Empliciti(elotuzumab 埃罗妥珠单抗) 为新一种多发性骨髓瘤新刺激免疫疗法 近日，美国FDA批准Empliciti与其他两种治疗方法联合治疗之前已经尝试过1到3肿药物的多发性骨髓瘤患者。 多发性骨髓瘤是来源于骨髓中的抗感染的浆细胞的异常增长，阻碍其他血细胞的正常生长，从而导致免疫系统功能降低，并导致其他骨骼和肾脏疾病。美国国立癌症协会估计美国每年有26850多发性骨髓瘤新发病例，11240例多发性骨髓瘤患者死亡。 “我们正在不断研究免疫系统是如何对抗癌症的，包括多发性骨髓瘤。“FDA药物评估和研究中心血液肿瘤产品部主任Richard Pazdur表示，“Empliciti是第二代治疗多发性骨髓瘤的单克隆抗体，与其他药物一起联合治疗多发性骨髓瘤。“Darzalex(daratumumab)这个月早些时候通过FDA批准上市，Darzalex(daratumumab)与Empliciti（elotuzumab）是仅有的两种治疗多发性骨髓瘤的单克隆抗体。 Empliciti（elotuzumab）通过激发人体的免疫系统对抗并杀死多发性骨髓瘤细胞。与Revlimid(lenalidomide)和dexamethasone（一种皮质类固醇）一起治疗多发性骨髓瘤。 Empliciti的安全性和效用性评估是基于一项随机，非盲临床试验，公有646名多发性骨髓瘤复发患者或者对之前治疗没有反应的多发性骨髓瘤患者纳入这项试验。服用Empliciti，Revlimid和dexamethasone三种药物与仅服用Revlimid和dexamethasone两种药物相比较，患者的无进展生存期分别为19.4个月和14.9个月。另外，完全或者部分肿瘤缩小的比例分别为78.5%和65.5%。 Empliciti被FDA授予了突破疗法认定，突破性疗法奖特别颁发于相比于之前的治疗方法，对于难治性疾病的治疗效果在临床试验中表现出本质性的提高。Empliciti获得了优先审核权并达到了孤儿药物标准，意味着如果批准将会给这项难治性疾病的治疗带来很大的提高，同时税费减低，用户使用费取消优惠来加速这种药物的发展。 批准日期：2015年11月30日；公司：Bristol-Myers Squibb公司和AbbVie 注射用EMPLICITI™(埃罗妥珠单抗[elotuzumab])，为静脉使用 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EMPLICITI safely and effectively. See full prescribing information for EMPLICITI. EMPLICITI TM (elotuzumab) injection, for intravenous use Initial U.S. Approval: 2015 INDICATIONS AND USAGE EMPLICITI is a SLAMF7-directed immunostimulatory antibody indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. (1) DOSAGE AND ADMINISTRATION • With lenalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter until disease progression or unacceptable toxicity. (2.1) • Premediate with dexamethasone, diphenhydramine, ranitidine and acetaminophen. (2.2) DOSAGE FORMS AND STRENGTHS For Injection: 300 mg or 400 mg lyophilized powder in a single-dose vial for reconstitution. (3) CONTRAINDICATIONS • None. (4) WARNINGS AND PRECAUTIONS • Infusion reactions: Premedication is required. Interrupt EMPLICITI for Grade 2 or higher and permanently discontinue for severe infusion reaction. (2.2, 2.3, 5.1) • Infections: Monitor for fever and other signs of infection and treat promptly. (5.2) • Second Primary Malignancies (SPM): Higher incidences of SPM were observed in a controlled clinical trial of patients with multiple myeloma receiving EMPLICITI. (5.3) • Hepatotoxicity: Monitor liver function and stop EMPLICITI if hepatotoxicity is suspected. (5.4) • Interference with determination of complete response: EMPLICITI can interfere with assays used to monitor M-protein. This interference can impact the determination of complete response. (5.5) ADVERSE REACTIONS Most common adverse reactions (20% or higher) are fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia. (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. USE IN SPECIFIC POPULATIONS • Pregnancy: Embryo-fetal toxicity with combination three drug dosage regimen. (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE EMPLICITI is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles 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. Patients must be premedicated before each dose of EMPLICITI [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. Administer dexamethasone as follows: • On days that EMPLICITI is administered, give dexamethasone 28 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI. • On days that EMPLICITI is not administered but a dose of dexamethasone is scheduled (Days 8 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally. The recommended dosing is presented in Table 1. Table 1: Recommended Dosing Schedule of EMPLICITI in Combination with Lenalidomide and Dexamethasone Cycle 28-Day Cycles 1 and 2 28-Day Cycles 3+ Day of Cycle 1 8 15 22 1 8 15 22 Premedication* ✓ ✓ ✓ ✓ ✓ ✓ EMPLICITI (mg/kg) intravenously 10 10 10 10 10 10 Lenalidomide (25 mg) orally Days 1-21 Days 1-21 Dexamethasone (mg) orally 28 28 28 28 28 40 28 40 Dexamethasone(mg) intravenously 8 8 8 8 8 8 Day of Cycle 1 8 15 22 1 8 15 Premedicate with the following 45 to 90 minutes prior to EMPLICITI infusion: 8 mg intravenous dexamethasone, H1 blocker: diphenhydramine (25-50 mg orally or intravenously) or equivalent; H2 blocker: ranitidine (50 mg intravenously) or equivalent; acetaminophen (650-1000 mg orally). Oral dexamethasone (28 mg) taken between 3 and 24 hours before EMPLICITI infusion. 