DRUG INTERACTIONS- (summary)

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

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 .

U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 9

Name of the Drug-    SARCLISA

Active Ingredient -   Isatuximab

Pharmacological Classification- To treat multiple myloma                                                                                                                                                                                               

 Date of Approval-          Mar 2020     

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.

 • See Full Prescribing Information for instructions on preparation and administration.

DOSAGE FORMS AND STRENGTHS-

­ Injection: • 100 mg/5 mL (20 mg/mL) solution in single-dose vial (3) • 500 mg/25 mL (20 mg/mL) solution in single-dose vial

(3) ---------------------------CONTRAINDICATIONS---------------------------------­ Patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Infusion-Related Reactions: Interrupt SARCLISA and manage medically. Permanently discontinue for grade =3 reactions. (5.1)

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.

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.

 • See Full Prescribing Information for instructions on preparation and administration.

DOSAGE FORMS AND STRENGTHS-

­ Injection: • 100 mg/5 mL (20 mg/mL) solution in single-dose vial (3) • 500 mg/25 mL (20 mg/mL) solution in single-dose vial

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reaction-                                                                               

 Instruct patients to immediately report any occurrence of symptoms occurring within 24 hours of start of infusion to their healthcare provider

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.

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.

 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

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

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.

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

CLINICAL PHARMACOLOGY

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).

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.

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%).

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.

8 USE IN SPECIFIC POPULATIONS

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 

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.

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.

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 .

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.

4. Pediatric Use-                                                                                                          Safety and effectiveness in pediatric patients have not been established.

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  10 years and over and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 

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.