Sarclisa Drug Information

SARCLISA ESCENA is indicated: in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 1 prior line of therapy 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).

Important Dosage Information SARCLISA ESCENA and intravenous isatuximab-irfc have different dosage and administration instructions. SARCLISA ESCENA is for subcutaneous use only. Check the product label to ensure that the correct formulation (SARCLISA ESCENA or intravenous isatuximab-irfc) is being prescribed and administered.

Recommended Dosage

Administer premedications before SARCLISA ESCENA administration. SARCLISA ESCENA should be administered by a health care professional. Patients currently receiving intravenous isatuximab-irfc may transition to SARCLISA ESCENA solution for injection after the completion of the first cycle.

The recommended dose of SARCLISA ESCENA is 1,400 mg administered as a subcutaneous injection with the CirCLIQ On-Body Delivery System (OBDS) or with a syringe and infusion set for manual administration, in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone, or in combination with bortezomib, lenalidomide, and dexamethasone. SARCLISA ESCENA dosing schedules are provided in Tables 1 and 2. Table 1: SARCLISA ESCENA Dosing Schedule in Combination with Pomalidomide and Dexamethasone or in Combination with Carfilzomib and Dexamethasone Table 2: SARCLISA ESCENA Dosing Schedule in Combination with Bortezomib, Lenalidomide, and Dexamethasone Treatment is repeated until disease progression or unacceptable toxicity.

For dosing instructions of combination agents administered with SARCLISA ESCENA, see Clinical Studies and manufacturer's prescribing information. Missed SARCLISA ESCENA Doses If a planned dose of SARCLISA ESCENA is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval.

Recommended Premedications and Antimicrobial Prophylaxis Recommended Premedications Administer the following premedications 15 to 60 minutes prior to SARCLISA ESCENA administration to reduce the risk and severity of systemic administration reactions: When administered in combination with SARCLISA ESCENA and pomalidomide: Dexamethasone 40 mg orally or intravenously (or 20 mg orally or intravenously for patients 75 years of age or older). When administered in combination with SARCLISA ESCENA, bortezomib, and lenalidomide: Dexamethasone 20 mg orally. Leukotriene receptor antagonist, at cycle 1 only Days Acetaminophen 650 mg to 1,000 mg orally.

Diphenhydramine 25 mg to 50 mg orally or intravenously (or equivalent). The intravenous route of diphenhydramine is preferred for at least the first 4 administrations of SARCLISA ESCENA. The above recommended dose of dexamethasone (orally or intravenously) corresponds to the total dose to be administered before SARCLISA ESCENA administration as part of the premedication and part of the backbone treatment.

If no systemic administration reaction occurs during Cycle 1, assess patient specific factors and consider omitting subsequent premedication during future treatment cycles. Recommended Antimicrobial Prophylaxis Initiate antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) if needed based on standard guidelines.

Dosage Modifications for Adverse Reactions

No dose reduction of SARCLISA ESCENA is recommended. Dose delay or omission may be required.

• Preparation SARCLISA ESCENA is only for abdominal subcutaneous administration using: CirCLIQ On-Body Delivery System (OBDS ) OR 20 mL syringe and infusion set (manual administration using commercially available syringe and infusion set). SARCLISA ESCENA should be administered by a healthcare provider. To prevent medication errors, check SARCLISA ESCENA vial label to ensure it is the correct medication for subcutaneous use (vial with green cap). Do not administer SARCLISA ESCENA intravenously. SARCLISA ESCENA is ready to use and should not be diluted. Prepare and administer SARCLISA ESCENA subcutaneously using clean technique. Prior to use‚ allow SARCLISA ESCENA to reach ambient temperature between 18°C to 28°C (64°F to 82°F) for approximately 20 minutes. Keep the unpunctured vial in the original carton prior to use to protect from light. Do not heat. Do not shake. Once the vial has been taken out of the refrigerator, it must not be returned to the refrigerator. Unpunctured vials may be stored at ambient temperature between 18°C to 28°C (64°F to 82°F) for a single period of up to 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution may contain a few translucent to white particles. SARCLISA ESCENA should not be used if the solution is cloudy or discolored, or if particles other than those described above are present. Preparation with CirCLIQ On-Body Delivery System Refer to the Instructions for Use for CirCLIQ OBDS provided with the device for full preparation and administration information. Once the vial is punctured, the injection with the CirCLIQ On-Body Injector should be performed as soon as possible. If the injection is not completed within 4 hours, discard the vial and the On-Body Delivery System. Preparation with syringe and infusion set for manual administration Before you begin, collect your supplies: The syringe must be a 20 mL polypropylene syringe with Luer-fitting connector. The transfer needle with filter must be made of 18G stainless steel with 5-micron filter and Luer-fitting connector. The subcutaneous infusion set must have a 23G stainless steel needle for administration and tubing up to 12 inches (30 cm) length made of polyethylene, or polyvinyl chloride (PVC), with a Luer-fitting connector. Check the expiration date. Remove green vial cap and wipe vial rubber stopper with an alcohol wipe and allow to air dry. Attach the transfer needle with 5-micron filter to the syringe and fill the syringe. Withdraw the full content of the SARCLISA ESCENA vial into a 20 mL compatible syringe. Note: if the syringe containing SARCLISA ESCENA is not used immediately: Remove the transfer needle with filter. Attach a syringe closing cap to the syringe. Label the syringe with the SARCLISA ESCENA peel-off label provided in the vial carton and as per institutional standards. Store it for up to 4 hours at room temperature between 15°C to 25°C (59°F to 77°F) and ambient light, including the administration time. Discard after 4 hours, if not used. Attach the subcutaneous infusion set to the syringe. Note: To avoid needle clogging, attach the subcutaneous infusion set to the syringe immediately prior to injection.