2.2 Premedication Dexamethasone When EMPLICITI is used in combination with lenalidomide, divide dexamethasone into an oral and intravenous dose and administer as shown in Table 1 [see Dosage and Administration (2.1)]. Other Medications In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to EMPLICITI infusion: • H1 blocker: diphenhydramine (25-50 mg orally or intravenously) or equivalent H1 blocker. • H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker. • Acetaminophen (650-1000 mg orally). 2.3 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 2). 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 [see Warnings and Precautions (5.1)]. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment. Dose delays and modifications for dexamethasone and lenalidomide should be performed as recommended in their Prescribing Information. 2.4 Administration Administer the entire EMPLICITI infusion with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 micrometer) using an automated infusion pump. Initiate EMPLICITI infusion at a rate of 0.5 mL per minute. The infusion rate may be increased in a stepwise fashion as described in Table 2 if no infusion reactions develop. The maximum infusion rate should not exceed 2 mL per minute. Table 2: Infusion Rate for EMPLICITI Cycle 1, Dose 1 Cycle 1, Dose 2 Cycle 1, Dose 3 and 4 and All Subsequent Cycles Time Interval Rate Time Interval Rate Rate 0 to 30 min 0.5 mL/min 0 to 30 min 1 mL/min 30 to 60 min 1 mL/min 30 min or more 2 mL/min 2 mL/min 60 min or more 2 mL/min Adjust the infusion rate following a Grade 2 or higher infusion reaction [seeDosage and Administration (2.3)]. In patients who have received 4 cycles of EMPLICITI treatment, the infusion rate may be increased to a maximum of 5 mL/min. 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. 2.5 Reconstitution and Preparation Calculation of Dose • Calculate the dose (mg) and determine the number of vials needed for the 10 mg/kg dosage based on patient weight. • Determine the volume of sterile water for injection (SWFI) needed for reconstitution as shown in Table 3. Table 3: Reconstitution Instructions for EMPLICITI Strength Amount of Sterile Water for Injection, USP Required for Reconstitution Deliverable Volume of Reconstituted EMPLICITI in the Vial Postreconstitution Concentration 300 mg vial 13 mL 12 mL* 25 mg/mL 400 mg vial 17 mL 16 mL* 25 mg/mL * After reconstitution, each vial contains overfill to allow for withdrawal of 12 mL (300 mg) and 16 mL (400 mg), respectively. Reconstitution • Aseptically reconstitute each EMPLICITI vial with a syringe of adequate size and an 18-gauge or smaller needle (e.g., 17, 16, 15). 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 230 mL of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, into an infusion bag made of polyvinyl chloride or polyolefin. • The volume of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP can 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: 2ºC to 8ºC (36ºF-46ºF) 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 [68°F-77°F], and room light). 3 DOSAGE FORMS AND STRENGTHS For injection: 300 mg or 400 mg of elotuzumab as a white to off-white lyophilized powder in a single-dose vial for reconstitution. 4 CONTRAINDICATIONS There are no contraindications to EMPLICITI. Because EMPLICITI is indicated for use in combination with lenalidomide and dexamethasone, healthcare providers should consult the prescribing information of these products for a complete description of contraindications before starting therapy. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions EMPLICITI can cause infusion reactions. Infusion reactions were reported in approximately 10% of patients treated with EMPLICITI with lenalidomide and dexamethasone in the randomized trial in multiple myeloma. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients. The most common symptoms of an infusion reaction included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. Administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers) and acetaminophen prior to EMPLICITI infusion [see Dosage and Administration (2.2)]. Interrupt EMPLICITI infusion for Grade 2 or higher infusion reactions and institute appropriate medical management [see Dosage and Administration (2.3)]. 