Standard Dose
2 DOSAGE AND ADMINISTRATION ELREXFIO Dosing Schedule ( 2.2 ) Dosing Schedule Day ELREXFIO Dose Step-up Dosing Schedule Day 1 Step-up dose 1 12 mg Day 4 Step-up dose 2 32 mg Day 8 First treatment dose 76 mg Weekly Dosing Schedule One week after first treatment dose and weekly thereafter through week 24 Subsequent treatment doses 76 mg Biweekly (Every 2 Week) Dosing Schedule Responders only week 25 onward. Week 25 and every 2 weeks thereafter through week 48 Subsequent treatment doses 76 mg Every 4 Week Dosing Schedule In patients who have maintained the response following 24 weeks of treatment at the biweekly dosing schedule. Week 49 and every 4 weeks thereafter Subsequent treatment doses 76 mg • Patients should be hospitalized for 48 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose. ( 2.1 ) • For subcutaneous injection only. ( 2.2 ) • Administer pre-treatment medications as recommended. ( 2.3 ) • See Full Prescribing Information for instructions on preparation and administration. ( 2.6 ) 2.1 Important Dosing Information Administer ELREXFIO subcutaneously according to the step-up dosing schedule to reduce the incidence and severity of cytokine release syndrome (CRS). Administer pre-treatment medications prior to each dose in the ELREXFIO step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose as recommended [see Dosage and Administration (2.2 , 2.3 )] . ELREXFIO should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 , 5.2 )] . Due to the risk of CRS, patients should be hospitalized for 48 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose. 2.2 Recommended Dosage For subcutaneous injection only. The recommended dosing schedule for ELREXFIO is provided in Table 1. The recommended dosages of ELREXFIO subcutaneous injection are: step-up dose 1 of 12 mg on Day 1, step-up dose 2 of 32 mg on Day 4, followed by the first treatment dose of 76 mg on Day 8, and then 76 mg weekly thereafter through week 24. For patients who have received at least 24 weeks of treatment with ELREXFIO and have achieved a response [partial response (PR) or better] and maintained this response for at least 2 months, the dose interval should transition to an every two-week schedule. For patients who have received at least 24 weeks of treatment with ELREXFIO at the every two-week dosing schedule and have maintained the response, the dose interval should transition to an every four-week schedule. Continue treatment with ELREXFIO until disease progression or unacceptable toxicity. Administer pre-treatment medications prior to each dose in the ELREXFIO step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose as recommended [see Dosage and Administration (2.3) ] . Table 1. ELREXFIO Dosing Schedule Note: See Table 2 for recommendations on restarting ELREXFIO after dose delays. Dosing Schedule Day ELREXFIO Dose Step-up Dosing Schedule Day 1 Administer pre-treatment medications prior to each dose in the ELREXFIO step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose [see Dosage and Administration (2.3) ] . Step-up dose 1 12 mg Day 4 A minimum of 2 days should be maintained between step-up dose 1 (12 mg) and step-up dose 2 (32 mg). Step-up dose 2 32 mg Day 8 A minimum of 3 days should be maintained between step-up dose 2 (32 mg) and the first treatment (76 mg) dose. First treatment dose 76 mg Weekly Dosing Schedule One week after first treatment dose and weekly thereafter A minimum of 6 days should be maintained between treatment doses. through week 24 Subsequent treatment doses 76 mg Biweekly (Every 2 Week) Dosing Schedule *Responders only week 25 onward Week 25 and every 2 weeks thereafter through week 48 Subsequent treatment doses 76 mg Every 4 Week Dosing Schedule *In patients who have maintained the response following 24 weeks of treatment at the biweekly dosing schedule Week 49 and every 4 weeks thereafter Subsequent treatment doses 76 mg 2.3 Recommended Pre-treatment Medications Administer the following pre-treatment medications approximately 1 hour before the first three doses of ELREXFIO in the step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose as described in Table 1 to reduce the risk of CRS [see Warnings and Precautions (5.1) ] : • acetaminophen (or equivalent) 650 