Empliciti Drug Information

• EMPLICITI is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.
• EMPLICITI is 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. EMPLICITI is a SLAMF7-directed immunostimulatory 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.

Recommended Dosing when EMPLICITI Is Used in Combination with Lenalidomide and Dexamethasone The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles (28-day cycle) and every 2 weeks thereafter in conjunction with the recommended dosing of lenalidomide and low-dose dexamethasone as described below. Continue treatment until disease progression or unacceptable toxicity. Refer to the dexamethasone and lenalidomide prescribing information for additional information.

Administer premedications before each dose of EMPLICITI. The recommended dosing is presented in Table 1. Table 1: Recommended Dosing Schedule of EMPLICITI in Combination with Lenalidomide and Dexamethasone

Starting at cycle 3 (28-day cycle), administer EMPLICITI 20 mg/kg intravenously every 4 weeks. Administer EMPLICITI in conjunction with pomalidomide and low-dose dexamethasone as described below (Table 2). The recommended dosing is presented in Table 2.

Other Medications In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to EMPLICITI infusion: • H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent H1 blocker. • H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker. • Acetaminophen (650 to 1000 mg orally).

Dose Modifications If the dose of one drug in the regimen is delayed, interrupted, or discontinued, the treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, base the decision whether to administer EMPLICITI on clinical judgment (i.e., risk of hypersensitivity). If a Grade 2 or higher infusion reaction occurs during EMPLICITI administration, interrupt the infusion and institute appropriate medical and supportive measures.

Upon resolution to Grade 1 or lower, restart EMPLICITI at 0.5 mL per minute and gradually increase at a rate of 0.5 mL per minute every 30 minutes as tolerated to the rate at which the infusion reaction occurred. Resume the escalation regimen if there is no recurrence of the infusion reaction (see Table 3 and Table 4). In patients who experience an infusion reaction, monitor vital signs every 30 minutes for 2 hours after the end of the EMPLICITI infusion.

If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment. Dose delays and modifications for dexamethasone, pomalidomide and lenalidomide should be performed as recommended in their Prescribing Information.

Administration Administer the entire

EMPLICITI infusion with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2 to 1.2 micrometer) using an automated infusion pump. Initiate EMPLICITI infusion at a rate of 0.5 mL per minute for 10 mg/kg dose. The infusion rate may be increased in a stepwise fashion as described in Table 3 if no infusion reactions develop.

The maximum infusion rate should not exceed 5 mL per minute. Table 3: Infusion - - Initiate EMPLICITI infusion rate at 3 mL per minute for 20 mg/kg dose. Patients who have escalated to Adjust the infusion rate following a Grade 2 or higher infusion reaction.

Do not mix EMPLICITI with, or administer as an infusion with, other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of EMPLICITI with other agents.

Reconstitution and Preparation Calculation of Dose • Calculate the dose (mg) and determine the number of vials needed for the 10 mg/kg and 20 mg/kg dosage based on patient weight. • Determine the volume of sterile water for injection (SWFI) needed for reconstitution as shown in Table 5. Table 5: Reconstitution Instructions for EMPLICITI Reconstitution • Aseptically reconstitute each EMPLICITI vial with a syringe of adequate size and a less than or equal to 18-gauge needle (e.g., 17-gauge). A slight back pressure may be experienced during administration of the Sterile Water for Injection, USP, which is considered normal. • Hold the vial upright and swirl the solution by rotating the vial to dissolve the lyophilized cake.

Invert the vial a few times in order to dissolve any powder that may be present on top of the vial or the stopper. Avoid vigorous agitation. DO NOT SHAKE.

