ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity and Other Administration Reactions [see Warnings and Precautions (5.1)]. Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Warnings and Precautions (5.2)]. Neutropenia [see Warnings and Precautions (5.3)]. Thrombocytopenia [see Warnings and Precautions (5.4)].. Hypersensitivity and Other Administration Reactions [see Warnings and Precautions (5.1)].. Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Warnings and Precautions (5.2)].. Neutropenia [see Warnings and Precautions (5.3)].. Thrombocytopenia [see Warnings and Precautions (5.4)].. The most common adverse reaction (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO monotherapy is upper respiratory tract infection. (6.1)The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. (6.1)The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. (6.1)The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-Pd are fatigue, pneumonia, upper respiratory tract infection, and diarrhea (6.1)The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-Kd are upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral. (6.1)The most common adverse reactions (>=20%) in patients with light chain (AL) amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. (6.1)The most common (>=40%) hematology laboratory abnormalities with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. (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.. The most common adverse reaction (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO monotherapy is upper respiratory tract infection. (6.1). The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. (6.1). The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. (6.1). The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-Pd are fatigue, pneumonia, upper respiratory tract infection, and diarrhea (6.1). The most common adverse reactions (>=20%) in patients with multiple myeloma who received DARZALEX FASPRO-Kd are upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral. (6.1). The most common adverse reactions (>=20%) in patients with light chain (AL) amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. (6.1). The most common (>=40%) hematology laboratory abnormalities with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. (6.1). 6.1Clinical 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.. Newly Diagnosed Multiple Myeloma. In Combination with Bortezomib, Melphalan and PrednisoneThe safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in single-arm cohort of PLEIADES [see Clinical Studies (14.1)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 6, once every weeks from weeks to 54 and once every weeks starting with week 55 until disease progression or unacceptable toxicity (N=67) in combination with bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for months or longer and 19% were exposed for greater than one year.Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than patient was neutropenic sepsis.Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia.The most common adverse reactions (>=20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.Table summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.Table 6: Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADESAdverse ReactionDARZALEX FASPRO with Bortezomib, Melphalan and Prednisone(N=67) All Grades(%) Grades >=3(%) Infections Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. 390 Bronchitis160 PneumoniaPneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. 157Only grade adverse reactions occurred. Gastrointestinal disorders Constipation370 Nausea360 Diarrhea333 Vomiting210 Abdominal painAbdominal pain includes abdominal pain, and abdominal pain upper. 130General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 363 Pyrexia340 Edema peripheralEdema peripheral includes edema, edema peripheral, and peripheral swelling. 131 Nervous system disorders Peripheral sensory neuropathy341 Dizziness100Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 240Psychiatric disorders Insomnia223 Musculoskeletal and connective tissue disorders Back pain213 Musculoskeletal chest pain120Metabolism and nutrition disorders Decreased appetite151 Skin and subcutaneous tissue disorders Rash130 Pruritus120Vascular disorders Hypertension136 Hypotension103 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone included:General disorders and administration site conditions: infusion reaction, injection site reaction, chillsInfections: herpes zoster, urinary tract infection, influenza, sepsisMusculoskeletal and connective tissue disorders: arthralgia, muscle spasmsNervous system disorders: headache, paresthesiaMetabolism and nutrition disorders: hypocalcemia, hyperglycemiaRespiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edemaCardiac disorders: atrial fibrillationTable summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.Table 7: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADESLaboratory AbnormalityDARZALEX FASPRO with Bortezomib, Melphalan and PrednisoneDenominator is based on the safety population treated with DARZALEX FASPRO-VMP (N=67). All Grades(%) Grades 3-4(%) Decreased leukocytes9652Decreased lymphocytes9384Decreased platelets9342Decreased neutrophils8849Decreased hemoglobin4819. General disorders and administration site conditions: infusion reaction, injection site reaction, chills. Infections: herpes zoster, urinary tract infection, influenza, sepsis. Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms. Nervous system disorders: headache, paresthesia. Metabolism and nutrition disorders: hypocalcemia, hyperglycemia. Respiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edema. Cardiac disorders: atrial fibrillation. Relapsed/Refractory Multiple Myeloma. In Combination with Lenalidomide and DexamethasoneThe safety of DARZALEX FASPRO with lenalidomide and dexamethasone was evaluated in single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for months or longer and 20% were exposed for greater than one year.Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients.Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than patient were pneumonia and anemia.Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased.The most common adverse reactions (>=20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.Table summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.Table 8: Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADESAdverse ReactionDARZALEX FASPRO with Lenalidomide and Dexamethasone(N=65) All Grades(%)Grades >=3(%)General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 525Only grade adverse reactions occurred. Pyrexia232 Edema peripheral183 Gastrointestinal disorders Diarrhea455 Constipation262 Nausea120 Vomiting110Infections Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 433 PneumoniaPneumonia includes lower respiratory tract infection, lung infection, and pneumonia. 2317 BronchitisBronchitis includes bronchitis, and bronchitis viral. 