mg orally • dexamethasone (or equivalent) 20 mg orally or intravenously • diphenhydramine (or equivalent) 25 mg orally 2.4 Restarting ELREXFIO After Dosage Delay If a dose of ELREXFIO is delayed, restart therapy based on the recommendations listed in Table 2 and resume the dosing schedule accordingly [see Dosage and Administration (2.2) ] . Administer pre-treatment medications as indicated in Table 2. Table 2. Recommendation for Restarting Therapy with ELREXFIO After Dosage Delay Last Dose Administered Time Since the Last Dose Administered Action for Next Dose Step-up dose 1 (12 mg) 2 weeks or less (≤14 days) Restart ELREXFIO at step-up dose 2 (32 mg). Administer pre-treatment medications prior to the ELREXFIO dose [see Dosage and Administration (2.3) ] . If tolerated, increase to 76 mg 4 days later. Greater than 2 weeks (>14 days) Restart ELREXFIO step-up dosing schedule at step-up dose 1 (12 mg). Step-up dose 2 (32 mg) 2 weeks or less (≤14 days) Restart ELREXFIO at 76 mg. Greater than 2 weeks to less than or equal to 4 weeks (15 days to ≤28 days) Restart ELREXFIO at step-up dose 2 (32 mg). If tolerated, increase to 76 mg 1 week later. Greater than 4 weeks (>28 days) Restart ELREXFIO step-up dosing schedule at step-up dose 1 (12 mg). Any weekly treatment dose (76 mg) 8 weeks or less (≤ 56 days) Restart ELREXFIO at 76 mg. Greater than 8 weeks to less or equal to 12 weeks (57 days to ≤84 days) Consider benefit-risk of restarting ELREXFIO in patients who require a dose delay of more than 56 days due to an adverse reaction. Restart ELREXFIO at step-up dose 2 (32 mg). If tolerated, increase to 76 mg 1 week later. Greater than 12 weeks (>84 days) Restart ELREXFIO step-up dosing schedule at step-up dose 1 (12 mg). Any biweekly or every-4-week treatment dose (76 mg) 12 weeks or less (≤84 days) Restart ELREXFIO at 76 mg . Greater than 12 weeks (>84 days) Restart ELREXFIO step-up dosing schedule at step-up dose 1 (12 mg). 2.5 Dosage Modifications for Adverse Reactions Dosage reductions of ELREXFIO are not recommended. Dosage delays may be required to manage toxicities related to ELREXFIO [see Warnings and Precautions (5) ] . Recommendations on restarting ELREXFIO after a dose delay are provided in Table 2. See Table 3 and Table 4 for recommended actions for adverse reactions of CRS and ICANS, respectively. See Table 5 for recommended actions for neurologic toxicity excluding ICANS and Table 6 for recommended actions for other adverse reactions following administration of ELREXFIO. Consider further management per current practice guidelines. Management of CRS, Neurologic Toxicity Including ICANS Cytokine Release Syndrome (CRS) Management recommendations for CRS are summarized in Table 3. Identify CRS based on clinical presentation [see Warnings and Precautions (5.1) ] . Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold ELREXFIO until CRS resolves. Manage CRS according to the recommendations in Table 3 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. Table 3. Recommendations for Management of CRS Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading criteria for CRS. Presenting Symptoms Actions Grade 1 Temperature ≥100.4 °F (38 °C) Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anti-cytokine therapy. • Withhold ELREXFIO until CRS resolves. See Table 2 for recommendations on restarting ELREXFIO after dose delays. • Administer pretreatment medications prior to next dose of ELREXFIO. Grade 2 Temperature ≥100.4 °F (38 °C) with either: • Hypotension responsive to fluid and not requiring vasopressors, and/or • Oxygen requirement of low-flow nasal cannula Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min. or blow-by • Withhold ELREXFIO until CRS resolves. • Monitor patients daily for 48 hours following the next dose of ELREXFIO. Instruct patients to remain within proximity of a healthcare facility, and consider hospitalization. • Administer pretreatment medications prior to next dose of ELREXFIO. Grade 3 (First occurrence) Temperature ≥100.4 °F (38 °C) with either: • Hypotension requiring one vasopressor with or without vasopressin, and/or • Oxygen requirement of high-flow nasal cannula , facemask, non-rebreather mask, or Venturi mask • Withhold ELREXFIO until CRS resolves. • Provide supportive therapy, which may include intensive care. • Patients should be hospitalized for 48 hours following the next dose of ELREXFIO. • Administer pretreatment medications prior to next dose of ELREXFIO. Grade 3 (Recurrent) Temperature ≥100.4 °F (38 °C) with either: • Hypotension requiring one vasopressor with or without vasopressin, and/or • Oxygen requirement of high-flow nasal cannula , facemask, non-rebreather mask, or Venturi mask • Permanently discontinue therapy with ELREXFIO. • Provide supportive therapy, which may include intensive care. Grade 4 Temperature ≥100.4 °F (38 °C) with either: • Hypotension requiring multiple vasopressors (excluding vasopressin), and/or • Oxygen requirement of positive pressure (e.g., continuous positive airway pressure [CPAP], bilevel positive airway pressure [BiPAP], intubation, and mechanical ventilation) • Permanently discontinue therapy with ELREXFIO. • Provide supportive therapy, which may include intensive care. Neurologic Toxicity Including ICANS Management recommendations for ICANS and neurologic toxicity are summarized in Table 4 and Table 5. At the first sign of neurologic toxicity, including ICANS, withhold ELREXFIO and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS [see Warnings and Precautions (5.2) ] . Manage ICANS according to the recommendations in Table 4 and consider further management per current practice guidelines. Table 4. Recommendations for Management of ICANS Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading criteria for ICANS. Presenting Symptoms Management is determined by the most severe event, not attributable to any other cause. Actions Grade 1 ICE score 7-9 If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. Or depressed level of consciousness Not attributable to any other cause. : awakens spontaneously. • Withhold ELREXFIO until ICANS resolves. See Table 2 for recommendations on restarting ELREXFIO after dose delays. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medications (e.g., levetiracetam) for seizure prophylaxis. Grade 2 ICE score 3-6 Or depressed level of consciousness : awakens to voice. • Withhold ELREXFIO until ICANS resolves. • Administer dexamethasone All references to dexamethasone administration are dexamethasone or equivalent medications. 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medications (e.g., levetiracetam) for seizure prophylaxis. • Monitor patients daily for 48 hours following the next dose of ELREXFIO. Instruct patients to remain within proximity of a healthcare facility, and consider hospitalization. Grade 3 (First occurrence) ICE score 0-2 or depressed level of consciousness : awakens only to tactile stimulus, or seizures , either: • any clinical seizure, focal or generalized, that resolves rapidly, or • non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local edema on neuroimaging • Withhold ELREXFIO until ICANS resolves. • Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medications (e.g., levetiracetam) for seizure prophylaxis. • Provide supportive therapy, which may include intensive care. • Patients should be hospitalized for 48 hours following the next dose of ELREXFIO. Grade 3 (recurrent) ICE score 0-2 or depressed level of consciousness : awakens only to tactile stimulus, or seizures , either: • any clinical seizure, focal or generalized, that resolves rapidly, or • non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local edema on neuroimaging • Permanently discontinue ELREXFIO. • Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medications (e.g., levetiracetam) for seizure prophylaxis. • Provide supportive therapy, which may include intensive care. Grade 4 ICE score 0 Or, depressed level of consciousness either: • patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or • stupor or coma, or seizures , either: • life-threatening prolonged seizure (>5 minutes), or • repetitive clinical or electrical seizures without return to baseline in between, or motor findings : • deep focal motor weakness such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema , with signs/symptoms such as: • diffuse cerebral edema on neuroimaging, or • decerebrate or decorticate posturing, or • cranial nerve VI palsy, or • papilledema, or • Cushing’s triad • Permanently discontinue ELREXFIO. • Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously for 3 days. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medications (e.g., levetiracetam) for seizure prophylaxis. • Provide supportive therapy, which may include intensive care. Table 5. Recommendations for Management of Neurologic Toxicity, Excluding ICANS Adverse Reaction Severity Actions Neurologic Toxicity (excluding ICANS) Grade 1 • Withhold ELREXFIO until neurologic toxicity symptoms resolve or stabilize. Grade 2 Grade 3 (First occurrence) • Withhold ELREXFIO until neurologic toxicity symptoms improve to Grade 1 or less. • Provide supportive therapy. Grade 3 (Recurrent) Grade 4 • Permanently discontinue ELREXFIO. • Provide supportive therapy, which may include intensive care. Table 6. Recommended Dosage Modifications for Other Adverse Reactions Adverse Reactions Severity Actions Hematologic Adverse Reactions [see Warnings and Precautions (5.5) ] Absolute neutrophil count less than 0.5 x 10 9 /L • Withhold ELREXFIO until absolute neutrophil count is 0.5 x 10 9 /L or higher. See Table 2 for recommendations on restarting ELREXFIO after dose delays. Febrile neutropenia • Withhold ELREXFIO until absolute neutrophil count is 1 x 10 9 /L or higher and fever resolves. Hemoglobin less than 8 g/dL • Withhold ELREXFIO until hemoglobin is 8 g/dL or higher. Platelet count less than 25,000/mcL Platelet count between 25,000/mcL and 50,000/mcL with bleeding • Withhold ELREXFIO until platelet count is 25,000/mcL or higher and no evidence of bleeding. Infections and Other Non-hematologic Adverse Reactions Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0. [see Warnings and Precautions (5.4, 5.6) and Adverse Reactions (6.1) ] Grade 3 • Withhold ELREXFIO until adverse reaction improves to ≤Grade 1 or baseline. Grade 4 • Consider permanent discontinuation of ELREXFIO. • If ELREXFIO is not permanently discontinued, withhold subsequent treatment doses of ELREXFIO (e.g., doses administered after ELREXFIO step-up dosing schedule) until adverse reaction improves to Grade 1 or less. 2.6 Preparation and Administration Instructions ELREXFIO is intended for subcutaneous use by a healthcare provider only. ELREXFIO should be administered by a healthcare provider with adequate medical personnel and appropriate medical equipment to manage severe reactions, including CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 , 5.2 )] . ELREXFIO 76 mg/1.9 mL (40 mg/mL) vial and 44 mg/1.1 mL (40 mg/mL) vial are supplied as ready-to-use solution that do not need dilution prior to administration. ELREXFIO is a clear to slightly opalescent, and colorless to pale brown liquid solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer if solution is discolored or contains particulate matter. Use aseptic technique to prepare and administer ELREXFIO. Preparation ELREXFIO vials are for one-time use in a single patient and do not contain any preservatives. Prepare ELREXFIO following the instructions below (see Table 7 ) depending on the required dose. Table 7. Injection Volumes Total Dose (mg) Volume of Injection 12 mg 0.3 mL 32 mg 0.8 mL 76 mg 1.9 mL Remove the appropriate strength ELREXFIO vial from refrigerated storage [2 °C to 8 °C (36 °F to 46 °F)]. Once removed from refrigerated storage, equilibrate ELREXFIO to ambient temperature [15 °C to 30 °C (59 °F to 86 °F)]. Do not warm ELREXFIO in any other way. Withdraw the required injection volume of ELREXFIO from the vial into an appropriately sized syringe with stainless steel injection needles (30G or wider) and polypropylene or polycarbonate syringe material. Discard unused portion. Administration Inject the required volume of ELREXFIO into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, ELREXFIO may be injected into the subcutaneous tissue at other sites (e.g., thigh). Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact. Storage of Prepared Syringe If the prepared dosing syringe is not used immediately, the syringe may be stored refrigerated between 2 °C to 8 °C (36 °F to 46 °F) for a maximum of 72 hours or between 8 °C to 25 °C (46 °F to 77 °F) for a maximum of 24 hours. Once removed from refrigerated storage, the prepared syringe must be used or discarded.