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

Cytokine Release Syndrome (CRS)

LYNOZYFIC can cause cytokine release syndrome (CRS), which can be serious or lifethreatening.

In LINKER-MM1, CRS occurred in 46% (54/117) of patients who received LYNOZYFIC at the recommended dose, with Grade 1 CRS occurring in 35% (41/117) of patients, Grade 2 in 10% (12/117), and Grade 3 in 0.9% (1/117) [see Adverse Reactions (6.1)]. Thirty-eight percent (45/117) of patients had CRS following step-up dose 1, including 1 patient who experienced Grade 3 CRS; 8% (9/117) had an initial CRS event following a subsequent dose. Seventeen percent (19/113) of patients developed CRS after step-up dose 2, 10% (11/111) developed CRS after the first full 200 mg dose of LYNOZYFIC, and 3.6% (4/110) developed CRS after the second full dose. Recurrent CRS occurred in 20% (23/117) of patients. The median time to onset of CRS from the end of infusion was 11 (range: -1 to 184) hours after the most recent dose with a median duration of 15 (range: 1 to 76) hours.

Clinical signs and symptoms of CRS included, but were not limited to pyrexia, chills, hypoxia, tachycardia, and hypotension.

Administer pretreatment medications and initiate therapy according to LYNOZYFIC step-up dosing to reduce the incidence and severity of CRS [see Dosage and Administration (2.2) and Dosage and Administration (2.3)].

Monitor patients for signs and symptoms of CRS after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur.

At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold LYNOZYFIC until CRS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity [see Dosage and Administration (2.5)].

Infusion Related Reactions

Infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medications [see Dosage and Administration (2.2) and Dosage and Administration (2.3)], the rate of IRR was 9% [11/117 including Grade 2 IRR (4.3%) and Grade 3 IRR (1.7%)]. For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction [see Dosage and Administration (2.5)].

LYNOZYFIC is available only through a restricted program under a REMS [see

Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome

LYNOZYFIC can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1)].

In LINKER-MM1, neurologic toxicity occurred in 54% of patients, with Grade 3 or 4 neurologic toxicity occurring in 8%, at the recommended dose [see Adverse Reactions (6.1)]. Neurologic toxicities included ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy. ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6%. Most patients experienced ICANS following step-up dose 1 (5%). Two patients (1.8%) experienced initial ICANS following step-up dose 2 and one patient developed the first occurrence of ICANS following a subsequent full dose of LYNOZYFIC. Recurrent ICANS occurred in one patient. The median time to onset of ICANS was 1 (range: 1 to 4) day after the most recent dose with a median duration of 2 (range: 1 to 11) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

The most common clinical signs and symptoms of ICANS are confusion, depressed level of consciousness, and lethargy. Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient; provide supportive therapy and consider further management per current practice guidelines. Withhold LYNOZYFIC until ICANS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity [see Dosage and Administration (2.5)]. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time.

Due to the potential for neurologic toxicity, including ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness. Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 48 hours after completion of each of the step-up doses [see Dosage and Administration (2.2)] and in the event of new onset of any neurological symptoms, until symptoms resolve.

LYNOZYFIC is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].