Cytokine Release Syndrome and Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Cytokine Release Syndrome (CRS) 

• ELREXFIO can cause CRS, including life-threatening or fatal reactions [see Adverse Reactions (6.1)].
• In the clinical trial, CRS occurred in 58% of patients who received ELREXFIO at the recommended dosing schedule [see Dosage and Administration (2.2)], with Grade 1 CRS in 44% of patients, Grade 2 CRS in 14% of patients, and Grade 3 CRS in 0.5% of patients. Recurrent CRS occurred in 13% of patients. Most patients experienced CRS after the first step-up dose (43%) or the second step-up dose (19%), with 7% of patients having CRS after the first treatment dose and 1.6% of patients after a subsequent dose. The median time to onset of CRS was 2 (range: 1 to 9) days after the most recent dose, with a median duration of 2 (range: 1 to 19) days.
• Clinical signs and symptoms of CRS may include, but are not limited to, fever, hypoxia, chills, hypotension, tachycardia, headache, and elevated liver enzymes.
• Initiate therapy according to the ELREXFIO step-up dosing schedule to reduce risk of CRS and monitor patients following administration of ELREXFIO accordingly [see Dosage and Administration (2.2, 2.5)]. Administer pre-treatment medications prior to each dose in the step-up dosing schedule to reduce risk of CRS [see Dosage and Administration (2.3)]
• Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, evaluate patients immediately for hospitalization. Manage CRS according to the recommendations and consider further management per current practice guidelines. Withhold or permanently discontinue ELREXFIO based on severity [see Dosage and Administration (2.5)].

Neurologic Toxicity, Including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

• ELREXFIO can cause serious or life-threatening neurologic toxicity, including ICANS [see Adverse Reactions (6.1)].
• In the clinical trial, neurologic toxicity occurred in 59% of patients who received ELREXFIO at the recommended dosing schedule [see Dosage and Administration (2.2)], with Grade 3 or 4 neurologic toxicity occurring in 7% of patients. Neurologic toxicities included headache (18%), encephalopathy (15%), motor dysfunction (13%), sensory neuropathy (13%), and Guillain-Barré Syndrome (0.5%).
• In the clinical trial, ICANS occurred in 3.3% of patients who received ELREXFIO at the recommended dosing schedule [see Dosage and Administration (2.2)]. Most patients had ICANS after the first step-up dose (2.7%), 1 (0.5%) patient had ICANS after the second step-up dose and 1 (0.5%) patient had ICANS after subsequent dose(s). Recurrent ICANS occurred in 1.1% of patients. The median time to onset was 3 (range: 1 to 4) days after the most recent dose, with a median duration of 2 (range: 1 to 18) days. The most frequent clinical manifestations of ICANS included a depressed level of consciousness and Grade 1 or Grade 2 Immune Effector Cell-Associated Encephalopathy (ICE) scores. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
• Counsel patients to seek medical attention should signs or symptoms of neurologic toxicity occur. Monitor patients for signs and symptoms of neurologic toxicities during treatment with ELREXFIO. At the first sign of neurologic toxicity, including ICANS, evaluate and treat patients immediately based on severity. Withhold or permanently discontinue ELREXFIO based on severity per recommendations [see Dosage and Administration (2.5)] and consider further management per current practice guidelines.
• Due to the potential for neurologic toxicity including ICANS, patients receiving ELREXFIO are at risk of depressed level of consciousness. Advise patients not to drive or operate heavy or potentially dangerous machinery for 48 hours after completing each of the 2 step-up doses and the first treatment dose within the ELREXFIO step-up dosing schedule and in the event of new onset of any neurological toxicity symptoms until symptoms resolve [see Dosage and Administration (2.2)].