Administration On the days when both SARCLISA ESCENA and carfilzomib are administered, administer dexamethasone first, followed by SARCLISA ESCENA administration, then followed by carfilzomib infusion. Data are only available with an injection performed into the abdomen. Change (rotate) the site of each subcutaneous administration – at least 1 inch (2.5 cm) from previous injection site - with every injection to avoid accumulation of fatty tissue.

Do not inject other medications in the area where SARCLISA ESCENA is injected. Do not inject into areas where the skin is injured, tender, red, hot, has scars, or is excessively hairy. Administration with syringe and infusion set for manual administration Prepare injection site and insert needle.

Wipe injection site with an alcohol swab and allow it to dry. Avoid injecting within 2 inches (5 cm) around the belly button. Remove protective needle cover.

Pinch skin at the injection site on the abdomen. It is important to pinch enough skin to inject under the skin and not into the muscle. Insert needle at a 45-degree angle with a quick, dart-like motion.

Note: Try to limit needle and syringe movement during the injection. If needed, secure the subcutaneous infusion set in place with a bandage. Inject 10 mL of SARCLISA ESCENA subcutaneously into the abdomen, over approximately 6 minutes.

Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

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 (SARCLISA ESCENA-Pd versus intravenous isatuximab-irfc-Pd) IRAKLIA The safety of SARCLISA ESCENA was evaluated in IRAKLIA, a randomized, open-label phase 3 clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA ESCENA 1,400 mg administered subcutaneously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (SARCLISA ESCENA-Pd, n=263) or isatuximab-irfc administered intravenously in combination with pomalidomide and dexamethasone (intravenous isatuximab-irfc-Pd, n=264).

The median duration of the injection with OBDS was 13 minutes. Serious adverse reactions occurred in 53% of patients receiving SARCLISA ESCENA-Pd. Serious adverse reactions in ≥5% of patients who received SARCLISA ESCENA-Pd included pneumonia (20.5%).

Permanent treatment discontinuation due to an adverse reaction occurred in 8% of patients who received SARCLISA ESCENA-Pd. Adverse reactions which resulted in permanent discontinuation of SARCLISA ESCENA-Pd in more than 1 patient included pneumonia, death, COVID-19, sepsis, anemia, and neutrophil count decreased. The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, pneumonia, musculoskeletal pain, and diarrhea.

The most common hematology laboratory abnormalities (≥40%) were decreased leukocytes, decreased neutrophils, decreased lymphocytes, decreased platelets, and decreased hemoglobin. Table 3 summarizes the adverse reactions in IRAKLIA. Table 4: Laboratory Abnormalities That Worsened (≥30%) From Baseline in Patients Who Received SARCLISA ESCENA-Pd versus Intravenous Isatuximab-irfc-Pd in IRAKLIA 0 Combination treatment with carfilzomib and dexamethasone (SARCLISA ESCENA-Kd) IZALCO The safety of SARCLISA ESCENA was evaluated in IZALCO, a randomized, open-label phase 2 clinical trial in patients with previously treated multiple myeloma.

In IZALCO, patients received SARCLISA ESCENA 1,400 mg subcutaneously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (SARCLISA ESCENA-Kd) (n=74). SARCLISA ESCENA was administered either by CirCLIQ OBDS or by manual administration. Serious adverse reactions occurred in 41% of patients receiving SARCLISA ESCENA-Kd.

