HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                  SARCLISA safely and effectively.                                                                                   See full prescribing information for SARCLISA. SARCLISA® (isatuximab-irfc) injection, for intravenous use

Initial U.S. Approval: 2020

INDICATIONS AND USAGE

­ 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 two prior therapies including lenalidomide and a proteasome inhibitor. 

DOSAGE AND ADMINISTRATION

­ • Premedicate with dexamethasone, acetaminophen, H2 antagonists, and diphenhydramine. 

• The recommended dose of SARCLISA is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity.

 DOSAGE FORMS AND STRENGTHS

­ Injection: • 100 mg/5 mL (20 mg/mL) solution in single-dose vial                                     • 500 mg/25 mL (20 mg/mL) solution in single-dose vial 

CONTRAINDICATIONS

­ Patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients

WARNINGS AND PRECAUTIONS

­ • Infusion-Related Reactions: Interrupt SARCLISA and manag

ADVERSE REACTIONS

­ The most common adverse reactions (in =20% of patients) were neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, and diarrhea. (6.1) The most common hematology laboratory abnormalities (in =80% of patients) were anemia, neutropenia, lymphopenia, and thrombocytopenia.

CONTRAINDICATIONS

­ Patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients

WARNINGS AND PRECAUTIONS

­ • Infusion-Related Reactions: Interrupt SARCLISA and manage medically. Permanently discontinue for grade =3 reactions.

Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. SARCLISA dose delays and the use of colony-stimulating factor may be required to allow improvement of neutrophil count. 

• Second Primary Malignancies (SPM): Monitor patients for the development of second primary malignancies, as per IMWG guidelines.

 • Laboratory Test Interference: o Interference with Serological Testing (Indirect Antiglobulin Test): Type and screen patients prior to starting treatment. Inform blood banks that a patient has received SARCLISA.

 o Interference with Serum Protein Electrophoresis and Immunofixation Tests: SARCLISA may interfere with the assays used to monitor Mprotein, which may impact the determination of complete response.

 • Embryo-Fetal Toxicity: Can cause fetal harm. 

------------------------------ADVERSE REACTIONS------------------------------­ The most common adverse reactions (in =20% of patients) were neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, and diarrhea. (6.1) The most common hematology laboratory abnormalities (in =80% of patients) were anemia, neutropenia, lymphopenia, and thrombocytopenia. 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.

------------------------USE IN SPECIFIC POPULATIONS----------------------­ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Infusion-Related Reaction Reference ID: 4568826 15 Instruct patients to immediately report any occurrence of symptoms occurring within 24 hours of start of infusion to their healthcare provider [see Warnings and Precautions (5.1)]. Neutropenia Inform patients about the risk of neutropenia and infection during SARCLISA treatment and the importance of reporting immediately any fever or symptoms of infection to their healthcare provider [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Second Primary Malignancies Inform patients of the risk of developing second primary malignancies during treatment with SARCLISA in combination with pomalidomide and low-dose dexamethasone [see Warnings and Precautions (5.3)]. Interference with Laboratory Tests Advise patients to inform healthcare providers and transfusion center personnel that they are treated with SARCLISA in case a red blood cell transfusion is planned [see Warnings and Precautions (5.4) and Drug Interactions (7.1)]. Embryo-Fetal Toxicity Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for at least 5 months after the last dose of SARCLISA [see Use in Specific Populations (8.1, 8.3)]. Advise patients that pomalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Advise patients to report suspected or known pregnancies. Pomalidomide is only available through a REMS program [see Use in Specific Populations (8.1, 8.3)].

Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY U.S. License No. 1752 SARCLISA is a registered trademark of Sanofi ©2020 sanofi-aventis U.S. LLC