5.2 Infections In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the EMPLICITI combined with lenalidomide and dexamethasone (E-Ld) arm and 74.4% in lenalidomide and dexamethasone (Ld). Grade 3 to 4 infections were noted in 28% and 24.3% of E-Ld- and Ld-treated patients, respectively. Discontinuations due to infections occurred in 3.5% of E-Ld-treated and 4.1% of Ld-treated patients. Fatal infections were reported in 2.5% and 2.2% of E-Ld- and Ld-treated patients. Opportunistic infections were reported in 22% of patients in the E-Ld arm and 12.9% of patients in the Ld arm. Fungal infections occurred in 9.7% of patients in the E-Ld arm and 5.4% of patients in the Ld arm. Herpes zoster was reported in 13.5% of patients treated with E-Ld and 6.9% of patients treated with Ld. Monitor patients for development of infections and treat promptly. 5.3 Second Primary Malignancies In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) have been observed in 9.1% of patients treated with E-Ld and 5.7% of patients treated with Ld. The rate of hematologic malignancies were the same between E-Ld and Ld treatment arms (1.6%). Solid tumors were reported in 3.5% and 2.2% of E-Ld- and Ld-treated patients, respectively. Skin cancer was reported in 4.4% and 2.8% of patients treated with E-Ld and Ld, respectively. Monitor patients for the development of second primary malignancies. 5.4 Hepatotoxicity Elevations in liver enzymes (aspartate transaminase/alanine transaminase [AST/ALT] greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were reported in 2.5% and 0.6% of E-Ld- and Ld-treated patients in a clinical trial of patients with multiple myeloma (N=635). Two patients experiencing hepatotoxicity were not able to continue treatment; however, 6 out of 8 patients had resolution and were able to continue treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered. 5.5 Interference with Determination of Complete Response EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.2)]. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. 6 ADVERSE REACTIONS The following 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)]. 6.1 Clinical Trial 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. The safety data described in this section are based on a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In this study, 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 65.4% of patients treated on the EMPLICITI arm and 56.5% for patients treated on the control arm. The most frequent serious adverse reactions in the EMPLICITI arm compared to the control arm were: pneumonia (15.4% vs. 11%), pyrexia (6.9% vs. 4.7%), 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 4. Table 4: 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 Fatigue* 61.6 12.6 51.7 11.7 Diarrhea 46.9 5.0 36.0 4.1 Pyrexia 37.4 2.5 24.6 2.8 Constipation 35.5 1.3 27.1 0.3 Cough 34.3 0.3 18.9 0 Peripheral Neuropathy‡ 26.7 3.8 20.8 2.2 Nasopharyngitis 24.5 0 19.2 0 Upper Respiratory Tract Infection 22.6 0.6 17.4 1.3 Decreased Appetite 20.8 1.6 12.6 1.3 Pneumonia§ 20.1 14.2 14.2 9.5 Pain in Extremities 16.4 0.9 10.1 0.3 Headache 15.4 0.3 7.6 0.3 Vomiting 14.5 0.3 8.8 0.9 Weight Decreased 13.8 1.3 6.0 0 Lymphopenia 13.2 8.8 6.9 3.2 Cataracts 11.9 6.3 6.3 2.8 Oropharyngeal Pain 10.1 0 4.4 0 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. Other clinically important adverse reactions reported in patients treated with EMPLICITI that did not meet the criteria for inclusion in Table 4 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 Immune system disorders: hypersensitivity Nervous system disorders: hypoesthesia Psychiatric disorders: mood altered Skin and subcutaneous tissue disorders: night sweats 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 the randomized trial in multiple myeloma are presented in Table 5. Table 5: 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 99.4 76.7 98.4 48.7      Leukopenia 90.6 32.4 88.3 25.6      Thrombocytopenia 83.6 19.2 77.8 20.3 Liver and Renal Function Tests      Hypoalbuminemia 73.3 3.9 65.6 2.3      Elevated Alkaline Phosphatase 38.7 1.3 29.8 0 Chemistry      Hyperglycemia 89.3 17.0 85.4 10.2      Hypocalcema 78.0 11.3 76.7 4.7      Low Bicarbonate 62.9 0.4 45.1 0      Hyperkalemia 32.1 