Adverse reactions which resulted in permanent discontinuation of SARCLISA ESCENA-Kd in 1 patient each included lower respiratory tract infection, meningitis, acute pulmonary edema, acute respiratory distress syndrome, erythema multiforme, and death. Table 5 summarizes the adverse reactions in IZALCO. Table 5: Adverse Reactions (≥10%) in Patients Who Received SARCLISA ESCENA-Kd in IZALCO Clinically relevant adverse reactions in <10% of patients who received SARCLISA ESCENA in combination with carfilzomib and dexamethasone included cardiac failure.

Table 6 summarizes the laboratory abnormalities in IZALCO. Table 6: Laboratory Abnormalities That Worsened (≥30%) From Baseline in Patients Who Received SARCLISA ESCENA-Kd in IZALCO Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant Combination treatment with bortezomib, lenalidomide, and dexamethasone (SARCLISA ESCENA-VRd) IsaSoCut The safety of SARCLISA ESCENA was evaluated in IsaSoCut, a multicenter, open-label single-arm, phase 2 clinical trial in patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation. Patients received SARCLISA ESCENA 1,400 mg administered subcutaneously with CirCLIQ OBDS in combination with bortezomib, lenalidomide, and dexamethasone (SARCLISA ESCENA-VRd).

Serious adverse reactions occurred in 45% of patients who received SARCLISA ESCENA-VRd. Serious adverse reactions >5% of patients included pneumonia (8%). Fatal adverse reactions occurred in 2.7% of patients who received SARCLISA ESCENA-VRd, including cardio-respiratory arrest (1.4%) and myocardial infarction (1.4%).

Permanent treatment discontinuation due to an adverse reaction occurred in 4.1% of patients who received SARCLISA ESCENA-VRd. Adverse reactions which resulted in permanent discontinuation of SARCLISA ESCENA-VRd in 1 patient each included pyelonephritis, cardio-respiratory arrest, and myocardial infarction. The most common adverse reactions (≥20%) were peripheral neuropathy, constipation, diarrhea, fatigue, musculoskeletal pain, upper respiratory tract infections, injection site reaction, insomnia, edema, rash, and erythema.

Table 7 summarizes the adverse reactions in IsaSoCut. Table 7: Adverse Reactions (≥10%) in Patients Who Received SARCLISA ESCENA-VRd in IsaSoCut 0 Clinically relevant adverse reactions in <10% of patients who received SARCLISA ESCENA in combination with bortezomib, lenalidomide, and dexamethasone included systemic administration reactions. Table 8 summarizes the laboratory abnormalities in IsaSoCut.

Table 8: Laboratory Abnormalities That Worsened (≥30%) From Baseline in Patients Who Received SARCLISA ESCENA-VRd in IsaSoCut 0

Laboratory Test Interference Interference with Serological Testing Isatuximab-irfc, 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 isatuximab-irfc. Interference with Serum Protein Electrophoresis and Immunofixation Tests Isatuximab-irfc 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. Because of this interference, Hydrashift assay was routinely used in IRAKLIA and IZALCO clinical studies for efficacy assessment to determine the complete response in patients with IgG kappa myeloma protein.

In patients with persistent very good partial response, where interference is suspected, consider using an FDA-cleared isatuximab-irfc-specific IFE assay to distinguish isatuximab-irfc from any remaining endogenous M-protein in the patient's serum to facilitate determination of a complete response.

Pregnancy Risk Summary Based on its mechanism of action, SARCLISA ESCENA can cause fetal harm when administered to a pregnant woman. There are no available data on SARCLISA ESCENA use in pregnant women to evaluate for a drug-associated risk. The assessment of isatuximab-irfc-associated risks is based on its mechanism of action and data from target antigen CD38 knockout animal models (see Data ).

No animal reproduction studies were conducted with isatuximab-irfc. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

The combination of SARCLISA ESCENA and pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide and lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy. Pomalidomide and lenalidomide are only available through a REMS program.

Clinical Considerations Fetal/neonatal adverse reactions Immunoglobulin G1 monoclonal antibodies are known to cross the placenta. Based on its mechanism of action, SARCLISA ESCENA may cause depletion of fetal CD38-positive immune cells and decreased bone density. Defer administration of live vaccines to neonates and infants exposed to SARCLISA ESCENA 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).

Pediatric Use The safety and effectiveness of SARCLISA ESCENA in pediatric patients have not been established.

SARCLISA ESCENA is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients.