CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (>=20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.. Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant. Combination Treatment with Lenalidomide and Dexamethasone (DRd)The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies (14.1)]. Adverse reactions described in Table reflect exposure to DARZALEX for median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).Serious adverse reactions with 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).Table 7: Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the DRd Arm in MAIABody System Adverse ReactionDRd (N=364)Rd (N=365)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Gastrointestinal disorders Diarrhea57704640 Constipation411<136<10 Nausea32102310 Vomiting171012<10Infections Upper respiratory tract infectionAcute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 522<1362<1 BronchitisBronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis 29302110 PneumoniaAtypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis 261411471 Urinary tract infection18201020General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 412<1000 Peripheral edemaGeneralized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling 41203310 Fatigue40802840 Asthenia3240253<1 Pyrexia23201820 Chills1300200Musculoskeletal and connective tissue disorders Back pain343<1263<1 Muscle spasms29102210Respiratory, thoracic and mediastinal disorders DyspneaDyspnea, Dyspnea exertional 323<12010 CoughCough, Productive cough 30<101800Nervous system disorders Peripheral sensory neuropathy24101500 Headache19101100 Paresthesia1600800Metabolism and nutrition disorders Decreased appetite221015<1<1 Hyperglycemia1461831 Hypocalcemia141<1911Vascular disorders HypertensionBlood pressure increased, Hypertension 136<1740Laboratory abnormalities worsening during treatment from baseline listed in Table 8.Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIADRd (N=364)Rd (N=365)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%)Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Leukopenia9030582204Neutropenia913917772811Lymphopenia84411175366Thrombocytopenia67635874Anemia4713057240. Combination Treatment with Bortezomib, Melphalan and PrednisoneThe safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies (14.1)]. Adverse reactions described in Table reflect exposure to DARZALEX for median treatment duration of 14.7 months (range: to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.Serious adverse reactions with at least 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).Table 9: Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the D-VMP Arm in ALCYONEBody SystemAdverse ReactionD-VMP (N=346)VMP (N=354)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, VMP=bortezomib-melphalan-prednisoneInfections Upper respiratory tract infectionupper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection 48502830 Pneumoniapneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis 1612< 165< 1General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 2841000 Peripheral edemaedema peripheral, generalized edema, peripheral swelling 211< 11410Respiratory, thoracic and mediastinal disorders Coughcough, productive cough 16< 108< 10 Dyspneadyspnea, dyspnea exertional 1321510Vascular disorders Hypertensionhypertension, blood pressure increased 104< 1320Laboratory abnormalities worsening during treatment from baseline listed in Table 10.Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONED-VMP (N=346)VMP (N=354)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%)Key: D=daratumumab, VMP=bortezomib-melphalan-prednisoneThrombocytopenia882711882616Neutropenia863410873211Lymphopenia85461283449Anemia4718050210. Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant. Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies (14.1)]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.Serious adverse reactions with 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%).Table 11: Adverse Reactions Reported in >= 10% of Patients and With at Least 5% Greater Frequency in the DVTd Arm in CASSIOPEIABody System Adverse ReactionDVTd (N=536)VTd (N=538)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.Note: Hematology laboratory related toxicities were excluded and reported separately in the table belowGeneral disorders and administration site conditionsInfusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 353<1000Pyrexia262<12120Gastrointestinal disorders Nausea3040242<1 Vomiting16201020Infections Upper respiratory tract infectionLaryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 27101710 BronchitisBronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis 20101310Respiratory, thoracic and mediastinal disorders CoughCough, Productive cough 1700900Vascular disorders Hypertension1040520Table 12:Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA DVTd (N=536)VTd (N=538)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.Lymphopenia954415913710Leukopenia8214105769Thrombocytopenia81955883Neutropenia63191441109Anemia36403550. Relapsed/Refractory Multiple Myeloma. Combination Treatment with Lenalidomide and DexamethasoneThe safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Clinical Studies (14.2)]. Adverse reactions described in Table 13 reflect exposure to DARZALEX for median treatment duration of 13.1 months (range: to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd).Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with at least 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each).Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.Table 13: Adverse Reactions Reported in >= 10% of Patients and With at Least 5% Greater Frequency in the DRd Arm in POLLUXAdverse ReactionDRd (N=283)Rd (N=281)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%) Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Infections Upper respiratory tract infectionupper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection 656< 15140General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 4850000 Fatigue356< 12820 Pyrexia20201110Gastrointestinal disorders Diarrhea43502530 Nausea24101400 Vomiting1710510Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 30001500 Dyspneadyspnea, dyspnea exertional 213< 11210Musculoskeletal and connective tissue disorders Muscle spasms26101920Nervous system disorders Headache1300700Laboratory abnormalities worsening during treatment from baseline listed in Table 14.Table 14: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUXDRd (N=283)Rd (N=281)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Lymphopenia95421087326Neutropenia92361787328Thrombocytopenia737667105Anemia5213057190. Combination Treatment with Bortezomib and DexamethasoneThe safety of DARZALEX in combination with bortezomib and dexamethasone was evaluated in CASTOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 15 reflect exposure to DARZALEX for median treatment duration of 6.5 months (range: to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm.Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with at least 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each).Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.Table 15: Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the DVd Arm CASTORAdverse ReactionDVd (N=243)Vd (N=237)All Grades(%)Grade 3(%) Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%)Key: D=daratumumab, Vd=bortezomib-dexamethasone.Nervous system disorders Peripheral sensory neuropathy4750386< 1General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 4590000 Peripheral edemaedema peripheral, edema, generalized edema, peripheral swelling 22101300 Pyrexia16101110Infections Upper respiratory tract infectionupper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection 4460303< 1Gastrointestinal disorders Diarrhea323< 12210 Vomiting1100400Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 27001400 Dyspneadyspnea, dyspnea exertional 21401110Laboratory abnormalities worsening during treatment are listed in Table 16.Table 16: Treatment-Emergent Hematology Laboratory Abnormalities in CASTORDVd (N=243) Vd (N=237) All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Vd=bortezomib-dexamethasone.Thrombocytopenia902819852213Lymphopenia8941781243Neutropenia58123405< 1Anemia4813056140. Combination Treatment with Twice-Weekly (20/56 mg/m2) Carfilzomib and DexamethasoneThe safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 17 reflect exposure to DARZALEX for median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd).Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%).Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia.Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%.Table 17: Adverse Reactions (>=15%) in Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone (DKd) in CANDORAdverse ReactionDKd (N=308)Kd (N=153)All GradesGrades or 4All GradesGrades or 4(%)(%)(%)(%)Key: D=daratumumab; Kd=carfilzomib-dexamethasoneGeneral Disorders and Administration Site Conditions Infusion-related reactionsThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd or Kd administration. 4112285 FatigueFatigue includes fatigue and asthenia. 3211288 Pyrexia201.9150.7Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 40Includes fatal adverse reactions. 7293.3 Pneumonia18 13129 Bronchitis172.6121.3Blood and lymphatic system disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 37253016 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 33173114Gastrointestinal disorders Diarrhea323.9140.7 Nausea180130.7Vascular Disorders Hypertension31182813Respiratory, Thoracic and Mediastinal Disorders CoughCough includes productive cough and cough. 210210 Dyspnea203.9222.6Psychiatric disorders Insomnia183.9112Musculoskeletal and connective tissue disorders Back pain161.9101.3. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropeniaCardiac disorders: atrial fibrillationGastrointestinal disorders: vomiting, constipationGeneral disorders and administration site conditions: peripheral edema, asthenia, chillsInfections: influenza, urinary tract infection, sepsis, septic shockMetabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydrationMusculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest painNervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndromeRespiratory, thoracic and mediastinal disorders: pulmonary edemaSkin and subcutaneous tissue disorders: rash, pruritus. Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia. Cardiac disorders: atrial fibrillation. Gastrointestinal disorders: vomiting, constipation. General disorders and administration site conditions: peripheral edema, asthenia, chills. Infections: influenza, urinary tract infection, sepsis, septic shock. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration. Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain. Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndrome. Respiratory, thoracic and mediastinal disorders: pulmonary edema. Skin and subcutaneous tissue disorders: rash, pruritus. Combination Treatment with Once-Weekly (20/70 mg/m2) Carfilzomib and DexamethasoneThe safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)]. Adverse reactions described in Table 18 reflect exposure to DARZALEX for median treatment duration of 19.8 months (range: 0.3 to 34.5 months).Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient.Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively.Table 18: Adverse Reactions (>=15%) of Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone in EQUULEUSAdverse ReactionDKd (N=85)All Grades (%)Grades or (%)Key: D=daratumumab; Kd=carfilzomib-dexamethasoneBlood and lymphatic system disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 6832 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 5221 NeutropeniaNeutropenia includes neutrophil count decreased and neutropenia. 3121 LymphopeniaLymphopenia includes lymphocyte count decreased and lymphopenia 2925General disorder and administration site conditions FatigueFatigue includes fatigue and asthenia. 5418 Infusion-related reactionsThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd administration. 5312 Pyrexia371.2Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 533.5 Bronchitis190 Nasopharyngitis180 Influenza173.5Gastrointestinal disorders Nausea421.2 Vomiting401.2 Diarrhea382.4 Constipation170Respiratory, thoracic and mediastinal disorders Dyspnea353.5 CoughCough includes productive cough and cough. 330Vascular disorders Hypertension3320Psychiatric disorders Insomnia334.7Nervous system disorders Headache271.2Musculoskeletal and connective tissue disorders Back pain250 Pain in extremity150. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: leukopenia, febrile neutropeniaCardiac disorders: atrial fibrillationGastrointestinal disorders: pancreatitisGeneral disorders and administration site conditions: peripheral edema, chillsInfections: pneumonia, urinary tract infection, sepsis, septic shockMetabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgiaNervous system disorders: dizziness, paresthesia, peripheral sensory neuropathySkin and subcutaneous tissue disorders: pruritus, rash. Blood and lymphatic system disorders: leukopenia, febrile neutropenia. Cardiac disorders: atrial fibrillation. Gastrointestinal disorders: pancreatitis. General disorders and administration site conditions: peripheral edema, chills. Infections: pneumonia, urinary tract infection, sepsis, septic shock. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia. Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia. Nervous system disorders: dizziness, paresthesia, peripheral sensory neuropathy. Skin and subcutaneous tissue disorders: pruritus, rash. Combination Treatment with Pomalidomide and DexamethasoneThe safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)]. Adverse reactions described in Table 19 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for median treatment duration of months (range: 0.03 to 16.9 months).The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in >=5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.Table 19: Adverse Reactions With Incidence >=10% Reported in EQUULEUS Adverse ReactionDPd (N=103)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Pd=pomalidomide-dexamethasone.General disorders and administration site conditions Fatigue50100 Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 5040 Pyrexia2510 Chills2000 Edema peripheraledema, edema peripheral, peripheral swelling. 1740 Asthenia1500 Non-cardiac chest pain1500 Pain1100Infections Upper respiratory tract infectionacute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection 5041 Pneumonialung infection, pneumonia, pneumonia aspiration 1582Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 4310 Dyspneadyspnea, dyspnea exertional 3361 Nasal congestion1600Gastrointestinal disorders Diarrhea3830 Constipation3300 Nausea3000 Vomiting2120Musculoskeletal and connective tissue disorders Muscle spasms2610 Back pain2560 Arthralgia2220 Pain in extremity1500 Bone pain1340 Musculoskeletal chest pain1320Psychiatric disorders Insomnia2320 Anxiety1300Nervous system disorders Dizziness2120 Tremor1930 Headache1700Metabolism and nutrition disorders Hypokalemia1630 Hyperglycemia1351 Decreased appetite1100Laboratory abnormalities worsening during treatment are listed in Table 20.Table 20: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUSDPd(N=103)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Pd=pomalidomide-dexamethasone.Neutropenia953646Lymphopenia944526Thrombocytopenia751010Anemia57300. MonotherapyThe safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months).Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for (4%) patients.Adverse reactions occurring in at least 10% of patients are presented in Table 21. Table 22 describes Grade 3-4 laboratory abnormalities reported at rate of >=10%.Table 21: Adverse Reactions With Incidence >=10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg Adverse ReactionDARZALEX(N=156)All Grades(%)Grade 3(%)Grade 4(%)General disorders and administration site conditions Infusion-related reactionInfusion-related reaction includes terms determined by investigators to be related to infusion 4830 Fatigue3920 Pyrexia2110 Chills1000Gastrointestinal disorders Nausea2700 Diarrhea1610 Constipation1500 Vomiting1400Musculoskeletal and connective tissue disorders Back pain2320 Arthralgia1700 Pain in extremity1510 Musculoskeletal chest pain1210Respiratory, thoracic and mediastinal disorders Cough2100 Nasal congestion1700 Dyspnea1510Infections Upper respiratory tract infection2010 Nasopharyngitis1500 PneumoniaPneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. 1160Metabolism and nutrition disorders Decreased appetite1510Nervous system disorders Headache1210Vascular disorders Hypertension1050Table 22: Treatment-Emergent Grade 3-4 Laboratory Abnormalities (>=10%)Daratumumab 16 mg/kg (N=156) All Grades(%) Grade 3(%) Grade 4(%) Lymphopenia723010Neutropenia60173Thrombocytopenia48108Anemia45190. Herpes Zoster Virus ReactivationProphylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2-5% of patients receiving DARZALEX.. InfectionsGrade or infections were reported as follows:Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKdwhere carfilzomib 20/56 mg/m2 was administered twice-weekly: 37%, Kd: 29%; DKdwhere carfilzomib 20/70 mg/m2 was administered once-weekly: 21%Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.Pneumonia was the most commonly reported severe (Grade or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients.Fatal infections (Grade 5) were reported as follows:Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd: 5%, Kd: 3%; DKd: 0%Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.. Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKdwhere carfilzomib 20/56 mg/m2 was administered twice-weekly: 37%, Kd: 29%; DKdwhere carfilzomib 20/70 mg/m2 was administered once-weekly: 21%. Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.. Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd: 5%, Kd: 3%; DKd: 0%. Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.. Hepatitis Virus (HBV) ReactivationHepatitis virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.. Other Clinical Trials ExperienceThe following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection:Nervous System disorders: Syncope.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Infusion-related reactions [see Warning and Precautions (5.1)].Neutropenia [see Warning and Precautions (5.3)].Thrombocytopenia [see Warning and Precautions (5.4)].. Infusion-related reactions [see Warning and Precautions (5.1)].. Neutropenia [see Warning and Precautions (5.3)].. Thrombocytopenia [see Warning and Precautions (5.4)].. The most frequently reported adverse reactions (incidence >=20%) are: upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) 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 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 below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (>=20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.. Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant. Combination Treatment with Lenalidomide and Dexamethasone (DRd)The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies (14.1)]. Adverse reactions described in Table reflect exposure to DARZALEX for median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).Serious adverse reactions with 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).Table 7: Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the DRd Arm in MAIABody System Adverse ReactionDRd (N=364)Rd (N=365)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Gastrointestinal disorders Diarrhea57704640 Constipation411<136<10 Nausea32102310 Vomiting171012<10Infections Upper respiratory tract infectionAcute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 522<1362<1 BronchitisBronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis 29302110 PneumoniaAtypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis 261411471 Urinary tract infection18201020General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 412<1000 Peripheral edemaGeneralized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling 41203310 Fatigue40802840 Asthenia3240253<1 Pyrexia23201820 Chills1300200Musculoskeletal and connective tissue disorders Back pain343<1263<1 Muscle spasms29102210Respiratory, thoracic and mediastinal disorders DyspneaDyspnea, Dyspnea exertional 323<12010 CoughCough, Productive cough 30<101800Nervous system disorders Peripheral sensory neuropathy24101500 Headache19101100 Paresthesia1600800Metabolism and nutrition disorders Decreased appetite221015<1<1 Hyperglycemia1461831 Hypocalcemia141<1911Vascular disorders HypertensionBlood pressure increased, Hypertension 136<1740Laboratory abnormalities worsening during treatment from baseline listed in Table 8.Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIADRd (N=364)Rd (N=365)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%)Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Leukopenia9030582204Neutropenia913917772811Lymphopenia84411175366Thrombocytopenia67635874Anemia4713057240. Combination Treatment with Bortezomib, Melphalan and PrednisoneThe safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies (14.1)]. Adverse reactions described in Table reflect exposure to DARZALEX for median treatment duration of 14.7 months (range: to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.Serious adverse reactions with at least 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).Table 9: Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the D-VMP Arm in ALCYONEBody SystemAdverse ReactionD-VMP (N=346)VMP (N=354)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, VMP=bortezomib-melphalan-prednisoneInfections Upper respiratory tract infectionupper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection 48502830 Pneumoniapneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis 1612< 165< 1General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 2841000 Peripheral edemaedema peripheral, generalized edema, peripheral swelling 211< 11410Respiratory, thoracic and mediastinal disorders Coughcough, productive cough 16< 108< 10 Dyspneadyspnea, dyspnea exertional 1321510Vascular disorders Hypertensionhypertension, blood pressure increased 104< 1320Laboratory abnormalities worsening during treatment from baseline listed in Table 10.Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONED-VMP (N=346)VMP (N=354)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%)Key: D=daratumumab, VMP=bortezomib-melphalan-prednisoneThrombocytopenia882711882616Neutropenia863410873211Lymphopenia85461283449Anemia4718050210. Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant. Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies (14.1)]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.Serious adverse reactions with 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%).Table 11: Adverse Reactions Reported in >= 10% of Patients and With at Least 5% Greater Frequency in the DVTd Arm in CASSIOPEIABody System Adverse ReactionDVTd (N=536)VTd (N=538)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.Note: Hematology laboratory related toxicities were excluded and reported separately in the table belowGeneral disorders and administration site conditionsInfusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 353<1000Pyrexia262<12120Gastrointestinal disorders Nausea3040242<1 Vomiting16201020Infections Upper respiratory tract infectionLaryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 27101710 BronchitisBronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis 20101310Respiratory, thoracic and mediastinal disorders CoughCough, Productive cough 1700900Vascular disorders Hypertension1040520Table 12:Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA DVTd (N=536)VTd (N=538)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.Lymphopenia954415913710Leukopenia8214105769Thrombocytopenia81955883Neutropenia63191441109Anemia36403550. Relapsed/Refractory Multiple Myeloma. Combination Treatment with Lenalidomide and DexamethasoneThe safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Clinical Studies (14.2)]. Adverse reactions described in Table 13 reflect exposure to DARZALEX for median treatment duration of 13.1 months (range: to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd).Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with at least 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each).Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.Table 13: Adverse Reactions Reported in >= 10% of Patients and With at Least 5% Greater Frequency in the DRd Arm in POLLUXAdverse ReactionDRd (N=283)Rd (N=281)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%) Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Infections Upper respiratory tract infectionupper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection 656< 15140General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 4850000 Fatigue356< 12820 Pyrexia20201110Gastrointestinal disorders Diarrhea43502530 Nausea24101400 Vomiting1710510Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 30001500 Dyspneadyspnea, dyspnea exertional 213< 11210Musculoskeletal and connective tissue disorders Muscle spasms26101920Nervous system disorders Headache1300700Laboratory abnormalities worsening during treatment from baseline listed in Table 14.Table 14: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUXDRd (N=283)Rd (N=281)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Lymphopenia95421087326Neutropenia92361787328Thrombocytopenia737667105Anemia5213057190. Combination Treatment with Bortezomib and DexamethasoneThe safety of DARZALEX in combination with bortezomib and dexamethasone was evaluated in CASTOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 15 reflect exposure to DARZALEX for median treatment duration of 6.5 months (range: to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm.Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with at least 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each).Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.Table 15: Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the DVd Arm CASTORAdverse ReactionDVd (N=243)Vd (N=237)All Grades(%)Grade 3(%) Grade 4(%)All Grades(%)Grade 3(%) Grade 4(%)Key: D=daratumumab, Vd=bortezomib-dexamethasone.Nervous system disorders Peripheral sensory neuropathy4750386< 1General disorders and administration site conditions Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 4590000 Peripheral edemaedema peripheral, edema, generalized edema, peripheral swelling 22101300 Pyrexia16101110Infections Upper respiratory tract infectionupper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection 4460303< 1Gastrointestinal disorders Diarrhea323< 12210 Vomiting1100400Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 27001400 Dyspneadyspnea, dyspnea exertional 21401110Laboratory abnormalities worsening during treatment are listed in Table 16.Table 16: Treatment-Emergent Hematology Laboratory Abnormalities in CASTORDVd (N=243) Vd (N=237) All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Vd=bortezomib-dexamethasone.Thrombocytopenia902819852213Lymphopenia8941781243Neutropenia58123405< 1Anemia4813056140. Combination Treatment with Twice-Weekly (20/56 mg/m2) Carfilzomib and DexamethasoneThe safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 17 reflect exposure to DARZALEX for median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd).Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%).Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia.Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%.Table 17: Adverse Reactions (>=15%) in Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone (DKd) in CANDORAdverse ReactionDKd (N=308)Kd (N=153)All GradesGrades or 4All GradesGrades or 4(%)(%)(%)(%)Key: D=daratumumab; Kd=carfilzomib-dexamethasoneGeneral Disorders and Administration Site Conditions Infusion-related reactionsThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd or Kd administration. 4112285 FatigueFatigue includes fatigue and asthenia. 3211288 Pyrexia201.9150.7Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 40Includes fatal adverse reactions. 7293.3 Pneumonia18 13129 Bronchitis172.6121.3Blood and lymphatic system disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 37253016 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 33173114Gastrointestinal disorders Diarrhea323.9140.7 Nausea180130.7Vascular Disorders Hypertension31182813Respiratory, Thoracic and Mediastinal Disorders CoughCough includes productive cough and cough. 210210 Dyspnea203.9222.6Psychiatric disorders Insomnia183.9112Musculoskeletal and connective tissue disorders Back pain161.9101.3. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropeniaCardiac disorders: atrial fibrillationGastrointestinal disorders: vomiting, constipationGeneral disorders and administration site conditions: peripheral edema, asthenia, chillsInfections: influenza, urinary tract infection, sepsis, septic shockMetabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydrationMusculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest painNervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndromeRespiratory, thoracic and mediastinal disorders: pulmonary edemaSkin and subcutaneous tissue disorders: rash, pruritus. Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia. Cardiac disorders: atrial fibrillation. Gastrointestinal disorders: vomiting, constipation. General disorders and administration site conditions: peripheral edema, asthenia, chills. Infections: influenza, urinary tract infection, sepsis, septic shock. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration. Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain. Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndrome. Respiratory, thoracic and mediastinal disorders: pulmonary edema. Skin and subcutaneous tissue disorders: rash, pruritus. Combination Treatment with Once-Weekly (20/70 mg/m2) Carfilzomib and DexamethasoneThe safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)]. Adverse reactions described in Table 18 reflect exposure to DARZALEX for median treatment duration of 19.8 months (range: 0.3 to 34.5 months).Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient.Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively.Table 18: Adverse Reactions (>=15%) of Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone in EQUULEUSAdverse ReactionDKd (N=85)All Grades (%)Grades or (%)Key: D=daratumumab; Kd=carfilzomib-dexamethasoneBlood and lymphatic system disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 6832 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 5221 NeutropeniaNeutropenia includes neutrophil count decreased and neutropenia. 3121 LymphopeniaLymphopenia includes lymphocyte count decreased and lymphopenia 2925General disorder and administration site conditions FatigueFatigue includes fatigue and asthenia. 5418 Infusion-related reactionsThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd administration. 5312 Pyrexia371.2Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 533.5 Bronchitis190 Nasopharyngitis180 Influenza173.5Gastrointestinal disorders Nausea421.2 Vomiting401.2 Diarrhea382.4 Constipation170Respiratory, thoracic and mediastinal disorders Dyspnea353.5 CoughCough includes productive cough and cough. 330Vascular disorders Hypertension3320Psychiatric disorders Insomnia334.7Nervous system disorders Headache271.2Musculoskeletal and connective tissue disorders Back pain250 Pain in extremity150. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: leukopenia, febrile neutropeniaCardiac disorders: atrial fibrillationGastrointestinal disorders: pancreatitisGeneral disorders and administration site conditions: peripheral edema, chillsInfections: pneumonia, urinary tract infection, sepsis, septic shockMetabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgiaNervous system disorders: dizziness, paresthesia, peripheral sensory neuropathySkin and subcutaneous tissue disorders: pruritus, rash. Blood and lymphatic system disorders: leukopenia, febrile neutropenia. Cardiac disorders: atrial fibrillation. Gastrointestinal disorders: pancreatitis. General disorders and administration site conditions: peripheral edema, chills. Infections: pneumonia, urinary tract infection, sepsis, septic shock. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia. Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia. Nervous system disorders: dizziness, paresthesia, peripheral sensory neuropathy. Skin and subcutaneous tissue disorders: pruritus, rash. Combination Treatment with Pomalidomide and DexamethasoneThe safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)]. Adverse reactions described in Table 19 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for median treatment duration of months (range: 0.03 to 16.9 months).The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in >=5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.Table 19: Adverse Reactions With Incidence >=10% Reported in EQUULEUS Adverse ReactionDPd (N=103)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Pd=pomalidomide-dexamethasone.General disorders and administration site conditions Fatigue50100 Infusion-related reactionsInfusion-related reaction includes terms determined by investigators to be related to infusion 5040 Pyrexia2510 Chills2000 Edema peripheraledema, edema peripheral, peripheral swelling. 1740 Asthenia1500 Non-cardiac chest pain1500 Pain1100Infections Upper respiratory tract infectionacute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection 5041 Pneumonialung infection, pneumonia, pneumonia aspiration 1582Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 4310 Dyspneadyspnea, dyspnea exertional 3361 Nasal congestion1600Gastrointestinal disorders Diarrhea3830 Constipation3300 Nausea3000 Vomiting2120Musculoskeletal and connective tissue disorders Muscle spasms2610 Back pain2560 Arthralgia2220 Pain in extremity1500 Bone pain1340 Musculoskeletal chest pain1320Psychiatric disorders Insomnia2320 Anxiety1300Nervous system disorders Dizziness2120 Tremor1930 Headache1700Metabolism and nutrition disorders Hypokalemia1630 Hyperglycemia1351 Decreased appetite1100Laboratory abnormalities worsening during treatment are listed in Table 20.Table 20: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUSDPd(N=103)All Grades(%)Grade 3(%)Grade 4(%)Key: D=daratumumab, Pd=pomalidomide-dexamethasone.Neutropenia953646Lymphopenia944526Thrombocytopenia751010Anemia57300. MonotherapyThe safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months).Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for (4%) patients.Adverse reactions occurring in at least 10% of patients are presented in Table 21. Table 22 describes Grade 3-4 laboratory abnormalities reported at rate of >=10%.Table 21: Adverse Reactions With Incidence >=10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg Adverse ReactionDARZALEX(N=156)All Grades(%)Grade 3(%)Grade 4(%)General disorders and administration site conditions Infusion-related reactionInfusion-related reaction includes terms determined by investigators to be related to infusion 4830 Fatigue3920 Pyrexia2110 Chills1000Gastrointestinal disorders Nausea2700 Diarrhea1610 Constipation1500 Vomiting1400Musculoskeletal and connective tissue disorders Back pain2320 Arthralgia1700 Pain in extremity1510 Musculoskeletal chest pain1210Respiratory, thoracic and mediastinal disorders Cough2100 Nasal congestion1700 Dyspnea1510Infections Upper respiratory tract infection2010 Nasopharyngitis1500 PneumoniaPneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. 1160Metabolism and nutrition disorders Decreased appetite1510Nervous system disorders Headache1210Vascular disorders Hypertension1050Table 22: Treatment-Emergent Grade 3-4 Laboratory Abnormalities (>=10%)Daratumumab 16 mg/kg (N=156) All Grades(%) Grade 3(%) Grade 4(%) Lymphopenia723010Neutropenia60173Thrombocytopenia48108Anemia45190. Herpes Zoster Virus ReactivationProphylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2-5% of patients receiving DARZALEX.. InfectionsGrade or infections were reported as follows:Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKdwhere carfilzomib 20/56 mg/m2 was administered twice-weekly: 37%, Kd: 29%; DKdwhere carfilzomib 20/70 mg/m2 was administered once-weekly: 21%Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.Pneumonia was the most commonly reported severe (Grade or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients.Fatal infections (Grade 5) were reported as follows:Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd: 5%, Kd: 3%; DKd: 0%Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.. Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKdwhere carfilzomib 20/56 mg/m2 was administered twice-weekly: 37%, Kd: 29%; DKdwhere carfilzomib 20/70 mg/m2 was administered once-weekly: 21%. Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.. Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd: 5%, Kd: 3%; DKd: 0%. Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.. Hepatitis Virus (HBV) ReactivationHepatitis virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.. Other Clinical Trials ExperienceThe following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection:Nervous System disorders: Syncope. 6.2 Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity. 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 the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products may be misleading.In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and of the 1,383 evaluable combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of daratumumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System disorders: Anaphylactic reaction, IRR (including deaths)Gastrointestinal disorders: PancreatitisInfections: Cytomegalovirus, Listeriosis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Newly Diagnosed Multiple Myeloma. Combination Treatment with Lenalidomide and Dexamethasone in Patients Ineligible for Autologous Stem Cell TransplantMAIA (NCT02252172), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as pre-infusion medication. Treatment was continued in both arms until disease progression or unacceptable toxicity.A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of the patients >=75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of and 17% had an ECOG performance score of >=2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd.Figure 1: Kaplan-Meier Curve of PFS in MAIAAdditional efficacy results from MAIA are presented in Table 23.Table 23: Additional Efficacy Results From MAIABased on intent-to-treat population DRd (N=368)Rd (N=369)DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence intervalOverall response (sCR+CR+VGPR+PR) n(%) 342 (92.9%)300 (81.3%)p-valuep-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001 Stringent complete response (sCR)112 (30.4%)46 (12.5%) Complete response (CR)63 (17.1%)46 (12.5%) Very good partial response (VGPR)117 (31.8%)104 (28.2%) Partial response (PR)50 (13.6%)104 (28.2%)CR or better (sCR CR)175 (47.6%)92 (24.9%) p-value <0.0001VGPR or better (sCR CR VGPR)292 (79.3%)196 (53.1%) p-value <0.0001MRD negativity rate Based on threshold of 10-5 using next-generation sequencing assay (clonoSEQ). n(%)89 (24.2%)27 (7.3%) 95% CI (%)(19.9%, 28.9%)(4.9%, 10.5%) p-valuep-value from Fishers exact test <0.0001MRD negativity rate in patients with CR or better Number of patients with CR or betterN=175N=92 MRD negativity rate n(%)89 (50.9%)27 (29.3%) 95% CI (%)(43.2%, 58.5%)(20.3%, 39.8%)In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.. Figure 1. Combination Treatment with Bortezomib, Melphalan and Prednisone (VMP) in Patients Ineligible for Autologous Stem Cell TransplantALCYONE (NCT02195479), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Bortezomib was administered by subcutaneous (SC) injection at dose of 1.3 mg/m2 body surface area twice weekly at Weeks 1, 2, and for the first 6-week cycle (Cycle 1; doses), followed by once weekly administrations at Weeks 1, 2, and for eight more 6-week cycles (Cycles 2-9; doses per cycle). Melphalan at mg/m2, and prednisone at 60 mg/m2 were orally administered on Days to of the nine 6-week cycles (Cycles 1-9). DARZALEX was continued until disease progression or unacceptable toxicity.A total of 706 patients were randomized: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients >=75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of and 25% had an ECOG performance score of 2. Nineteen percent of patients had ISS Stage I, 42% had ISS Stage II and 38% had ISS Stage III disease. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).ALCYONE demonstrated an improvement in PFS in the D-VMP arm as compared to the VMP arm (HR=0.50; 95% CI: 0.38, 0.65; p<0.0001), representing 50% reduction in the risk of disease progression or death in patients treated with D-VMP. After median follow-up of 40 months, the median PFS was 36.4 months (95% CI: 32.1, 45.9) in the D-VMP arm and 19.3 months (95% CI: 18.0, 20.4) in the VMP arm.Figure 2:Kaplan-Meier Curve of PFS in ALCYONEPFS median follow-up of 16.5 monthsAfter median follow-up of 40 months, ALCYONE demonstrated an improvement in overall survival (OS) in the D-VMP arm as compared to the VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing 40% reduction in the risk of death in patients treated in the D-VMP arm. Median OS was not reached for either arm.Figure 3: Kaplan-Meier Curve of OS in ALCYONEAdditional efficacy results from ALCYONE are presented in Table 24.Table 24: Additional Efficacy Results From ALCYONED-VMP (N=350)VMP (N=356)D-VMP daratumumab-bortezomib-melphalan-prednisone; VMP bortezomib-melphalan-prednisone; MRD minimal residual disease; CI confidence intervalOverall response (sCR+CR+VGPR+PR) n(%)Based on intent-to-treat population 318 (90.9%)263 (73.9%) p-valuep-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001 Stringent complete response (sCR)63 (18.0%)25 (7.0%) Complete response (CR)86 (24.6%)62 (17.4%) Very good partial response (VGPR)100 (28.6%)90 (25.3%) Partial response (PR)69 (19.7%)86 (24.2%)MRD negativity rate Based on threshold of 10-5 using next-generation sequencing assay (clonoSEQ). n(%)78 (22.3%)22 (6.2%) 95% CI (%)(18.0, 27.0)(3.9, 9.2) p-valuep-value from Fishers exact test. <0.0001MRD negativity rate in patients with CR or better Number of patients with CR or betterN=149N=87 MRD negativity rate n(%)74 (49.7%)22 (25.3%) 95% CI (%)(41.4, 58.0)(16.6, 35.7)In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median duration of response had not been reached in the D-VMP group and was 21.3 months (range: 0.5+, 23.7+) in the VMP group.. Figure 2. Combination Treatment with Bortezomib, Thalidomide and Dexamethasone in Patients Eligible for Autologous Stem Cell Transplant (ASCT)CASSIOPEIA (NCT02541383), an open-label, randomized, active-controlled trial compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. The trial was limited to patients 65 years of age and younger. Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as pre-infusion medication.A total of 1,085 patients were randomized: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 years (range: 22 to 65 years). The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.Efficacy was evaluated by stringent Complete Response (sCR) rate at Day 100 post-transplant, Complete Response Rate (CR) at Day 100 post-transplant, and Progression-Free Survival (PFS).Table 25: Efficacy Results From CASSIOPEIA at Day 100 Post-TransplantDVTd (N=543)VTd (N=542)D-VTd daratumumab-bortezomib-thalidomide-dexamethasone; VTd bortezomib-thalidomide-dexamethasone Overall response (sCR+CR+VGPR+PR) n(%)Based on intent-to-treat population 503 (92.6%)487 (89.9%) Stringent complete response (sCR)157 (28.9%)110 (20.3%) p-valuep-value from Cochran Mantel-Haenszel Chi-Squared test. 0.0010 Complete response (CR)54 (9.9%)31 (5.7%) Very good partial response (VGPR)242 (44.6%)282 (52.0%) Partial response (PR)50 (9.2%)64 (11.8%)CASSIOPEIA demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; with median follow up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001).Figure 4: Kaplan-Meier Curve of PFS in CASSIOPEIAbased on interim analysis and the boundary for PFS was crossed. Figure 3. Figure 4. 14.2Relapsed/Refractory Multiple Myeloma. Combination Treatment with Lenalidomide and DexamethasonePOLLUX (NCT02076009), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as pre-infusion medication and the remainder given the day after the infusion. For patients on reduced dexamethasone dose, the entire 20 mg dose was given as DARZALEX pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturers prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were >=75 years, 59% were male; 69% White, 18% Asian, and 3% African American. Patients had received median of prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received prior PI, 55% of patients had received prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by PFS based on IMWG criteria.POLLUX demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd. After median follow-up of 55 months, the median PFS was 45.0 months (95% CI: 34.1, 53.9) in the DRd arm and was 17.5 months (95% CI: 13.9, 20.8) in the Rd arm.Figure 5: Kaplan-Meier Curve of PFS in POLLUXPFS median follow-up of 13.5 monthsAdditional efficacy results from POLLUX are presented in Table 26.Table 26: Additional Efficacy Results From POLLUXBased on Intent-to-treat population DRd (N=286)Rd (N=283) DRd daratumumab- lenalidomide-dexamethasone; Rd lenalidomide-dexamethasoneOverall response (sCR+CR+VGPR+PR)261 (91.3%)211 (74.6%) p-valuep-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001 Stringent complete response (sCR)51 (17.8%)20 (7.1%) Complete response (CR)70 (24.5%)33 (11.7%) Very good partial response (VGPR)92 (32.2%)69 (24.4%) Partial response (PR)48 (16.8%)89 (31.4%)In responders, the median time to response was month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group.With median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group.. Figure 5. Combination Treatment with Bortezomib and DexamethasoneCASTOR (NCT02136134), an open-label, randomized, active-controlled Phase trial, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had received at least one prior therapy. Bortezomib was administered by SC injection or IV injection at dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for total of cycles. Dexamethasone was administered orally at dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of DARZALEX infusion, 20 mg of the dexamethasone dose was administered as pre-infusion medication. For patients on reduced dexamethasone dose, the entire 20 mg dose was given as DARZALEX pre-infusion medication. Bortezomib and dexamethasone were given for three-week cycles in both treatment arms; whereas DARZALEX was given until disease progression. However, dexamethasone 20 mg was continued as DARZALEX pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturers prescribing information.A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were >=75 years, 57% were male; 87% White, 5% Asian and 4% African American. Patients had received median of prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received prior PI (66% received bortezomib) and 76% of patients received an immunomodulatory agent (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were in general well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd arm respectively refractory to lenalidomide. Efficacy was evaluated by PFS based on IMWG criteria.CASTOR demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm (HR=0.39; 95% CI: 0.28, 0.53; p<0.0001), representing 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. After median follow-up of 50 months, the median PFS was 16.7 months (95% CI: 13.1, 19.4) in the DVd arm and was 7.1 months (95% CI: 6.2, 7.7) in the Vd arm.Figure 6: Kaplan-Meier Curve of PFS in CASTORPFS median follow-up of 7.4 monthsAdditional efficacy results from CASTOR are presented in Table 27.Table 27:Additional Efficacy Results From CASTORBased on Intent-to-treat population DVd (N=251)Vd (N=247) DVd daratumumab- bortezomib-dexamethasone; Vd bortezomib-dexamethasoneOverall response (sCR+CR+VGPR+PR)199 (79.3%)148 (59.9%) P-valuep-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001 Stringent complete response (sCR)11 (4.4%)5 (2.0%) Complete response (CR)35 (13.9%)16 (6.5%) Very good partial response (VGPR)96 (38.2%)47 (19.0%) Partial response (PR)57 (22.7%)80 (32.4%)In responders, the median time to response was 0.8 months (range: 0.7 to months) in the DVd group and 1.5 months (range: 0.7 to months) in the Vd group. The median duration of response had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ to 12+ months) in the Vd group.With median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in the Vd group were observed.. Figure 6. Combination Treatment with Twice-Weekly (20/56 mg/m2) Carfilzomib and DexamethasoneCANDOR (NCT03158688) was randomized, open-label, multicenter trial which evaluated the combination of DARZALEX with twice-weekly carfilzomib and dexamethasone (DKd) versus twice-weekly carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received at least to prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past years, known chronic obstructive pulmonary disease (COPD) with FEV1 <50% of predicted normal, and active congestive heart failure. Randomization was stratified by the ISS (stage or vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs >=2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).DARZALEX was administered intravenously at dose of mg/kg in Cycle on Days and 2. Thereafter, DARZALEX was administered intravenously at dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, and 15 and 22 of Cycle 2; Days and 15 of Cycles to 6; and Day of each 28-day cycle until disease progression. Carfilzomib was administered intravenously at dose of 20 mg/m2 in Cycle on Days and 2; at dose of 56 mg/m2 in Cycle on Days 8, 9, 15, and 16 and at dose 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. For patients >75 years on reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as DARZALEX pre-infusion medication on days when DARZALEX was administered. Dosing of dexamethasone was otherwise split across days when carfilzomib was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. The baseline demographic and disease characteristics were similar between arms. The median age was 64 years (range 29 to 84 years), 9% were >=75 years, 58% were male; 79% White, 14% Asian, and 2% Black. Patients had received median of prior lines of therapy and 58% of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (92%) received prior PI and of those 34% were refractory to PI including regimen. Fourty-two percent (42%) of patients had received prior lenalidomide and of those, 33% were refractory to lenalidomide containing regimen.Efficacy was evaluated by IRC evaluation of PFS based on the IMWG response criteria. Efficacy results are provided in Figure 7. CANDOR demonstrated an improvement in PFS in the DKd arm as compared to the Kd arm; the median PFS had not been reached in the DKd arm and was 15.8 months in the Kd arm (hazard ratio [HR]=0.63; 95% CI: 0.46, 0.85; p=0.0014), representing 37% reduction in the risk of disease progression or death for patients treated with DKd versus Kd.Figure 7: Kaplan-Meier Curve of PFS in CANDORAdditional efficacy results from CANDOR are presented in Table 28.Table 28: Additional Efficacy Results From CANDOR (Intent-to-Treat Population)DKd (N=312)Kd (N=154)DKd daratumumab-carfilzomib-dexamethasone; Kd =carfilzomib-dexamethasone; MRD [-] CR=minimal residual disease; CI=confidence intervalOverall response (sCR+CR+VGPR+PR) n(%)263 (84%)115 (75%) 95% CI (%)(80, 88)(67, 81) p-valuep-value from the stratified Cochran Mantel-Haenszel Chi-Squared test (1-sided)0.0040 Complete response (CR)89 (28%)16 (10%) Very good partial response (VGPR)127 (41%)59 (38%) Partial response (PR)47 (15%)40 (26%)MRD [-] CR rate at 12 months n(%)MRD[-]CR (at 10-5 level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) 39 (12%)2 (1.3%) 95% CI (%)(9, 17)(0.2, 4.6) p-value (1-sided)<0.0001MRD [-] CR 43 (14%)5 (3.2%)The median time to response was month (range: to 14 months) in the DKd group and month (range: to 10 months) in the Kd group. The median duration of response had not been reached in the DKd group and was 16.6 months (95% CI: 13.9, not estimable) in the Kd group.. Figure 7. Combination Treatment with Once-Weekly (20/70 mg/m2) Carfilzomib and DexamethasoneEQUULEUS (NCT01998971) was an open-label, multi-cohort trial which evaluated the combination of DARZALEX with one-weekly carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who had received at least to prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past years, known chronic obstructive pulmonary disease (COPD) with FEV1 <50% of predicted normal, or active congestive heart failure (defined as New York Heart Association Class III-IV).Ten patients were administered DARZALEX at dose of 16 mg/kg intravenously on Cycle 1, Day and the remaining patients were administered DARZALEX at dose of mg/kg intravenously on Cycle 1, Days and 2. Thereafter, DARZALEX was administered intravenously at dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2; Days and 15 of Cycles to 6; and then Day for the remaining cycles of each 28 day cycle. Carfilzomib was administered intravenously once weekly at dose of 20 mg/m2 on Cycle Day and escalated to dose of 70 mg/m2 on Cycle Days and 15, and Days 1, 8, and 15 of each subsequent 28-day cycle. In Cycles and 2, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22 and 23; in cycles to 6, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 15 and 16 and at dose of 40 mg on Day and 22; and in cycles and thereafter, dexamethasone 20 mg was administered orally or intravenously on Days and and at dose of 40 mg on Days 8, 15, and 22. For patients >75 years of age, dexamethasone 20 mg was administered orally or intravenously weekly after the first week. Treatment continued until disease progression or unacceptable toxicity.The EQUULEUS trial enrolled 85 patients. The median patient age was 66 years (range: 38 to 85 years) with 9% of patients >=75 years of age; 54% were male; 80% were White, 3.5% were Black and 3.5% were Asian. Patients in the study had received median of prior lines of therapy. Seventy-three percent (73%) of patients had received prior ASCT. All patients received prior bortezomib, and 95% of patients received prior lenalidomide. Fifty-nine percent (59%) of patients were refractory to lenalidomide and 29% of patients were refractory to both PI an IMiD.Efficacy results were based on overall response rate using IMWG criteria. Efficacy results are provided in Table 29. The median time to response was 0.95 months (range: 0.9, 14.3). The median duration of response was 28 months (95% CI: 20.5, not estimable). Table 29: Efficacy results for EQUULEUSN=85ORR sCR+CR+VGPR+PRCI confidence intervalOverall response rate (ORR)69 (81%)95% CI (%)(71, 89) Stringent complete response (sCR)18 (21%) Complete response (CR)12 (14%) Very good partial response (VGPR)28 (33%) Partial response (PR)11 (13%). Combination Treatment with Pomalidomide and DexamethasoneEQUULEUS (NCT01998971) was an open-label trial in which 103 patients with multiple myeloma who had received prior PI and an immunomodulatory agent, received 16 mg/kg DARZALEX in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as pre-infusion medication and the remainder given the day after the infusion. For patients on reduced dexamethasone dose, the entire 20 mg dose was given as DARZALEX pre-infusion medication.The median patient age was 64 years (range: 35 to 86 years) with 8% of patients >=75 years of age. Patients in the study had received median of prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see Table 30).Table 30: Efficacy Results for EQUULEUSN=103ORR sCR+CR+VGPR+PRCI Confidence IntervalOverall response rate (ORR)61 (59.2%)95% CI (%)(49.1, 68.8) Stringent complete response (sCR)8 (7.8%) Complete response (CR)6 (5.8%) Very good partial response (VGPR)29 (28.2%) Partial response (PR)18 (17.5%)The median time to response was month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months).. MonotherapySIRIUS (NCT01985126), was an open-label trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least prior lines of therapy including proteasome inhibitor and an immunomodulatory agent or who were double-refractory to proteasome inhibitor and an immunomodulatory agent. In 106 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were White. Patients had received median of prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents.Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 31).Table 31: Efficacy Results for SIRIUSN=106ORR sCR+CR+VGPR+PRCI confidence intervalOverall response rate (ORR)31 (29.2%)95% CI (%)(20.8, 38.9) Stringent complete response (sCR)3 (2.8%) Complete response (CR)0 Very good partial response (VGPR)10 (9.4%) Partial response (PR)18 (17.0%)The median time to response was month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months).Study GEN501 (NCT00574288) was an open-label dose escalation trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least different cytoreductive therapies. In 42 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were White. Patients in the study had received median of prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents.Overall response rate was 36% (95% CI: 21.6, 52.0%) with CR and VGPR. The median time to response was month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months).

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics. NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.. Exposure-Response RelationshipThe exposure-response relationship and time course of pharmacodynamics of DARZALEX have not been fully characterized.. Cardiac ElectrophysiologyDARZALEX as large protein has low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential. DARZALEX can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingWith the combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide, refer to the lenalidomide, pomalidomide, or thalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.. ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with DARZALEX and for months after the last dose. Additionally, refer to the lenalidomide, pomalidomide, or thalidomide labeling for additional recommendations for contraception.

PEDIATRIC USE SECTION.

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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. CD38 is transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1 human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory cells (CD38+Tregs) and cells (CD38+Bregs) are decreased by daratumumab.. 12.2Pharmacodynamics. NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.. Exposure-Response RelationshipThe exposure-response relationship and time course of pharmacodynamics of DARZALEX have not been fully characterized.. Cardiac ElectrophysiologyDARZALEX as large protein has low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.. 12.3Pharmacokinetics. Daratumumab area under the concentration-time curve (AUC) increases more than proportionally over dosage range from to 24 mg/kg (0.06 to 1.5 times the approved recommended dosage) as monotherapy or to 16 mg/kg (0.06 to time the approved recommended dosage) as combination therapy.Following administration of the approved recommended dosage of DARZALEX as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) was approximately 2.7 to 3-fold higher at the end of weekly dosing compared to the first dose. The mean +- standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 +- 332 ug/mL when DARZALEX was administered as monotherapy and 502 +- 196 to 607 +- 231 ug/mL when DARZALEX was administered as combination therapy. Split dosing of the first dose resulted in different PK profile in the first day compared to single dosing; however, similar Cmax and Cmin concentrations were both predicted and observed following the administration of the second split dose on Week Day 2.When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately months into the every 4-week dosing period (by the 21st infusion). At steady state, daratumumab mean +- SD accumulation ratio for Cmax was 1.6 +- 0.5.. DistributionDaratumumab volume of distribution was 4.7 +- 1.3 as monotherapy and 4.4 +- 1.5 as combination therapy following administration of the approved dosage.. EliminationDaratumumab clearance decreased with increasing dose and with multiple dosing. The mean +- SD linear clearance was estimated to be 171.4 +- 95.3 mL/day and the mean +- SD estimated terminal half-life associated with linear clearance was 18 +- days following administration of the approved recommended dosage of DARZALEX as monotherapy. Terminal half-life was similar when DARZALEX was administered as combination therapy.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of daratumumab as monotherapy or as combination therapy were observed based on sex, age (31 to 93 years), mild [total bilirubin to 1.5 times upper limit of normal (ULN) or aspartate aminotransaminase (AST)>ULN] and moderate (total bilirubin 1.5 to times ULN and any AST) hepatic impairment, or renal impairment [Creatinine clearance (CLcr) 15-89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on daratumumab pharmacokinetics is unknown.. Body WeightThe central volume of distribution and clearance of daratumumab increased with increasing body weight.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. DARZALEX is contraindicated in patients with history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation [see Warnings and Precautions (5.1)].. Patients with history of severe hypersensitivity to daratumumab or any of the components of the formulation. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Daratumumab is an immunoglobulin G1 kappa (IgG1) human monoclonal antibody that binds to CD38 antigen. It is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.DARZALEX(R) (daratumumab) injection is supplied as colorless to pale yellow preservative-free solution for intravenous use in single-dose vial. The pH is 5.5.Each DARZALEX 20 mL single-dose vial contains (NDC 57894-502-20) 400 mg daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and Water for Injection, USP.Each DARZALEX mL single-dose vial contains (NDC 57894-502-05) 100 mg daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and Water for Injection, USP.Each DARZALEX 20 mL single-dose vial contains (NDC 57894-505-20) 400 mg daratumumab, L-histidine (7 mg), L-histidine hydrochloride monohydrate (32.6 mg), L-methionine (20 mg), polysorbate 20 (8 mg), sorbitol (1093 mg), and Water for Injection, USP.Each DARZALEX mL single-dose vial contains (NDC 57894-505-05) 100 mg daratumumab, L-histidine (1.8 mg), L-histidine hydrochloride monohydrate (8.2 mg), L-methionine (5 mg), polysorbate 20 (2 mg), sorbitol (273.3 mg), and Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Pre-medicate with corticosteroids, antipyretics and antihistamines. (2.3)Dilute and administer as an intravenous infusion. (2.5)Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule (2.2)Administer post-infusion medications. (2.3). Pre-medicate with corticosteroids, antipyretics and antihistamines. (2.3). Dilute and administer as an intravenous infusion. (2.5). Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule (2.2). Administer post-infusion medications. (2.3). 2.1Important Dosing Information. Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.3)].Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)]. DARZALEX should be administered by healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur [see Warnings and Precautions (5.1)]. Type and screen patients prior to starting DARZALEX [see Warnings and Precautions (5.2)]. Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.3)].. Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)]. DARZALEX should be administered by healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur [see Warnings and Precautions (5.1)]. Type and screen patients prior to starting DARZALEX [see Warnings and Precautions (5.2)]. 2.2Recommended Dosage. Monotherapy and In Combination with Lenalidomide (D-Rd) or Pomalidomide (D-Pd) and DexamethasoneThe DARZALEX dosing schedule in Table is for combination therapy (4-week cycle regimens) and monotherapy as follows:-combination therapy with lenalidomide and low-dose dexamethasone for newly diagnosed patients ineligible for autologous stem cell transplant (ASCT) and in patients with relapsed/refractory multiple myeloma-combination therapy with pomalidomide and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma-monotherapy for patients with relapsed/refractory multiple myeloma.The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:Table 1: DARZALEX Dosing Schedule in Combination With Lenalidomide or Pomalidomide (4-Week Cycle) and Low-Dose Dexamethasone and for MonotherapyWeeksScheduleWeeks to 8weekly (total of doses)Weeks to 24First dose of the every-2-week dosing schedule is given at Week every two weeks (total of doses)Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25 every four weeksFor dosing instructions of combination agents administered with DARZALEX, see Clinical Studies (14) and manufacturers prescribing information.. -combination therapy with lenalidomide and low-dose dexamethasone for newly diagnosed patients ineligible for autologous stem cell transplant (ASCT) and in patients with relapsed/refractory multiple myeloma. -combination therapy with pomalidomide and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma. -monotherapy for patients with relapsed/refractory multiple myeloma.. In Combination with Bortezomib, Melphalan and Prednisone (D-VMP)The DARZALEX dosing schedule in Table is for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma ineligible for ASCT.The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:Table 2: DARZALEX Dosing Schedule in Combination With Bortezomib, Melphalan and Prednisone ([VMP], 6-Week Cycle)WeeksScheduleWeeks to 6weekly (total of doses)Weeks to 54First dose of the every-3-week dosing schedule is given at Week every three weeks (total of 16 doses)Week 55 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 55 every four weeksFor dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.1). In Combination with Bortezomib, Thalidomide and Dexamethasone (D-VTd)The DARZALEX dosing schedule in Table is for combination therapy with bortezomib, thalidomide, and dexamethasone (4-week cycle regimen) for patients with newly diagnosed multiple myeloma eligible for ASCT.The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule: Table 3: DARZALEX Dosing Schedule in Combination With Bortezomib, Thalidomide and Dexamethasone ([VTd]; 4-Week Cycle)Treatment phaseWeeksScheduleInduction Weeks to 8weekly (total of doses)Weeks to 16First dose of the every-2-week dosing schedule is given at Week every two weeks (total of doses)Stop for high dose chemotherapy and ASCTConsolidationWeeks to 8First dose of the every-2-week dosing schedule is given at Week upon re-initiation of treatment following ASCT every two weeks (total of doses)For dosing instructions of combination agents administered with DARZALEX, see Clinical Studies (14.1) and the manufacturers prescribing information.. In Combination with Bortezomib and Dexamethasone (D-Vd)The DARZALEX dosing schedule in Table is for combination therapy with bortezomib and dexamethasone (3-week cycle) for patients with relapsed/refractory multiple myeloma.The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:Table 4: DARZALEX Dosing Schedule With Bortezomib and Dexamethasone (3-Week Cycle)WeeksScheduleWeeks to 9weekly (total of doses)Weeks 10 to 24First dose of the every-3-week dosing schedule is given at Week 10 every three weeks (total of doses)Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25 every four weeksFor dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.2) and manufacturers prescribing information. In Combination with Carfilzomib and Dexamethasone (DKd)The recommended dosage for DARZALEX when administered in combination with carfilzomib and dexamethasone (4-week cycle) for patients with relapsed/refractory multiple myeloma is provided in Table 5.Table 5: DARZALEX Dosing Schedule With Carfilzomib and Dexamethasone (4-Week Cycle)WeeksDARZALEX DoseBased on actual body weight ScheduleWeek 18 mg/kgdays and (total doses)Weeks to 816 mg/kgweekly (total of doses)Weeks to 24First dose of the every-2-week dosing schedule is given at Week 16 mg/kgevery two weeks (total of doses)Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25 16 mg/kgevery four weeksFor dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.1) and manufacturers prescribing information. Infusion RatesAdminister DARZALEX intravenously at the infusion rate described below in Table 6. Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions. The recommended dose of 16 mg/kg to be administered on Day when DARZALEX is administered as monotherapy or in combination may be split over two consecutive days, such that an mg/kg dose is administered on Day and Day 2, respectively.Table 6: Infusion Rates for DARZALEX (16 mg/kg) AdministrationDilution volumeInitial rate (first hour)Rate incrementConsider incremental escalation of the infusion rate only in the absence of infusion-related reactions. Maximum rateWeek InfusionOption (Single dose infusion)Week Day (16 mg/kg)1,000 mL50 mL/hour50 mL/hour every hour200 mL/hourOption (Split dose infusion)Week Day (8 mg/kg)500 mL50 mL/hour50 mL/hour every hour200 mL/hourWeek Day (8 mg/kg)500 mL50 mL/hour50 mL/hour every hour200 mL/hourWeek (16 mg/kg)Use dilution volume of 500 mL for the 16 mg/kg dose only if there were no infusion-related reactions the previous week. Otherwise, use dilution volume of 1,000 mL.500 mL50 mL/hour50 mL/hour every hour200 mL/hourWeek onwards (16 mg/kg)Use modified initial rate (100 mL/hour) for subsequent infusions (i.e. Week onwards) only if there were no infusion-related reactions during the previous infusion. Otherwise, continue to use instructions indicated in the table for the Week infusion rate.500 mL100 mL/hour50 mL/hour every hour200 mL/hour. Missed DARZALEX DosesIf dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.. 2.3Recommended Concomitant Medications. Pre-infusion MedicationAdminister the following pre-infusion medications hour to hours before every DARZALEX infusion:Corticosteroid (long- or intermediate-acting) Monotherapy:Administer methylprednisolone 100 mg (or equivalent) intravenously. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally or intravenously.In Combination:Administer dexamethasone 20 mg (or equivalent) orally or intravenously.When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days [see Clinical Studies (14)].Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as pre-medication. Acetaminophen 650 mg to 1,000 mg orallyDiphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously.. Corticosteroid (long- or intermediate-acting) Monotherapy:Administer methylprednisolone 100 mg (or equivalent) intravenously. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally or intravenously.In Combination:Administer dexamethasone 20 mg (or equivalent) orally or intravenously.When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days [see Clinical Studies (14)].Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as pre-medication. Monotherapy:Administer methylprednisolone 100 mg (or equivalent) intravenously. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally or intravenously.In Combination:Administer dexamethasone 20 mg (or equivalent) orally or intravenously.When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days [see Clinical Studies (14)].Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as pre-medication.. Acetaminophen 650 mg to 1,000 mg orally. Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously.. Post-infusion MedicationAdminister the following post-infusion medications: Monotherapy:Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for days starting the day after the administration of DARZALEX.In Combination:Consider administering oral methylprednisolone at dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of DARZALEX infusion.If background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed [see Clinical Studies (14)].For patients with history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience major infusion-related reaction.. Monotherapy:Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for days starting the day after the administration of DARZALEX.In Combination:Consider administering oral methylprednisolone at dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of DARZALEX infusion.If background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed [see Clinical Studies (14)].. Prophylaxis for Herpes Zoster ReactivationInitiate antiviral prophylaxis to prevent herpes zoster reactivation within week after starting DARZALEX and continue for months following the end of treatment [see Adverse Reactions (6.1)]. 2.4Dosage Modifications for Adverse Reactions. No dose reductions of DARZALEX are recommended. Consider withholding DARZALEX to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.3, 5.4)].For information concerning drugs given in combination with DARZALEX, see manufacturers prescribing information.. Infusion-Related ReactionsFor infusion-related reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion-related reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below [see Warnings and Precautions (5.1)].Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6).Grade (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade symptoms. Permanently discontinue DARZALEX upon the third occurrence of Grade or greater infusion-related reaction.Grade (life-threatening): Permanently discontinue DARZALEX.. Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6).. Grade (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade symptoms. Permanently discontinue DARZALEX upon the third occurrence of Grade or greater infusion-related reaction.. Grade (life-threatening): Permanently discontinue DARZALEX.. 2.5Preparation and Administration. PreparationDARZALEX is for single dose only.Prepare the solution for infusion using aseptic technique as follows:Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag [see Description (11), How Supplied/Storage and Handling (16)].Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.Remove volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of DARZALEX solution.Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table [see Dosage and Administration (2.2)]. Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.Gently invert the bag/container to mix the solution. Do not shake.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.If not used immediately, store the diluted solution refrigerated for up to 24 hours at 2C to 8C (36F to 46F) and/or at room temperature up to 15 hours at 15C to 25C (59F to 77F). The room temperature storage includes infusion time. Protect from light during storage. Do not freeze.. Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.. DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag [see Description (11), How Supplied/Storage and Handling (16)].. Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.. Remove volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of DARZALEX solution.. Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table [see Dosage and Administration (2.2)]. Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.. Gently invert the bag/container to mix the solution. Do not shake.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.. If not used immediately, store the diluted solution refrigerated for up to 24 hours at 2C to 8C (36F to 46F) and/or at room temperature up to 15 hours at 15C to 25C (59F to 77F). The room temperature storage includes infusion time. Protect from light during storage. Do not freeze.. AdministrationIf stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 micrometer or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.. If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 micrometer or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.. Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.. Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. DARZALEX is colorless to pale yellow, preservative-free solution available as:Injection:100 mg/5 mL (20 mg/mL) in single-dose vial.400 mg/20 mL (20 mg/mL) in single-dose vial.. 100 mg/5 mL (20 mg/mL) in single-dose vial.. 400 mg/20 mL (20 mg/mL) in single-dose vial.. Injection: 100 mg/5 mL solution in single-dose vial (3) 400 mg/20 mL solution in single-dose vial (3). 100 mg/5 mL solution in single-dose vial (3). 400 mg/20 mL solution in single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1Effects of Daratumumab on Laboratory Tests. Interference with Indirect Antiglobulin Tests (Indirect Coombs Test)Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References (15)] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs.If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices.. Interference with Serum Protein Electrophoresis and Immunofixation TestsDaratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous protein in the patients serum, to facilitate determination of complete response.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 2,459 patients who received DARZALEX at the recommended dose, 38% were 65 to 74 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. The incidence of serious adverse reactions was higher in older than in younger patients [see Adverse Reactions (6.1)]. Among patients with relapsed and refractory multiple myeloma (n=1,213), the serious adverse reactions that occurred more frequently in patients 65 years and older were pneumonia and sepsis. Within the DKd group in CANDOR, fatal adverse reactions occurred in 14% of patients 65 years and older compared to 6% of patients less than 65 years. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the serious adverse reaction that occurred more frequently in patients 75 years and older was pneumonia.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedDARZALEX(R) (daratumumab) injection is colorless to pale yellow, preservative-free solution for intravenous infusion.NDC 57894-502-05 and NDC 57894-505-05 each contain one 100 mg/5 mL single-dose vialNDC 57894-502-20 and NDC 57894-505-20 each contain one 400 mg/20 mL single-dose vial. Storage and StabilityStore in refrigerator at 2C to 8C (36F to 46F).Do not freeze or shake. Protect from light. This product contains no preservative.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity. 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 the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products may be misleading.In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and of the 1,383 evaluable combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DARZALEX is indicated for the treatment of adult patients with multiple myeloma:in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplantin combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and proteasome inhibitor.as monotherapy, in patients who have received at least three prior lines of therapy including proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to PI and an immunomodulatory agent.. in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.. in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.. in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.. in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.. in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and proteasome inhibitor.. as monotherapy, in patients who have received at least three prior lines of therapy including proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to PI and an immunomodulatory agent.. DARZALEX is CD38-directed cytolytic antibody indicated for the treatment of adult patients with multiple myeloma:in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapyin combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplantin combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplantin combination with bortezomib and dexamethasone in patients who have received at least one prior therapyin combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapyin combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and proteasome inhibitoras monotherapy, in patients who have received at least three prior lines of therapy including proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to PI and an immunomodulatory agent. (1). in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy. in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant. in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and proteasome inhibitor. as monotherapy, in patients who have received at least three prior lines of therapy including proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to PI and an immunomodulatory agent. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Infusion-Related ReactionsAdvise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: itchy, runny or blocked nose; fever, chills, nausea, vomiting, throat irritation, cough, headache, dizziness or lightheadedness, tachycardia, chest discomfort, wheezing, shortness of breath or difficulty breathing, itching, and blurred vision [see Warnings and Precautions (5.1)].. NeutropeniaAdvise patients to contact their healthcare provider if they have fever [see Warnings and Precautions (5.3)].. ThrombocytopeniaAdvise patients to contact their healthcare provider if they notice signs of bruising or bleeding [see Warnings and Precautions (5.4)].. Interference with Laboratory TestsAdvise patients to inform their healthcare providers, including personnel at blood transfusion centers that they are taking DARZALEX, in the event of planned transfusion [see Warnings and Precautions (5.2)].Advise patients that DARZALEX can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response [see Warnings and Precautions (5.5)].. Hepatitis Virus (HBV) ReactivationAdvise patients to inform healthcare providers if they have ever had or might have hepatitis infection and that DARZALEX could cause hepatitis virus to become active again [see Adverse Reactions (6.1)].. Embryo-Fetal ToxicityAdvise pregnant women of the potential hazard to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to avoid becoming pregnant during treatment with DARZALEX and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].Advise patients that lenalidomide, pomalidomide, or thalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide, pomalidomide, and thalidomide are only available through REMS program [see Use in Specific Populations (8.1, 8.3)].. Hereditary Fructose Intolerance (HFI)DARZALEX contains sorbitol. Advise patients with HFI of the risks related to sorbitol [see Description (11)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no data on the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX is administered with lenalidomide, pomalidomide, or thalidomide, advise women not to breastfeed during treatment with DARZALEX. Refer to lenalidomide, pomalidomide, or thalidomide prescribing information for additional information.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. CD38 is transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1 human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory cells (CD38+Tregs) and cells (CD38+Bregs) are decreased by daratumumab.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg/5 mL Vial Carton. NDC 57894-502-05DARZALEX(R) (daratumumab)Injection100 mg/5 mL(20 mg/mL)For Intravenous Infusion OnlyDilute Before UseRx onlySingle-dose vial. Discard Unused Portionjanssen. PRINCIPAL DISPLAY PANEL 100 mg/5 mL Vial Carton.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Daratumumab area under the concentration-time curve (AUC) increases more than proportionally over dosage range from to 24 mg/kg (0.06 to 1.5 times the approved recommended dosage) as monotherapy or to 16 mg/kg (0.06 to time the approved recommended dosage) as combination therapy.Following administration of the approved recommended dosage of DARZALEX as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) was approximately 2.7 to 3-fold higher at the end of weekly dosing compared to the first dose. The mean +- standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 +- 332 ug/mL when DARZALEX was administered as monotherapy and 502 +- 196 to 607 +- 231 ug/mL when DARZALEX was administered as combination therapy. Split dosing of the first dose resulted in different PK profile in the first day compared to single dosing; however, similar Cmax and Cmin concentrations were both predicted and observed following the administration of the second split dose on Week Day 2.When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately months into the every 4-week dosing period (by the 21st infusion). At steady state, daratumumab mean +- SD accumulation ratio for Cmax was 1.6 +- 0.5.. DistributionDaratumumab volume of distribution was 4.7 +- 1.3 as monotherapy and 4.4 +- 1.5 as combination therapy following administration of the approved dosage.. EliminationDaratumumab clearance decreased with increasing dose and with multiple dosing. The mean +- SD linear clearance was estimated to be 171.4 +- 95.3 mL/day and the mean +- SD estimated terminal half-life associated with linear clearance was 18 +- days following administration of the approved recommended dosage of DARZALEX as monotherapy. Terminal half-life was similar when DARZALEX was administered as combination therapy.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of daratumumab as monotherapy or as combination therapy were observed based on sex, age (31 to 93 years), mild [total bilirubin to 1.5 times upper limit of normal (ULN) or aspartate aminotransaminase (AST)>ULN] and moderate (total bilirubin 1.5 to times ULN and any AST) hepatic impairment, or renal impairment [Creatinine clearance (CLcr) 15-89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on daratumumab pharmacokinetics is unknown.. Body WeightThe central volume of distribution and clearance of daratumumab increased with increasing body weight.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of daratumumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System disorders: Anaphylactic reaction, IRR (including deaths)Gastrointestinal disorders: PancreatitisInfections: Cytomegalovirus, Listeriosis.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryDARZALEX can cause fetal harm when administered to pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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% to 4% and 15% to 20%, respectively.The combination of DARZALEX and lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Lenalidomide, pomalidomide, and thalidomide are only available through REMS program. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsImmunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until hematology evaluation is completed.. Data. Animal DataMice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by months of age. 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).

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.5) 10/2021Warnings and Precautions (5.1) 1/2022.

REFERENCES SECTION.

15 REFERENCES. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 1/2022PATIENT INFORMATIONDARZALEX(R) (Dar-zah-lex)(daratumumab)injection, for intravenous useWhat is DARZALEXDARZALEX is prescription medicine used to treat adults with multiple myeloma:in combination with the medicines lenalidomide and dexamethasone in people with newly diagnosed multiple myeloma who cannot receive type of stem cell transplant that uses their own stem cells (autologous stem cell transplant) and in people whose multiple myeloma has come back or did not respond to treatment who have received at least one prior medicine to treat multiple myeloma.in combination with the medicines bortezomib, melphalan and prednisone, in people with newly diagnosed multiple myeloma who cannot receive type of stem cell transplant that uses their own stem cells (autologous stem cell transplant).in combination with the medicines bortezomib, thalidomide, and dexamethasone in newly diagnosed people who are eligible to receive type of stem cell transplant that uses their own stem cells (autologous stem cell transplant). in combination with the medicines bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma.in combination with the medicines carfilzomib and dexamethasone, in people whose multiple myeloma has come back or did not respond to treatment who have received one to three prior medicines to treat multiple myeloma.in combination with the medicines pomalidomide and dexamethasone in people who have received at least two prior medicines to treat multiple myeloma, including lenalidomide and proteasome inhibitor.alone in people who have received at least three prior medicines, including proteasome inhibitor and an immunomodulatory agent, or did not respond to proteasome inhibitor and an immunomodulatory agent.It is not known if DARZALEX is safe and effective in children.Do not receive DARZALEX: if you have history of severe allergic reaction to daratumumab or any of the ingredients in DARZALEX. See the end of this leaflet for complete list of ingredients in DARZALEX.Before you receive DARZALEX, tell your healthcare provider about all of your medical conditions, including if you:have history of breathing problems.have had shingles (herpes zoster).have ever had or might now have hepatitis infection as DARZALEX could cause hepatitis virus to become active again. Your healthcare provider will check you for signs of this infection before, during and for some time after treatment with DARZALEX. Tell your healthcare provider right away if you get worsening tiredness or yellowing of your skin or white part of your eyes.have hereditary fructose intolerance (HFI). DARZALEX contains sorbitol. Sorbitol is source of fructose. People with HFI cannot break down fructose, which may cause serious side effects.are pregnant or plan to become pregnant. DARZALEX may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with DARZALEX.Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment and for months after your last dose of DARZALEX. Talk to your healthcare provider about birth control methods that you can use during this time.Before starting DARZALEX in combination with lenalidomide, pomalidomide, or thalidomide, females and males must agree to the instructions in the lenalidomide, pomalidomide, or thalidomide REMS program.The lenalidomide, pomalidomide, and thalidomide REMS has more information about effective methods of birth control, pregnancy testing, and blood donation for females who can become pregnant.For males who have female partners who can become pregnant, there is information in the lenalidomide, pomalidomide, and thalidomide REMS about sperm donation and how lenalidomide, pomalidomide, and thalidomide can pass into human semen. are breastfeeding or plan to breastfeed. It is not known if DARZALEX passes into your breast milk. You should not breastfeed during treatment with DARZALEX. Talk to your healthcare provider about the best way to feed your baby during treatment with DARZALEX.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive DARZALEXDARZALEX may be given alone or together with other medicines used to treat multiple myeloma.DARZALEX will be given to you by your healthcare provider by intravenous (IV) infusion into your vein.Your healthcare provider will decide the time between doses as well as how many treatments you will receive.Your healthcare provider will give you medicines before each dose of DARZALEX and after each dose of DARZALEX to help reduce the risk of infusion-related reactions.If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of DARZALEXDARZALEX may cause serious reactions, including:Infusion-related reactions. Infusion-related reactions are common with DARZALEX. Serious allergic reactions and reactions due to release of certain substances by your body (systemic) that can lead to death, can happen with DARZALEX. Your healthcare provider may temporarily stop your infusion or completely stop treatment with DARZALEX if you have infusion-related reactions. Get medical help right away if you get any of the following symptoms:shortness of breath or trouble breathingdizziness or lightheadedness (hypotension)coughwheezingheart beating faster than usuallow oxygen in the blood (hypoxia)throat tightness or irritationrunny or stuffy noseheadacheitchinghigh blood pressurenauseavomitingchillsfeverchest discomfortblurred visionChanges in blood tests. DARZALEX can affect the results of blood tests to match your blood type. These changes can last for up to months after your final dose of DARZALEX. Your healthcare provider will do blood tests to match your blood type before you start treatment with DARZALEX. Tell all of your healthcare providers that you are being treated with DARZALEX before receiving blood transfusions. Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Your healthcare provider will check your blood cell counts during treatment with DARZALEX. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.The most common side effects of DARZALEX include:tirednessnauseadiarrheashortness of breathfeeling weakfevercoughcold-like symptoms (upper respiratory infection)nerve damage causing tingling, numbness or painswollen hands ankles or feetconstipationThese are not all the possible side effects of DARZALEX.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of DARZALEXMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about DARZALEX that is written for health professionals.What are the ingredients in DARZALEXActive ingredient: daratumumab Inactive ingredients: may include glacial acetic acid, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, mannitol, polysorbate 20, sodium acetate trihydrate, sodium chloride, sorbitol, and water for injection.Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044 U.S. License Number 1864For more information, call 1-800-526-7736 or go to www.DARZALEX.com.. in combination with the medicines lenalidomide and dexamethasone in people with newly diagnosed multiple myeloma who cannot receive type of stem cell transplant that uses their own stem cells (autologous stem cell transplant) and in people whose multiple myeloma has come back or did not respond to treatment who have received at least one prior medicine to treat multiple myeloma.. in combination with the medicines bortezomib, melphalan and prednisone, in people with newly diagnosed multiple myeloma who cannot receive type of stem cell transplant that uses their own stem cells (autologous stem cell transplant).. in combination with the medicines bortezomib, thalidomide, and dexamethasone in newly diagnosed people who are eligible to receive type of stem cell transplant that uses their own stem cells (autologous stem cell transplant). in combination with the medicines bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma.. in combination with the medicines carfilzomib and dexamethasone, in people whose multiple myeloma has come back or did not respond to treatment who have received one to three prior medicines to treat multiple myeloma.. in combination with the medicines pomalidomide and dexamethasone in people who have received at least two prior medicines to treat multiple myeloma, including lenalidomide and proteasome inhibitor.. alone in people who have received at least three prior medicines, including proteasome inhibitor and an immunomodulatory agent, or did not respond to proteasome inhibitor and an immunomodulatory agent.. if you have history of severe allergic reaction to daratumumab or any of the ingredients in DARZALEX. See the end of this leaflet for complete list of ingredients in DARZALEX.. have history of breathing problems.. have had shingles (herpes zoster).. have ever had or might now have hepatitis infection as DARZALEX could cause hepatitis virus to become active again. Your healthcare provider will check you for signs of this infection before, during and for some time after treatment with DARZALEX. Tell your healthcare provider right away if you get worsening tiredness or yellowing of your skin or white part of your eyes.. have hereditary fructose intolerance (HFI). DARZALEX contains sorbitol. Sorbitol is source of fructose. People with HFI cannot break down fructose, which may cause serious side effects.. are pregnant or plan to become pregnant. DARZALEX may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with DARZALEX.Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment and for months after your last dose of DARZALEX. Talk to your healthcare provider about birth control methods that you can use during this time.Before starting DARZALEX in combination with lenalidomide, pomalidomide, or thalidomide, females and males must agree to the instructions in the lenalidomide, pomalidomide, or thalidomide REMS program.The lenalidomide, pomalidomide, and thalidomide REMS has more information about effective methods of birth control, pregnancy testing, and blood donation for females who can become pregnant.For males who have female partners who can become pregnant, there is information in the lenalidomide, pomalidomide, and thalidomide REMS about sperm donation and how lenalidomide, pomalidomide, and thalidomide can pass into human semen. Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment and for months after your last dose of DARZALEX. Talk to your healthcare provider about birth control methods that you can use during this time.. Before starting DARZALEX in combination with lenalidomide, pomalidomide, or thalidomide, females and males must agree to the instructions in the lenalidomide, pomalidomide, or thalidomide REMS program.The lenalidomide, pomalidomide, and thalidomide REMS has more information about effective methods of birth control, pregnancy testing, and blood donation for females who can become pregnant.For males who have female partners who can become pregnant, there is information in the lenalidomide, pomalidomide, and thalidomide REMS about sperm donation and how lenalidomide, pomalidomide, and thalidomide can pass into human semen. The lenalidomide, pomalidomide, and thalidomide REMS has more information about effective methods of birth control, pregnancy testing, and blood donation for females who can become pregnant.. For males who have female partners who can become pregnant, there is information in the lenalidomide, pomalidomide, and thalidomide REMS about sperm donation and how lenalidomide, pomalidomide, and thalidomide can pass into human semen.. are breastfeeding or plan to breastfeed. It is not known if DARZALEX passes into your breast milk. You should not breastfeed during treatment with DARZALEX. Talk to your healthcare provider about the best way to feed your baby during treatment with DARZALEX.. DARZALEX may be given alone or together with other medicines used to treat multiple myeloma.. DARZALEX will be given to you by your healthcare provider by intravenous (IV) infusion into your vein.. Your healthcare provider will decide the time between doses as well as how many treatments you will receive.. Your healthcare provider will give you medicines before each dose of DARZALEX and after each dose of DARZALEX to help reduce the risk of infusion-related reactions.. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.. Infusion-related reactions. Infusion-related reactions are common with DARZALEX. Serious allergic reactions and reactions due to release of certain substances by your body (systemic) that can lead to death, can happen with DARZALEX. Your healthcare provider may temporarily stop your infusion or completely stop treatment with DARZALEX if you have infusion-related reactions. Get medical help right away if you get any of the following symptoms:. shortness of breath or trouble breathing. dizziness or lightheadedness (hypotension). cough. wheezing. heart beating faster than usual. low oxygen in the blood (hypoxia). throat tightness or irritation. runny or stuffy nose. headache. itching. high blood pressure. nausea. vomiting. chills. fever. chest discomfort. blurred vision. Changes in blood tests. DARZALEX can affect the results of blood tests to match your blood type. These changes can last for up to months after your final dose of DARZALEX. Your healthcare provider will do blood tests to match your blood type before you start treatment with DARZALEX. Tell all of your healthcare providers that you are being treated with DARZALEX before receiving blood transfusions. Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Your healthcare provider will check your blood cell counts during treatment with DARZALEX. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.. tiredness. nausea. diarrhea. shortness of breath. feeling weak. fever. cough. cold-like symptoms (upper respiratory infection). nerve damage causing tingling, numbness or pain. swollen hands ankles or feet. constipation.

SPL UNCLASSIFIED SECTION.

2.1Important Dosing Information. Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.3)].Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)]. DARZALEX should be administered by healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur [see Warnings and Precautions (5.1)]. Type and screen patients prior to starting DARZALEX [see Warnings and Precautions (5.2)]. Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.3)].. Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)]. DARZALEX should be administered by healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur [see Warnings and Precautions (5.1)]. Type and screen patients prior to starting DARZALEX [see Warnings and Precautions (5.2)].

STORAGE AND HANDLING SECTION.

Storage and StabilityStore in refrigerator at 2C to 8C (36F to 46F).Do not freeze or shake. Protect from light. This product contains no preservative.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryDARZALEX can cause fetal harm when administered to pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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% to 4% and 15% to 20%, respectively.The combination of DARZALEX and lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Lenalidomide, pomalidomide, and thalidomide are only available through REMS program. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsImmunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until hematology evaluation is completed.. Data. Animal DataMice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by months of age. 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).. 8.2 Lactation. Risk SummaryThere is no data on the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX is administered with lenalidomide, pomalidomide, or thalidomide, advise women not to breastfeed during treatment with DARZALEX. Refer to lenalidomide, pomalidomide, or thalidomide prescribing information for additional information.. 8.3Females and Males of Reproductive Potential. DARZALEX can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingWith the combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide, refer to the lenalidomide, pomalidomide, or thalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.. ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with DARZALEX and for months after the last dose. Additionally, refer to the lenalidomide, pomalidomide, or thalidomide labeling for additional recommendations for contraception.. 8.4 Pediatric Use. Safety and effectiveness of DARZALEX in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 2,459 patients who received DARZALEX at the recommended dose, 38% were 65 to 74 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. The incidence of serious adverse reactions was higher in older than in younger patients [see Adverse Reactions (6.1)]. Among patients with relapsed and refractory multiple myeloma (n=1,213), the serious adverse reactions that occurred more frequently in patients 65 years and older were pneumonia and sepsis. Within the DKd group in CANDOR, fatal adverse reactions occurred in 14% of patients 65 years and older compared to 6% of patients less than 65 years. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the serious adverse reaction that occurred more frequently in patients 75 years and older was pneumonia.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infusion-related reactions: Interrupt DARZALEX infusion for infusion-related reactions of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening infusion-related reactions and institute appropriate emergency care. (2.4, 5.1)Interference with cross-matching and red blood cell antibody screening: Type and screen patients prior to starting treatment. Inform blood banks that patient has received DARZALEX. (5.2, 7.1)Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Dose delay may be required to allow recovery of neutrophils. (5.3)Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets. (5.4)Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to fetus and advise females of reproductive potential to use effective contraception (5.6, 8.1, 8.3).. Infusion-related reactions: Interrupt DARZALEX infusion for infusion-related reactions of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening infusion-related reactions and institute appropriate emergency care. (2.4, 5.1). Interference with cross-matching and red blood cell antibody screening: Type and screen patients prior to starting treatment. Inform blood banks that patient has received DARZALEX. (5.2, 7.1). Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Dose delay may be required to allow recovery of neutrophils. (5.3). Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets. (5.4). Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to fetus and advise females of reproductive potential to use effective contraception (5.6, 8.1, 8.3).. 5.1Infusion-Related Reactions. DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported [see Adverse Reactions (6.3)].In clinical trials (monotherapy and combination: N=2,066), infusion-related reactions occurred in 37% of patients with the Week (16 mg/kg) infusion, 2% with the Week infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had Grade 3/4 infusion-related reaction at Week or subsequent infusions. The median time to onset was 1.5 hours (range: to 73 hours). The incidence of infusion modification due to reactions was 36%. Median durations of 16 mg/kg infusions for the Week 1, Week 2, and subsequent infusions were approximately 7, 4, and hours respectively. Nearly all reactions occurred during infusion or within hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion-related reactions occurred up to 48 hours after infusion.Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision [see Adverse Reactions (6.1)].When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption for ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade or 4:<1%) with those reported in previous studies at Week or subsequent infusions.In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week split over two days i.e. mg/kg on Day and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day of Week 1, 4% on Day of Week 1, and 8% with subsequent infusions. The median time to onset of reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 hours for Week 1-Day 1, 4.2 hours for Week 1-Day 2, and 3.4 hours for the subsequent infusions.Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion [see Dosage and Administration (2.3)]. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.4)].To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions [see Dosage and Administration (2.3)]. Patients with history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease [see Dosage and Administration (2.3)].Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.. 5.2Interference with Serological Testing. Daratumumab binds to CD38 on red blood cells (RBCs) and results in positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patients serum [see References (15)]. The determination of patients ABO and Rh blood type are not impacted [see Drug Interactions (7.1)].Notify blood transfusion centers of this interference with serological testing and inform blood banks that patient has received DARZALEX. Type and screen patients prior to starting DARZALEX [see Dosage and Administration (2.1)].. 5.3Neutropenia. DARZALEX may increase neutropenia induced by background therapy [see Adverse Reactions (6.1)]. Monitor complete blood cell counts periodically during treatment according to manufacturers prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX until recovery of neutrophils.. 5.4Thrombocytopenia. DARZALEX may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1)]. Monitor complete blood cell counts periodically during treatment according to manufacturers prescribing information for background therapies. Consider withholding DARZALEX until recovery of platelets.. 5.5Interference with Determination of Complete Response. Daratumumab is human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.1)]. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.. 5.6Embryo-Fetal Toxicity. Based on the mechanism of action, DARZALEX can cause fetal harm when administered to pregnant woman. DARZALEX may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.