566 hours).
• 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 IMDELLTRA infusions as described in Table 3 to reduce the risk of CRS [see Dosage and Administration (2.3)]. Administer IMDELLTRA in an appropriate health care 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 [see Dosage and Administration (2.5)]. Counsel patients to seek medical attention should signs if symptoms of CRS occur.

Neurologic Toxicity Including ICANS

• IMDELLTRA can cause serious or life-threatening neurologic toxicity, including ICANS.
• In the pooled safety population [see Adverse Reactions (6.1)], neurologic toxicity including ICANS, occurred in 47% of patients who received IMDELLTRA, including 10% Grade 3. The most frequent neurologic toxicities were headache (14%), peripheral neuropathy (7%), dizziness (7%), insomnia (6%), muscular weakness (3.7%), delirium (2.1%), syncope (1.6%) and neurotoxicity (1.1%).
• ICANS occurred in 9% of IMDELLTRA-treated patients [see Adverse Reactions (6.1)]. Recurrent ICANS occurred in 1.6% of patients. Most patients experienced ICANS following cycle 2 day 1 (24%). Following Day 1, Day 8, and Day 15 infusions, 0.5%, 0.5% and 3.7% of patients experienced ≥ Grade 2 ICANS, respectively. The median time to onset of ICANS from the first dose of IMDELLTRA was 29.5 days (range: 1 to 154 days). ICANS can occur several weeks following administration of IMDELLTRA. The median time to resolution of ICANS was 33 days (range: 1 to 93 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, in the event of any neurologic symptoms until they resolve.
• Closely monitor patients for signs and symptoms of neurologic toxicity and ICANS during treatment. At the first sign of ICANS, immediately evaluate the patient and provide supportive therapy based on severity. Withhold IMDELLTRA or permanently discontinue based on severity [see Dosage and Administration (2.5)].