Isatuximab

1 INDICATIONS AND USAGE SARCLISA is indicated: in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy. in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT). SARCLISA is a CD38-directed cytolytic antibody indicated: in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy. in combination with bortezomib, lenalidomide and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT). ( 1 )

2 DOSAGE AND ADMINISTRATION Premedicate with dexamethasone, acetaminophen, H2 antagonists, and diphenhydramine. ( 2.2 ) The recommended dosage of SARCLISA is 10 mg/kg as an intravenous infusion. See full prescribing information for SARCLISA schedules of administration and drugs used in combination. ( 2.1 ) 2.1 Recommended Dosage Administer pre-infusion medications [see Dosage and Administration (2.2) ] . SARCLISA should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur [see Warnings and Precautions (5.1) ] . The recommended dose of SARCLISA is 10 mg/kg actual body weight administered as an intravenous infusion in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone, or in combination with bortezomib, lenalidomide, and dexamethasone. SARCLISA dosing schedules are provided in Tables 1 and 2 [see Clinical Studies (14) ] . Table 1: SARCLISA Dosing Schedule in Combination with Pomalidomide and Dexamethasone or in Combination with Carfilzomib and Dexamethasone Cycles Dosing schedules Cycle 1 (28-day cycle) Days 1, 8, 15, and 22 (weekly) Cycle 2 and beyond (28-day cycles) Days 1, 15 (every 2 weeks) Table 2: SARCLISA Dosing Schedule in Combination with Bortezomib, Lenalidomide, and Dexamethasone Cycles Dosing schedules Cycle 1 (42-day cycle) Days 1, 8, 15, 22, and 29 Cycles 2 to 4 (42-day cycles) Days 1, 15, and 29 (every 2 weeks) Cycles 5 to 17 (28-day cycles) Days 1 and 15 (every 2 weeks) Cycles 18 and beyond (28-day cycles) Day 1 (every 4 weeks) Treatment is repeated until disease progression or unacceptable toxicity. SARCLISA is used in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone or in combination with bortezomib, lenalidomide, and dexamethasone. For dosing instructions of combination agents administered with SARCLISA, see Clinical Studies (14) and manufacturer's prescribing information. Missed SARCLISA Doses If a planned dose of SARCLISA is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval. 2.2 Recommended Premedications and Antimicrobial Prophylaxis Recommended Premedications Administer the following premedications prior to SARCLISA infusion to reduce the risk and severity of infusion-related reactions [see Warnings and Precautions (5.1) ] : When administered in combination with SARCLISA and pomalidomide: Dexamethasone 40 mg orally or intravenously (or 20 mg orally or intravenously for patients ≥75 years of age). When administered in combination with SARCLISA and carfilzomib: Dexamethasone 20 mg (intravenously on the days of SARCLISA and/or carfilzomib infusions, orally on day 22 in cycle 2 and beyond, and orally on day 23 in all cycles). When administered in combination with SARCLISA, bortezomib, and lenalidomide: Dexamethasone 20 mg (intravenously on the days of SARCLISA infusions, orally on the other days). Acetaminophen 650 mg to 1,000 mg orally (or equivalent). H2 antagonist Diphenhydramine 25 mg to 50 mg orally or intravenously (or equivalent). The intravenous route is preferred for at least the first 4 infusions. The above recommended dose of dexamethasone (orally or intravenously) corresponds to the dose to be administered before infusion as part of the premedication and part of the backbone treatment. Administer dexamethasone before SARCLISA and pomalidomide, before SARCLISA and carfilzomib, and before SARCLISA, bortezomib, and lenalidomide administration. Administer the recommended premedication agents 15 to 60 minutes prior to starting a SARCLISA infusion. Recommended Antimicrobial Prophylaxis Initiate antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) if needed based on standard guidelines [see Warnings and Precautions (5.2) ] . 2.3 Dosage Modifications No dose reduction of SARCLISA is recommended. Dose delay may be required to allow recovery of blood counts in the event of hematological toxicity [see Warnings and Precautions (5.3 , 5.5) ] . For information concerning drugs given in combination with SARCLISA, see manufacturer's prescribing information. 2.4 Preparation Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg) of required SARCLISA based on actual patient weight (measured prior to each cycle to have the administered dose adjusted accordingly) [see Dosage and Administration (2.1) ] . More than one SARCLISA vial may be necessary to obtain the required dose for the patient. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Remove the volume of diluent from the 250 mL Sodium Chloride Injection, or 5% Dextrose Injection, diluent bag that is equal to the required volume of SARCLISA injection. Withdraw the necessary volume of SARCLISA injection from the vial and dilute by adding to the infusion bag of 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. Discard any unused portion left in the vial. The infusion bag must be made of polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with di-(2-ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate (EVA). Gently homogenize the diluted solution by inverting the bag. Do not shake. 