Empliciti Drug Information

• The following clinically significant adverse reactions are described in detail in other sections of the label:
• Infusion reaction [see Warnings and Precautions (5.1) ] .
• Infections [see Warnings and Precautions (5.2) ] .
• Second Primary Malignancies [ see Warnings and Precautions (5.3) ] .
• Hepatotoxicity [see Warnings and Precautions (5.4) ] .
• Interference with determination of complete response [see Warnings and Precautions (5.5) ] . Most common adverse reactions (20% or higher)
• with lenalidomide and dexamethasone are fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia. (6.1)
• with pomalidomide and dexamethasone are constipation and hyperglycemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 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. EMPLICITI in Combination with Lenalidomide and Dexamethasone [ELOQUENT-2] 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 [see Clinical Studies (14) ] . 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. Sixty percent (60%) of the population were male, 84% were white, 10% were Asian, and 4% were black. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients. These data reflect exposure of 318 patients to EMPLICITI and 317 to control with a median number of cycles of 19 for EMPLICITI and 14 for control. Serious adverse reactions were reported in 65% of patients treated on the EMPLICITI arm and 57% for patients treated on the control arm. The most frequent serious adverse reactions in the EMPLICITI arm compared to the control arm were: pneumonia (15% vs. 11%), pyrexia (7% vs. 5%), respiratory tract infection (3.1% vs. 1.3%), anemia (2.8% vs. 1.9%), pulmonary embolism (3.1% vs. 2.5%), and acute renal failure (2.5% vs. 1.9%). 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 6: ELOQUENT-2: Adverse Reactions with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% or Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients [All Grades] EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Primary Term All Grades Grade 3/4 All Grades Grade 3/4 * The term fatigue is a grouping of the following terms: fatigue and asthenia. † The term cough is a grouping of the following terms: cough, productive cough, and upper airway cough. ‡ The term peripheral neuropathy is a grouping of the following terms: peripheral neuropathy, axonal neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. § The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia. Fatigue* 62 13 52 12 Diarrhea 47 5.0 36 4.1 Pyrexia 37 2.5 25 2.8 Constipation 36 1.3 27 0.3 Cough † 34 0.3 19 0 Peripheral Neuropathy ‡ 27 3.8 21 2.2 Nasopharyngitis 25 0 19 0 Upper Respiratory Tract Infection 23 0.6 17 1.3 Decreased Appetite 21 1.6 13 1.3 Pneumonia § 20 14 14 9 Pain in Extremities 16 0.9 10 0.3 Headache 15 0.3 8 0.3 Vomiting 14 0.3 9 0.9 Weight Decreased 14 1.3 6 0 Lymphopenia 13 9 7 3.2 Cataracts 12 6 6 2.8 Oropharyngeal Pain 10 0 4 0 Laboratory abnormalities worsening from baseline and occurring at a frequency of 10% or higher in the EMPLICITI group and 5% or higher than the lenalidomide and dexamethasone group (criteria met for all Grades or Grade 3/4) for ELOQUENT-2 are presented in Table 7. 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 [Criteria met for All Grades or Grade 3/4] EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Laboratory Parameter All Grades Grade 3/4 All Grades Grade 3/4 Hematology Lymphopenia 99 77 98 49 Leukopenia 91 32 88 26 Thrombocytopenia 84 19 78 20 Liver and Renal Function Tests Hypoalbuminemia 73 3.9 66 2.3 Elevated Alkaline Phosphatase 39 1.3 30 0 Chemistry Hyperglycemia 89 17 85 10 Hypocalcemia 78 11 77 4.7 Low Bicarbonate 63 0.4 45 0 Hyperkalemia 32 7 22 1.6 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. Table 8: ELOQUENT-2 Vital Sign Abnormalities EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Vital Sign Parameter % % Systolic Blood Pressure ≥160 mmHg 33 21 Diastolic Blood Pressure ≥100 mmHg 17 12 Systolic Blood Pressure <90 mmHg 29 8 Heart Rate ≥100 bpm 48 30 Heart Rate <60 bpm 66 31 EMPLICITI in Combination with Pomalidomide and Dexamethasone [ELOQUENT-3] The safety data described in this section are based on ELOQUENT-3, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In ELOQUENT-3, EMPLICITI 10 mg/kg and 20 mg/kg was administered with pomalidomide and dexamethasone [see Clinical Studies (14) ] . For adverse reaction evaluation, EMPLICITI combined with pomalidomide and dexamethasone was compared with pomalidomide and dexamethasone alone. The mean age of the population was 66 years and 63% of patients were 65 years of age or older. Fifty-seven percent of the population were male, 78% were white, 20% were Asian, and none were black. The ECOG performance status was 0 in 43%, 1 in 46%, and 2 in 10% of patients. These data reflect exposure of 60 patients to EMPLICITI and 55 to control with a median number of cycles of 9 for EMPLICITI and 5 for control. Serious adverse reactions were reported in 70% of patients treated on the EMPLICITI arm and 60% for patients treated on the control arm. The most frequent serious adverse reactions in the EMPLICITI arm compared to the control arm were: pneumonia (13% vs. 11%) and respiratory tract infection (7% vs. 3.6%). 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. Adverse reactions occurring at a frequency of 10% or higher in the EMPLICITI arm and 5% or higher than the pomalidomide and dexamethasone arm for the randomized trial in multiple myeloma are presented in Table 9. Table 9: ELOQUENT-3: Adverse Reactions with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% or Higher Incidence than Pomalidomide and Dexamethasone-Treated Patients [All Grades] EMPLICITI + Pomalidomide and Dexamethasone N=60 Pomalidomide and Dexamethasone N=55 Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 * The term pneumonia is grouping of the following terms: pneumonia, atypical pneumonia, lower respiratory tract infection, pneumoccocal sepsis, pneumonia bacterial, pneumonia influenza. Constipation 22 1.7 11 0 Hyperglycemia 20 8 15 7 Pneumonia* 18 10 13 11 Diarrhea 18 0 9 0 Respiratory Tract Infection 17 0 9 1.8 Bone Pain 15 3.3 9 0 Dyspnea 15 3.3 7 1.8 Muscle Spasms 13 0 5 0 Edema Peripheral 13 0 7 0 Lymphopenia 10 8 1.8 1.8 Other clinically important adverse reactions reported in patients treated with EMPLICITI that did not meet the criteria for inclusion in Table 6 and 9 but occurred at a frequency of 5% or greater in the EMPLICITI group and at a frequency at least twice the control rate for the randomized trial in multiple myeloma are listed below: General disorders and administration site conditions: chest pain, night sweats Immune system disorders: hypersensitivity Nervous system disorders: hypoesthesia Psychiatric disorders: mood altered Laboratory abnormalities worsening from baseline and occurring at a frequency of 10% or higher in ELOQUENT-3 in the EMPLICITI group and 5% or higher than the pomalidomide and dexamethasone group (criteria met for all Grades or Grade 3/4) for the randomized trial in multiple myeloma are presented in Table 10. Table 10: ELOQUENT-3: Laboratory Abnormalities Worsening from Baseline and with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% Higher Incidence than Pomalidomide and Dexamethasone-Treated Patients [Criteria met for All Grades or Grade 3/4] EMPLICITI + Pomalidomide and Dexamethasone N=60 Pomalidomide and Dexamethasone N=55 Laboratory Parameter All Grades Grade 3/4 All Grades Grade 3/4 Hematology Lymphopenia 98 70 91 35 Leukopenia 80 52 87 35 Thrombocytopenia 78 17 73 20 Liver and Renal Function Tests Hypoalbuminemia 65 1.7 56 1.8 Chemistry Hypocalcemia 58 3.3 40 1.8 Hyperglycemia 40 3.3 25 1.8 Hyponatremia 40 5 18 0 Hypokalemia 23 5 16 3.6 Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 11. Percentages are based on all treated patients Table 11: ELOQUENT-3: Vital Sign Abnormalities EMPLICITI + Pomalidomide and Dexamethasone N=60 Pomalidomide and Dexamethasone N=55 Vital Sign Parameter % % Systolic Blood Pressure ≥160 mmHg 18 13 Diastolic Blood Pressure ≥100 mmHg 8 4.0 Systolic Blood Pressure <90 mmHg 7 7 Heart Rate ≥100 bpm 23 24 Heart Rate <60 bpm 43 22 6.2 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. In 63 (88%) of the 72 patients in the four clinical trials, anti-product antibodies occurred within the first 2 months of the initiation of EMPLICITI treatment and resolved by 2 to 4 months in 49 (78%) patients. In the ELOQUENT-3 trial, in all 19 patients, anti-product antibodies occurred within the first 2 months of the initiation of EMPLICITI treatment and were resolved by 2 to 3 months in 18 (95%) patients. Neutralizing antibodies post-treatment were detected in 19 of 299 patients in the four clinical trials and 2 of 53 patients in the ELOQUENT-3 trial who were evaluable for the presence of neutralizing antibodies.

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.