The lyophilized powder should dissolve in less than 10 minutes. • After the remaining solids are completely dissolved, allow the reconstituted solution to stand for 5 to 10 minutes. The reconstituted preparation results in a colorless to slightly yellow, clear to slightly opalescent solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard the solution if any particulate matter or discoloration is observed. Dilution • Once the reconstitution is completed, withdraw the necessary volume for the calculated dose from each vial, up to a maximum of 16 mL from 400 mg vial and 12 mL from 300 mg vial. • Further dilute with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, into an infusion bag made of polyvinyl chloride or polyolefin. The final infusion concentration should range between 1 mg/mL and 6 mg/mL. • The volume of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP should be adjusted so as not to exceed 5 mL/kg of patient weight at any given dose of EMPLICITI.

Complete the EMPLICITI infusion within 24 hours of reconstitution of the EMPLICITI lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°C to 8°C (36°F-46°F) and protected from light for up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature, 20°C to 25°C, and room light).

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. EMPLICITI in Combination with Lenalidomide and Dexamethasone The safety data described in this section are based on the ELOQUENT-2 study, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In ELOQUENT-2, EMPLICITI 10 mg/kg was administered with lenalidomide and dexamethasone.

For adverse reaction evaluation, EMPLICITI combined with lenalidomide and dexamethasone was compared with lenalidomide and dexamethasone alone. The mean age of the population was 66 years and 57% of patients were 65 years of age or older. The Eastern Cooperative Oncology Group (ECOG) performance status was of patients.

Serious adverse reactions were reported in 65% of patients treated on the EMPLICITI arm and 57% for patients treated on the control arm. The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions as listed below was similar for both treatment arms; 6.0% for patients treated on the EMPLICITI arm and 6.3% for patients treated on the control. Adverse reactions occurring at a frequency of 10% or higher in the EMPLICITI arm and 5% or higher than the lenalidomide and dexamethasone arm for the randomized trial in multiple myeloma are presented in Table 6.

Table 7: ELOQUENT-2: Laboratory Abnormalities Worsening from Baseline and with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 8. Percentages are based on patients who had at least one vital sign abnormality any time during the course of study. In ELOQUENT-3, EMPLICITI 10 mg/kg and 20 mg/kg was administered with pomalidomide and dexamethasone.

Fifty-seven percent of the population were male, 78% were white, 20% were Asian, and none were black. The ECOG performance status was of patients. Serious adverse reactions were reported in 70% of patients treated on the EMPLICITI arm and 60% for patients treated on the control arm.

The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions were 5% of the patients in the EMPLICITI arm and 1.8% of the patients in the control arm. Percentages are based on all treated patients Table

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity to EMPLICITI. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of incidence of antibodies to EMPLICITI in the studies described below with the incidences of antibodies in other studies or to other products may be misleading. Of 390 patients across four clinical studies including ELOQUENT-2 and in 53 patients in the ELOQUENT-3 trial, who were treated with EMPLICITI and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) in the four clinical trials and 19 patients (36%) in the ELOQUENT-3 trial tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay.

Drug Interactions

For important drug interactions involving lenalidomide, pomalidomide and dexamethasone, refer to their respective prescribing information.

Laboratory Test Interference EMPLICITI may be detected in the SPEP and serum immunofixation assays of myeloma patients and could interfere with correct response classification. A small peak in the early gamma region on SPEP that is IgGƙ on serum immunofixation may potentially be attributed to EMPLICITI, particularly in patients whose endogenous myeloma protein is IgA, IgM, IgD, or lambda light chain restricted. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Pregnancy Risk Summary There are no available data on EMPLICITI use in pregnant women to inform a drug associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted with elotuzumab. EMPLICITI is administered in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone.

Lenalidomide and pomalidomide can cause embryo-fetal harm and are contraindicated for use in pregnancy. Refer to the lenalidomide, pomalidomide and dexamethasone prescribing information for additional information. Lenalidomide and pomalidomide are only available through a REMS program.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, 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 2-4% and 15-20%, respectively.

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

The dose of EMPLICITI at which severe toxicity occurs is not known. EMPLICITI does not appear to be removed by dialysis as determined in a study of patients with renal impairment. In case of overdosage, monitor patients closely for signs or symptoms of adverse reactions and institute appropriate symptomatic treatment.