2.5 Administration Administer the infusion solution by intravenous infusion using an intravenous tubing infusion set (in PE, PVC with or without DEHP, polybutadiene [PBD], or polyurethane [PU]) with a 0.22 micron in-line filter (polyethersulfone [PES], polysulfone, or nylon). The infusion solution should be administered for a period of time that will depend on the infusion rate (see Table 3 ). Use prepared SARCLISA infusion solution within 48 hours when stored refrigerated at 2°C to 8°C, followed by 8 hours (including the infusion time) at room temperature. Do not administer SARCLISA infusion solution concomitantly in the same intravenous line with other agents. On the days where both SARCLISA and carfilzomib are administered, administer dexamethasone first, followed by SARCLISA infusion, then followed by carfilzomib infusion. Infusion Rates Following dilution, administer the SARCLISA infusion solution intravenously at the infusion rates presented in Table 3. Incremental escalation of the infusion rate should be considered only in the absence of infusion-related reactions [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Table 3: Infusion Rates of SARCLISA Administration Dilution Volume Initial Rate Absence of Infusion-Related Reaction Rate Increment Maximum Rate First infusion 250 mL 25 mL/hour For 60 minutes 25 mL/hour every 30 minutes 150 mL/hour Second infusion 250 mL 50 mL/hour For 30 minutes 50 mL/hour for 30 minutes then increase by 100 mL/hour 200 mL/hour Subsequent infusions 250 mL 200 mL/hour – – 200 mL/hour

6 ADVERSE REACTIONS The following clinically significant adverse reactions from SARCLISA are also described in other sections of the labeling: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Neutropenia [see Warnings and Precautions (5.3) ] Second Primary Malignancies [see Warnings and Precautions (5.4) ] In combination with pomalidomide and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea. The most common hematology laboratory abnormalities (≥80%) are decreased hemoglobin, decreased neutrophils, decreased lymphocytes, and decreased platelets. ( 6.1 ) In combination with carfilzomib and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. The most common hematology laboratory abnormalities (≥80%) are decreased hemoglobin, decreased lymphocytes, and decreased platelets. ( 6.1 ) In combination with bortezomib, lenalidomide and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) are decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 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 and/or Refractory Multiple Myeloma Combination treatment with pomalidomide and dexamethasone (Isa-Pd) The safety of SARCLISA was evaluated in ICARIA-MM, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (Isa-Pd) (n=152) or pomalidomide and dexamethasone (Pd) (n=149) [see Clinical Studies (14) ] . Among patients receiving Isa-Pd, 66% were exposed to SARCLISA for 6 months or longer and 24% were exposed for greater than 12 months or longer. Serious adverse reactions occurred in 62% of patients receiving Isa-Pd. Serious adverse reactions in >5% of patients who received Isa-Pd included pneumonia (26%), upper respiratory tract infections (7%), and febrile neutropenia (7%). Fatal adverse reactions occurred in 11% of patients (those that occurred in more than 1% of patients were pneumonia and other infections [3%]). Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 7% of patients who received Isa-Pd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Pd were infections (2.6%). SARCLISA alone was discontinued in 3% of patients due to infusion-related reactions. Dosage interruptions due to an adverse reaction occurred in 31% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (28%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea. Table 4 summarizes the adverse reactions in ICARIA-MM. Table 4: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Pomalidomide, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in ICARIA-MM Trial Adverse Reactions SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd) Pomalidomide + Dexamethasone (Pd) (N=152) (N=149) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) CTCAE version 4.03 General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and drug hypersensitivity. 38 1.3 1.3 0 0 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes bronchiolitis, bronchitis, bronchitis viral, chronic sinusitis, fungal pharyngitis, influenza-like illness, laryngitis, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tracheitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 57 9 0 42 3.4 0 Pneumonia Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, candida pneumonia, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal, and pneumocystis jirovecii pneumonia. 31 22 3.3 23 16 2.7 Blood and lymphatic system disorders Febrile neutropenia 12 11 1.3 2 1.3 0.7 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest. 17 5 0 12 1.3 0 Gastrointestinal disorders Diarrhea 26 2 0 19 0.7 0 Nausea 15 0 0 9 0 0 Vomiting 12 1.3 0 3.4 0 0 Table 5 summarizes the hematology laboratory abnormalities in ICARIA-MM. Table 5: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Pd versus Pd in ICARIA-MM Laboratory Parameter SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd) Pomalidomide + Dexamethasone (Pd) (N=152) (N=149) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) The denominator used to calculate the percentages was based on the safety population. Hemoglobin decreased 99 32 0 97 28 0 Neutrophils decreased 96 24 61 92 38 31 Lymphocytes decreased 92 42 13 92 35 8 Platelets decreased 84 14 16 79 9 15 Combination treatment with carfilzomib and dexamethasone (Isa-Kd) The safety of SARCLISA was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (Isa-Kd) (n=177) or carfilzomib and dexamethasone (Kd) (n=122) [see Clinical Studies (14) ] . Among patients receiving Isa-Kd, 68% were exposed to SARCLISA for 12 months or longer and 51% were exposed for greater than 18 months. Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients). Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). SARCLISA alone was discontinued in 0.6% of patients due to infusion-related reactions. Dosage interruptions due to an adverse reaction occurred in 33% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (30%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. Table 6 summarizes the adverse reactions in IKEMA. Table 6: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Carfilzomib, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in IKEMA Adverse Reactions SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd) Carfilzomib + Dexamethasone (Kd) (N=177) (N=122) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. 46 0.6 0 3.3 0 0 Fatigue Fatigue includes fatigue and asthenia. 42 5 0 32 3.3 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. 67 9 0 57 7 0 Pneumonia Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. 36 19 3.4 30 15 2.5 Bronchitis Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis. 24 2.3 0 13 0.8 0 Vascular disorders Hypertension Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. 37 20 0.6 32 18 1.6 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 29 5 0 24 0.8 0 Cough Cough includes cough, productive cough, and allergic cough. 23 0 0 15 0 0 Gastrointestinal disorders Diarrhea 36 2.8 0 29 2.5 0 Vomiting 15 1.1 0 9 0.8 0 Table 7 summarizes the hematology laboratory abnormalities in IKEMA. Table 7: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Kd versus Kd in IKEMA Laboratory Parameter SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd) Carfilzomib + Dexamethasone (Kd) (N=177) (N=122) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) The denominator used to calculate the percentage was based on the safety population. Hemoglobin decreased 99 22 0 99 20 0 Lymphocytes decreased 94 52 17 95 43 14 Platelets decreased 94 19 11 88 16 8 Neutrophils decreased 55 18 1.7 43 7 0.8 Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant Combination treatment with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) The safety of SARCLISA was evaluated in IMROZ, a randomized, open-label clinical trial in patients with newly diagnosed multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously on day 1, 8, 15, 22, and 29 in the first 42-day cycle, followed by every two weeks from cycle 2 to 4 (42-day cycles), followed by every two weeks from cycle 5 to 17 (28-day cycles), and then on day 1 from cycle 18 and onwards (28-day cycles), in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) (n=263) or bortezomib, lenalidomide, and dexamethasone (VRd) (n= 181) [see Clinical Studies (14) ] . In IMROZ, median duration of exposure to treatment was 53 (range: 0.5–69) months in patients treated with Isa-VRd and 31 (range 0.6–67) months in patients treated with VRd. Serious adverse reactions occurred in 71% of patients receiving Isa-VRd. The serious adverse reaction in > 5% of patients who received Isa-VRd was pneumonia (30%). Fatal adverse reactions occurred in 11% of patients with Isa-VRd (those occurring in more than 1% of patients were pneumonia (5%). Permanent discontinuation of treatment due to an adverse reaction occurred in 22.8% of patients treated with Isa-VRd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-VRd were infections (8%). SARCLISA alone was discontinued in 2.3% of patients. Dosage interruptions due to an adverse reaction occurred in 21% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion related reaction (21%). The most common adverse reactions (≥20%) were upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) were decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils. Table 8 summarizes the adverse reactions in IMROZ. Table 8: Adverse Reactions (≥ 20%) in Patients Receiving SARCLISA, Bortezomib, Lenalidomide, and Dexamethasone in IMROZ IMROZ study Adverse Reactions SARCLISA + Bortezomib + Lenalidomide + Dexamethasone (N=263) Bortezomib + Lenalidomide + Dexamethasone (N=181) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Includes other related terms 65 4.6 57 Includes 1 patient (0.6%) with fatal URTI. 6 Pneumonia Pneumonia includes Atypical pneumonia, Bronchopulmonary aspergillosis, COVID-19 pneumonia, Lower respiratory tract infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia influenzal, Pneumonia klebsiella, Pneumonia legionella, Pneumonia parainfluenzae viral, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia viral, Pulmonary sepsis. 45 Includes 14 patients (5%) with fatal pneumonia. 26 31 Includes 4 patients (2.2%) with fatal pneumonia. 19 COVID-19 COVID-19 includes COVID-19 infections other than COVID-19 pneumonia. 22 0.8 17 Includes 2 patients (1.1%) with fatal COVID-19. 1.7 General disorders and administration site conditions Fatigue Fatigue includes Fatigue, Asthenia, or Malaise. 55 11 50 9 Edema peripheral 33 0 33 1.1 Infusion-related reaction 24 0.4 1.1 0 Gastrointestinal disorders Diarrhea 55 8 49 8 Constipation 36 2.3 41 1.7 Nervous system disorders Peripheral sensory neuropathy 54 7 61 6 Eye disorders Cataract 38 16 25 11 Musculoskeletal and connective tissue disorders Musculoskeletal pain 38 4.2 33 3.3 Skin and subcutaneous tissue disorders Rash Rash includes Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis atopic, Dermatitis exfoliative generalized, Drug eruption, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Skin exfoliation, Skin hyperpigmentation, Skin lesion, Skin reaction, and Toxic skin eruption. 32 5 34 5 Psychiatric disorders Insomnia 22 3.8 24 2.2 Table 9 summarizes the hematology laboratory abnormalities in IMROZ. Table 9: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-VRd Versus VRd in IMROZ Laboratory parameter SARCLISA + Bortezomib + Lenalidomide + Dexamethasone The denominator used to calculate the rate is based on the number of patients with a baseline value and at least one post-baseline value. Bortezomib + Lenalidomide + Dexamethasone All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Decreased hemoglobin 99 17 98 16 Decreased leukocytes 97 32 88 17 Decreased lymphocytes 95 60 92 53 Decreased platelets 95 30 85 28 Decreased neutrophils 87 54 80 37 Description of Selected Adverse Reactions Cardiac failure In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary edema) was reported in 7% of patients with the Isa-Kd group (grade ≥3 in 4%) and in 7% of patients with the Kd group (grade ≥3 in 4.1%). Serious cardiac failure was observed in 4% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. See the current prescribing information for carfilzomib for more information.

12.3 Pharmacokinetics Following administration of isatuximab-irfc in combination with pomalidomide and dexamethasone at the recommended dose and schedule, the steady-state mean (CV%) predicted maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) of isatuximab-irfc were 351 µg/mL (36.0%) and 72,600 µg∙h/mL (51.7%), respectively. Following administration of isatuximab-irfc in combination with carfilzomib and dexamethasone at the recommended dose and schedule, the steady state mean (CV%) predicted C max and AUC of isatuximab-irfc were 655 µg/mL (30.8%) and 159,000 µg∙h/mL (37.1%), respectively. The median time to reach steady state of isatuximab-irfc was 18 weeks with a 3.1-fold accumulation. Following administration of isatuximab-irfc in combination with bortezomib, lenalidomide, and dexamethasone at the recommended dose and schedule, the mean (CV%) predicted C max and AUC of isatuximab-irfc after the dose on Week 21 were 496 µg/mL (25.6%) and 120,000 µg∙h/mL (28.9%), respectively. The geometric mean (CV%) of accumulation ratio between steady state AUC and AUC after the dose on Week 21 is predicted to be 1.4 (35.8%). Isatuximab-irfc AUC increases in a greater than dose proportional manner over a dosage range from 1 mg/kg to 20 mg/kg (0.1 to 2 times the approved recommended dosage) every 2 weeks. Isatuximab-irfc AUC increases proportionally over a dosage range from 5 mg/kg to 20 mg/kg (0.5 to 2 times the approved recommended dosage) every week for 4 weeks followed by every 2 weeks. Distribution The mean (CV%) predicted total volume of distribution of isatuximab-irfc is of 8.13 L (26.2%). Metabolism Isatuximab-irfc is expected to be metabolized into small peptides by catabolic pathways. Elimination Isatuximab-irfc total clearance decreased with increasing dose and with multiple doses. At steady state, the near elimination (≥99%) of isatuximab-irfc from plasma after the last dose is predicted to occur in approximately 2 months. The elimination of isatuximab-irfc was similar when given as a single agent or as combination therapy. Specific Populations The following factors have no clinically meaningful effect on the exposure of isatuximab-irfc: age (36 to 85 years, 70 patients were ≥75 years old), sex, renal impairment including patients with End-Stage Renal Disease (ESRD) or on dialysis (eGFR <90 mL/min/1.73 m 2 ), and mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1 to 1.5 × ULN and any AST). The effect of moderate (total bilirubin >1.5 to 3 × ULN and any AST) and severe (total bilirubin >3 × ULN and any AST) hepatic impairment on isatuximab-irfc pharmacokinetics is unknown. No dose adjustments are recommended in these specific patient populations. Body weight The clearance of isatuximab-irfc increased with increasing body weight. Race White (n=377, 79%) or Asian (n=25, 5%) race have no clinically meaningful effect on the exposure of isatuximab-irfc. The effect of Black (n=18, 4%) race on the exposure of isatuximab-irfc is unknown.