6.6 22.2 1.6 Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 6. Percentages are based on patients who had at least one on-treatment vital sign abnormality any time during the course of therapy. Table 6: Vital Sign Abnormalities EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Vital Sign Parameter % % Systolic Blood Pressure ≥160 mmHg 33.3 20.9 Diastolic Blood Pressure ≥100 mmHg 17.3 11.7 Systolic Blood Pressure <90 mmHg 28.9 8.2 Heart Rate ≥100 bpm 47.8 29.7 Heart Rate <60 bpm 66 31.3 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity to EMPLICITI. Of 390 patients across four clinical studies who were treated with EMPLICITI and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. In 63 (88%) of these 72 patients, anti-product antibodies occurred within the first 2 months of the initiation of EMPLICITI treatment. Anti-product antibodies resolved by 2 to 4 months in 49 (78%) of these 63 patients. Neutralizing antibodies were detected in 19 of 299 patients in the randomized trial in multiple myeloma. 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 with the incidences of antibodies to other products may be misleading. 7 DRUG INTERACTIONS 7.1 Drug Interactions No formal drug-drug interaction studies have been conducted with EMPLICITI. However, EMPLICITI is used in combination with lenalidomide and dexamethasone. Refer to the prescribing information for those products for important drug-drug interactions. 7.2 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 [see Warnings and Precautions (5.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no studies with EMPLICITI with pregnant women to inform any drug associated risks. Animal reproduction studies have not been conducted with elotuzumab. EMPLICITI is administered in combination with lenalidomide and dexamethasone. Lenalidomide can cause embryo-fetal harm and is contraindicated for use in pregnancy. Refer to the lenalidomide and dexamethasone prescribing information for additional information. Lenalidomide is only available through a REMS program. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. 8.2 Lactation Risk Summary There is no information on the presence of EMPLICITI in human milk, the effect on the breast-fed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breast-fed infants from elotuzumab administered with lenalidomide/dexamethasone, breastfeeding is not recommended. Refer to the lenalidomide and dexamethasone prescribing information for additional information. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Refer to the lenalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. When EMPLICITI is used with lenalidomide, there is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide, and the need to follow requirements regarding pregnancy avoidance, including testing. Contraception Refer to the lenalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential and males. Lenalidomide is present in the blood and semen of patients receiving the drug. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Of the 646 patients across treatment groups in the randomized trial in multiple myeloma, 57% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. No overall differences in efficacy or safety were observed between patients 65 years or older and younger patients (less than 65 years of age). 10 OVERDOSAGE 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. 11 DESCRIPTION Elotuzumab is a humanized recombinant monoclonal antibody directed to SLAMF7, a cell surface glycoprotein. Elotuzumab consists of the complementary determining regions (CDR) of the mouse antibody, MuLuc63, grafted onto human IgG1 heavy and kappa light chain frameworks. Elotuzumab is produced in NS0 cells by recombinant DNA technology. Elotuzumab has a theoretical mass of 148.1 kDa for the intact antibody. EMPLICITI (elotuzumab) is a sterile, nonpyrogenic, preservative-free lyophilized powder that is white to off-white, whole or fragmented cake in single-dose vials. EMPLICITI for Injection is supplied as 300 mg per vial and 400 mg per vial and requires reconstitution with Sterile Water for Injection, USP (13 mL and 17 mL, respectively) to obtain a solution with a concentration of 25 mg/mL. After reconstitution, each vial contains overfill to allow for withdrawal of 12 mL (300 mg) and 16 mL (400 mg). The reconstituted solution is colorless to slightly yellow, clear to slightly opalescent. Prior to intravenous infusion, the reconstituted solution is diluted with 230 mL of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP [see Dosage and Administration (2.4)]. Each 300 mg single-dose vial of EMPLICITI also contains the following inactive ingredients: citric acid monohydrate (2.44 mg), polysorbate 80 (3.4 mg), sodium citrate (16.6 mg), and sucrose (510 mg). Each 400 mg single-dose vial of EMPLICITI also contains the following inactive ingredients: citric acid monohydrate (3.17 mg), polysorbate 80 (4.4 mg), sodium citrate (21.5 mg), and sucrose (660 mg). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7) protein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage. Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In preclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of Natural Killer cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo. 12.2 Pharmacodynamics Cardiac Electrophysiology EMPLICITI does not prolong the QT interval to any clinically relevant extent in combination with lenalidomide and dexamethasone at the recommended dose or as monotherapy (at a dose 2 times the recommended dose). 12.3 Pharmacokinetics Elotuzumab exhibits nonlinear pharmacokinetics (PK) resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance. The administration of the recommended 10 mg/kg EMPLICITI regimen in combination with lenalidomide/dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 194 μg/mL (52%). Elimination: The clearance of elotuzumab decreased from a geometric mean (CV%) of 17.5 (21.2%) to 5.8 (31%) mL/day/kg with an increase in dose from 0.5 (i.e., 0.05 times the recommended dosage) to 20 mg/kg (i.e., 2 times the recommended dosage). Based on a population PK model, when elotuzumab is given in combination with lenalidomide and dexamethasone, approximately 97% of the maximum steady-state concentration is predicted to be eliminated with a geometric mean (CV%) of 82.4 (48%) days. Specific Populations Clinically significant differences were not observed in the pharmacokinetics of elotuzumab based on age (37-88 years), gender, race, baseline LDH, albumin, renal impairment ranging from mild to severe (creatinine clearance (CLcr) 15 to 89 mL/min) renal impairment, end-stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis, and mild (NCI-CTEP) hepatic impairment. The pharmacokinetics of elotuzumab in patients with moderate to severe hepatic impairment is unknown. Body weight: The clearance of elotuzumab increased with increasing body weight supporting a weight-based dose. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity data are available for elotuzumab in animals or humans. Fertility studies have not been performed for elotuzumab. 14 CLINICAL STUDIES The efficacy and safety of EMPLICITI in combination with lenalidomide and dexamethasone were evaluated in a randomized, open-label trial in patients with multiple myeloma who had received one to three prior therapies and had documented progression following their most recent therapy. Eligible patients were randomized in a 1:1 ratio to receive either EMPLICITI in combination with lenalidomide and low-dose dexamethasone or lenalidomide and low-dose dexamethasone. Treatment was administered in 4-week cycles until disease progression or unacceptable toxicity. EMPLICITI 10 mg/kg was administered intravenously each week for the first 2 cycles and every 2 weeks thereafter. Prior to EMPLICITI infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without EMPLICITI, dexamethasone 40 mg was administered as a single oral dose weekly. Lenalidomide 25 mg was taken orally once daily for the first 3 weeks of each cycle. Assessment of tumor response was conducted every 4 weeks. A total of 646 patients were randomized to receive treatment: 321 to EMPLICITI in combination with lenalidomide and low-dose dexamethasone and 325 to lenalidomide and low-dose dexamethasone. Demographics and baseline disease characteristics were balanced between treatment arms. The median age was 66 years (range, 37-91); 57% of patients were 65 years or older; 60% of patients were male; whites comprised 84% of the study population, Asians 10%, and blacks 4%. The ECOG performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients, and ISS Stage was I in 43%, II in 32%, and III in 21% of patients. The cytogenetic categories of del 17p and t(4;14) were present in 32% and 9% of patients, respectively. The median number of prior therapies was 2. Thirty-five percent (35%) of patients were refractory (progression during or within 60 days of last therapy) and 65% were relapsed (progression after 60 days of last therapy). Prior therapies included stem cell transplant (55%), bortezomib (70%), melphalan (65%), thalidomide (48%), and lenalidomide (6%). The efficacy of EMPLICITI was evaluated by progression-free survival (PFS) as assessed by hazard ratio, and overall response rate (ORR) as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation (EBMT) response criteria. Efficacy results are shown in Table 7 and Figure 1. The median number of treatment cycles was 19 for the EMPLICITI group and 14 for the comparator arm with a minimum follow-up of two years. Table 7: Efficacy Results EMPLICITI + Lenalidomide/ Dexamethasone N=321 Lenalidomide/ Dexamethasone N=325 PFS Hazard Ration [95% CI] 0.70 [0.57, 0.85]      Stratifield log rank test p-value* 0.0004 Median PFS in months [95% CI] 19.4 [16.6, 22.2] 14.9 [12.1, 17.2] Response Overall Response (ORR)† n (%)      [95% CI] 252 (78.5) [73.6, 82.9] 213 (65.5) [60.1, 70.7]      p-value‡ 0.0002      Complete Response (CR + sCR)†,§ n (%) 14 (4.4)¶ 24 (7.4)      Very Good Partial Response (VGPR)† n (%) 91 (28.3) 67 (20.6)      Partial Response (PR)† n (%) 147 (45.8) 122 (37.5) p-value based on the log-rank test stratified by ß2 microglobulins (<3.5 mg/L vs ≥ 3.5 mg/L), number of prior lines of therapy (1 vs 2 or 3), and prior immunomodulatory therapy (no vs prior thalidomide only vs other). European Group for Blood and Marrow Transplantation (EBMT) criteria. p-value based on the Cochran-Mantel-Haenszel chi-square test stratified by ß2 microglobulins (<3.5 mg/L vs ≥ 3.5 mg/L), number of prior lines of therapy (1 vs 2 or 3), and prior immunomodulatory therapy (no vs prior thalidomide only vs other). Complete response (CR) + stringent complete response (sCR). EMPLICITI’s interference with the assessment of myeloma protein with immunofixation and serum protein electrophoresis assay may interfere with correct response classification [see Drug Interactions (7) ]. Figure 1: Study 1 Progression-Free Survival The 1- and 2-year rates of PFS for EMPLICITI in combination with lenalidomide and dexamethasone treatment were 68% and 41%, respectively, compared with 57% and 27%, respectively, for lenalidomide and dexamethasone treatment. At the time of the interim analysis, there were 94 (29%) deaths in the EMPLICITI in combination with lenalidomide and dexamethasone study arm compared to 116 (36%) in the lenalidomide and dexamethasone study arm. 16 HOW SUPPLIED/STORAGE AND HANDLING EMPLICITI (elotuzumab) is white to off-white lyophilized powder available as follows: Carton Content NDC One 300 mg single-dose vial 0003-2291-11 One 400 mg single-dose vial 0003-4522-11 Store EMPLICITI under refrigeration at 2°C to 8°C (36°F-46°F). Protect EMPLICITI from light by storing in the original package until time of use. Do not freeze or shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Infusion Reactions • EMPLICITI may cause infusion reactions. Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion reactions, including fever, chills, rash, or breathing problems within 24 hours of infusion [ see Warnings and Precautions (5.1)]. • Advise patients that they will be required to take the following oral medications prior to EMPLICITI dosing to reduce the risk of infusion reaction [ see Dosage and Administration (2.2)]: • Dexamethasone orally as prescribed • H1 blocker: diphenhydramine or equivalent (if oral) • H2 blocker: ranitidine or equivalent (if oral) • Acetaminophen (650-1000 mg orally) Pregnancy • Advise patients that lenalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide is only available through a REMS program [ see Use in Specific Populations (8.1)] . http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80686b7e-f6f4-4154-b5c0-c846425e2d91