Elrexfio

1 INDICATIONS AND USAGE ELREXFIO is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). ELREXFIO is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T‑cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). ( 1 )

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 …

5 WARNINGS AND PRECAUTIONS • Infections : Can cause severe, life-threatening, or fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. Do not initiate treatment in patients with active infections. ( 5.4 ) • Neutropenia : Monitor complete blood cell counts at baseline and periodically during treatment. ( 5.5 ) • Hepatotoxicity : Can cause elevated ALT, AST, and bilirubin. Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. ( 5.6 ) • Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.7 , 8.1 . 8.3 ) 5.1 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) ] . ELREXFIO is available only through a restricted program under a REMS [see Warnings and Precautions (5.3) ] . 5.2 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 sign…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with ELREXFIO. ELREXFIO causes release of cytokines [see Clinical Pharmacology (12.2) ] that may suppress activity of cytochrome P450 (CYP) enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates is more likely to occur after the first dose of ELREXFIO Day 1 and up to 14 days after the 32 mg dose on Day 4 and during and after CRS [see Warnings and Precautions (5.1) ].

8.1 Pregnancy Risk Summary Based on the mechanism of action, ELREXFIO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of ELREXFIO in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with ELREXFIO. Elranatamab-bcmm causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, elranatamab-bcmm can cause B-cell lymphocytopenia in infants exposed to elranatamab-bcmm in-utero. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, elranatamab-bcmm has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. ELREXFIO is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with ELREXFIO should be considered. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in labeling: • Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] . • Neurologic Toxicity, Including ICANS [see Warnings and Precautions (5.2) ] . • Infections [see Warnings and Precautions (5.4) ] . • Neutropenia [see Warnings and Precautions (5.5) ] . • Hepatotoxicity [see Warnings and Precautions (5.6) ] . Most common adverse reactions (incidence ≥20%) are CRS, fatigue, injection site reaction, diarrhea, upper respiratory tract infection, musculoskeletal pain, pneumonia, decreased appetite, rash, cough, nausea, and pyrexia. The most common Grade 3 to 4 laboratory abnormalities (≥30%) are decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased white blood cells, and decreased platelets. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed/Refractory Multiple Myeloma MagnetisMM-3 The safety of ELREXFIO was evaluated in MagnetisMM-3 [see Clinical Studies (14) ]. The safety population described (n = 183) includes patients who received the recommended dosage regimen of 12 mg subcutaneously on Day 1, 32 mg on Day 4, and 76 mg once weekly starting on Day 8. Among patients who received ELREXFIO, 42% were exposed for 6 months or longer and 9% were exposed for one year or longer. The median age of patients who received ELREXFIO was 68 years (range: 36 to 88 years); 48% were female; 61% were White, 10% were Hispanic/Latino, 9% were Asian, and 6% were Black or African American. Serious adverse reactions occurred in 68% of patients who received ELREXFIO at the recommended dosing schedule. Serious adverse reactions in >2% of patients included pneumonia (25%), sepsis (13%), CRS (13%), upper respiratory tract infection (4.4%), acute kidney injury (3.8%), urinary tract infection (3.3%), COVID-19 (3.3%), encephalopathy (3.3%), pyrexia (2.2%), and febrile neutropenia (2.2%). Fatal adverse reactions occurred in 10% of patients including pneumonia (3.3%), sepsis (2.7%), acute respiratory distress syndrome (0.5%), cardio-respiratory arrest (0.5%), cardiogenic shock (0.5%), cardiopulmonary failure (0.5%), COVID-19 (0.5%), failure to thrive (0.5%), and pulmonary embolism (0.5%). Permanent discontinuations of ELREXFIO due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of ELREXFIO in >2% of patients included septic shock (2.2%). Dosage interruptions of ELREXFIO due to an adverse reaction occurred in 73% of patients. Adverse reactions which resulted in dose interruptions of ELREXFIO in >5% of patients included neutropenia, pneumonia, COVID-19, upper respiratory tract infection, thrombocytopenia, and anemia. The most common adverse reactions (≥20%) were CRS, fatigue, injection site reaction, diarrhea, upper respiratory tract infection, musculoskeletal pain, pneumonia, decreased appetite, rash, cough, nausea, and pyrexia. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased white blood cells, and decreased platelets. Table 8 summarizes adverse reactions in MagnetisMM-3. Table 8. Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Multiple Myeloma Who Received ELREXFIO in MagnetisMM-3 Adverse reactions were graded based on CTCAE Version 5.0, with the exception of CRS, which was graded based on the ASTCT 2019 criteria. System Organ Class Preferred Term ELREXFIO N = 183 All Grades (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome 58 0.5 Only grade 3 adverse reactions occurred. Hy…