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Isatuximab-irfc is an IgG1-derived monoclonal antibody that binds to CD38 expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells. Isatuximab-irfc induces apoptosis of tumor cells and activation of immune effector mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). Isatuximab-irfc inhibits the ADP-ribosyl cyclase activity of CD38. Isatuximab-irfc can activate natural killer (NK) cells in the absence of CD38-positive target tumor cells and suppresses CD38-positive T-regulatory cells. The combination of isatuximab-irfc and pomalidomide enhanced ADCC activity and direct tumor cell killing compared to that of isatuximab-irfc alone in vitro, and enhanced antitumor activity compared to the activity of isatuximab-irfc or pomalidomide alone in a human multiple myeloma xenograft model. 12.2 Pharmacodynamics In multiple myeloma patients treated with SARCLISA combined with pomalidomide and dexamethasone, a decrease in absolute counts of total NK cells (including inflammatory CD16+ low CD56+ bright and cytotoxic CD16+ bright CD56+ dim NK cells) and CD19+ B cells was observed in peripheral blood. Cardiac Electrophysiology Up to 2 times the approved recommended dose, SARCLISA does not prolong the QT interval to any clinically relevant extent. Reference ID: 4568826 11 A relationship between isatuximab-irfc exposure and overall response rate and progression-free survival was observed. No apparent relationship was observed between an increase of isatuximab-irfc exposure and adverse reactions. 12.3 Pharmacokinetics Following the administration of isatuximab-irfc at the recommended dose and schedule, the steady state isatuximab-irfc mean (CV %) predicted maximum plasma concentration (Cmax) was 351 µg/mL (36.0%) and area under the plasma concentration-time curve (AUC) was 72,600 µg·h/mL (51.7%). The median time to reach steady state of isatuximab-irfc was 8 weeks with a 3.1-fold accumulation. 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 Isatuximab-irfc exposure (AUC) at steady state decreases with increasing body weight. 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, race (Caucasian, Black, Asian), renal impairment (eGFR<90 mL/min/1.73 m2 ), and mild hepatic impairment (total bilirubin 1 to 1.5 times upper limit of normal [ULN] or aspartate amino transferase [AST] > ULN). The effect of moderate (total bilirubin >1.5 times to 3 times ULN and any AST) and severe (total bilirubin >3 times ULN and any AST) hepatic impairment on isatuximab-irfc pharmacokinetics is unknown. No dose adjustments are recommended in these specific patient populations.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and genotoxicity studies have not been conducted with isatuximab-irfc. Fertility studies have not been conducted with isatuximab-irfc.

7 In ICARIA-MM, no patients tested positive for antidrug antibodies (ADA). Therefore, the neutralizing ADA status was not determined. Overall, across 6 clinical studies in multiple myeloma (MM) with SARCLISA single agent and combination therapies including ICARIAMM (N=564), the incidence of treatment emergent ADAs was 2.3%. No clinically significant differences in the pharmacokinetics, safety, or efficacy of isatuximab-irfc were observed in patients with ADAs. DRUG INTERACTIONS 7.1 Laboratory Test Interference Interference with Serological Testing SARCLISA, an anti-CD38 antibody, may interfere with blood bank serologic tests with false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches in patients treated with SARCLISA [see Warnings and Precautions (5.4)]. Interference with Serum Protein Electrophoresis and Immunofixation Tests SARCLISA may be incidentally detected by serum protein electrophoresis and immunofixation assays used for the monitoring of M-protein and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary SARCLISA can cause fetal harm when administered to a pregnant woman. The assessment of isatuximab-irfc-associated risks is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on SARCLISA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction toxicity studies have not been conducted with isatuximab-irfc. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. 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. The combination of SARCLISA and pomalidomide is contraindicated in pregnant women because pomalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide prescribing information on use during pregnancy. Pomalidomide is only available through a REMS program. Clinical Considerations Fetal/neonatal reactions Immunoglobulin G1 monoclonal antibodies are known to cross the placenta. Based on its mechanism of action, SARCLISA may cause depletion of fetal CD38-positive immune cells and Reference ID: 4568826 9 decreased bone density. Defer administration of live vaccines to neonates and infants exposed to SARCLISA in utero until a hematology evaluation is completed. Data Animal Data Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density which recovered 5 months after birth. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in regulating humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs). 8.2 Lactation Risk Summary There are no available data on the presence of isatuximab-irfc in human milk, milk production, or the effects on the breastfed child. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to SARCLISA are unknown. Because of the potential for serious adverse reactions in the breastfed child from isatuximab-irfc administered in combination with pomalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with SARCLISA. Refer to pomalidomide prescribing information for additional information. 8.3 Females and Males of Reproductive Potential Pregnancy Testing With the combination of SARCLISA with pomalidomide, refer to the pomalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. Contraception Females SARCLISA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of SARCLISA. Additionally, refer to the pomalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential. Males Refer to the pomalidomide prescribing information. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of SARCLISA, 53% (306 patients) were 65 and over, while 14% (82 patients) were 75 and over. No overall differences in safety or effectiveness were observed between subjects 65 and over and younger subjects, and other reported clinical experience has not identified differences in responses between the adults 65 Reference ID: 4568826 10 years and over and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 10 OVERDOSAGE There is no known specific antidote for SARCLISA overdose. In the event of overdose of SARCLISA, monitor the patients for signs or symptoms of adverse effects and take all appropriate measures immediately. 11 DESCRIPTION Isatuximab-irfc, a CD38-directed cytolytic antibody, is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody (mAb). Isatuximab-irfc is produced from a mammalian cell line (Chinese hamster ovary, CHO) using a fed-batch production process. Isatuximab-irfc is composed of two identical immunoglobulin kappa lig