142 Urinary tract infection110Musculoskeletal and connective tissue disorders Muscle spasms312 Back pain140Respiratory, thoracic and mediastinal disorders DyspneaDyspnea includes dyspnea, and dyspnea exertional. 223 CoughCough includes cough, and productive cough. 140Nervous system disorders Peripheral sensory neuropathy172 Psychiatric disorders Insomnia175 Metabolism and nutrition disorders Hyperglycemia129 Hypocalcemia110Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with lenalidomide and dexamethasone included:Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest painNervous system disorders: dizziness, headache, paresthesiaSkin and subcutaneous tissue disorders: rash, pruritusGastrointestinal disorders: abdominal painInfections: influenza, sepsis, herpes zosterMetabolism and nutrition disorders: decreased appetiteCardiac disorders: atrial fibrillationGeneral disorders and administration site conditions: chills, infusion reaction, injection site reactionVascular disorders: hypotension, hypertensionTable summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.Table 9: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADESLaboratory AbnormalityDARZALEX FASPRO with Lenalidomide and DexamethasoneDenominator is based on the safety population treated with DARZALEX FASPRO-Rd (N=65). All Grades(%)Grades 3-4(%)Decreased leukocytes9434Decreased lymphocytes8258Decreased platelets869Decreased neutrophils8952Decreased hemoglobin458. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain. Nervous system disorders: dizziness, headache, paresthesia. Skin and subcutaneous tissue disorders: rash, pruritus. Gastrointestinal disorders: abdominal pain. Infections: influenza, sepsis, herpes zoster. Metabolism and nutrition disorders: decreased appetite. Cardiac disorders: atrial fibrillation. General disorders and administration site conditions: chills, infusion reaction, injection site reaction. Vascular disorders: hypotension, hypertension. In Combination with Pomalidomide and DexamethasoneThe safety of DARZALEX FASPRO with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone (Pd) in patients who had received at least one prior line of therapy with lenalidomide and proteasome inhibitor (PI) was evaluated in APOLLO [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity in combination with pomalidomide and dexamethasone (n=149) or pomalidomide and dexamethasone (n=150). Among patients receiving DARZALEX FASPRO-Pd, 71% were exposed for months or longer and 50% were exposed for greater than one year.Serious adverse reactions occurred in 50% of patients who received DARZALEX FASPRO-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO-Pd were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients who received DARZALEX FASPRO-Pd.Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-Pd.The most common adverse reactions (>=20%) were fatigue, pneumonia, upper respiratory tract infection, and diarrhea.Table 10 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO.Table 10:Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the DARZALEX FASPRO-Pd Arm in APOLLOAdverse ReactionDARZALEX FASPRO-Pd (N=149) Pd (N=150)All Grades(%)Grades >=3(%)All Grades(%)Grades >=3(%)Key: Pd=pomalidomide-dexamethasoneGeneral disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 4613395Only grade adverse reactions occurred. Pyrexia190140 Edema peripheralEdema peripheral includes edema, edema peripheral and peripheral swelling. 15090Infections PneumoniaPneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. 3823Grade adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO-Pd arm and n=2 (1.3%) in the Pd arm. 2717 Upper respiratory infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection. 361 222 Gastrointestinal disorders Diarrhea225 141 Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 13080Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with pomalidomide and dexamethasone include:Metabolism and nutrition disorders: hypocalcemia, hypokalemia, decreased appetite, dehydrationNervous system disorders: peripheral sensory neuropathy, syncope, headache, paresthesia, dizzinessMusculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgiaPsychiatric disorders: insomniaGastrointestinal disorders: nausea, abdominal pain, vomitingSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: atrial fibrillationGeneral disorders and administration site conditions: infusion reactions, chills, injection site reactionInfections: urinary tract infection, influenza, hepatitis reactivation, herpes zoster, sepsisVascular disorders: hypertension, hypotensionTable 11 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in APOLLO.Table 11:Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Pd or Pd in APOLLOLaboratory AbnormalityDARZALEX FASPRO-PdDenominator is based on number of subjects with baseline and post-baseline laboratory value for each laboratory test: N=148 for DARZALEX FASPRO-Pd and N=149 for Pd. Pd All Grades(%) Grades 3-4(%) All Grades(%) Grades 3-4(%)Key: Pd=pomalidomide-dexamethasoneDecreased neutrophils97848463Decreased leukocytes95648240Decreased lymphocytes93597933Decreased platelets75196019Decreased hemoglobin51165715. Metabolism and nutrition disorders: hypocalcemia, hypokalemia, decreased appetite, dehydration. Nervous system disorders: peripheral sensory neuropathy, syncope, headache, paresthesia, dizziness. Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia. Psychiatric disorders: insomnia. Gastrointestinal disorders: nausea, abdominal pain, vomiting. Skin and subcutaneous tissue disorders: rash, pruritus. Cardiac disorders: atrial fibrillation. General disorders and administration site conditions: infusion reactions, chills, injection site reaction. Infections: urinary tract infection, influenza, hepatitis reactivation, herpes zoster, sepsis. Vascular disorders: hypertension, hypotension. In Combination with Carfilzomib and DexamethasoneThe safety of DARZALEX FASPRO with carfilzomib and dexamethasone was evaluated in single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from Weeks to 8, once every weeks from Weeks to 24 and once every weeks starting with Week 25 until disease progression or unacceptable toxicity (N=66) in combination with carfilzomib and dexamethasone. Among these patients, 77% were exposed for months or longer and 27% were exposed for greater than one year.Serious adverse reactions occurred in 27% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone.Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO.Dosage interruptions due to an adverse reaction occurred in 46% of patients who received DARZALEX FASPRO.The most common adverse reactions (>=20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.Table 12 summarizes the adverse reactions in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES.Table 12:Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO with Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) in PLEIADESAdverse ReactionDARZALEX FASPRO-Kd (N=66) All Grades (%)Grade >=3 (%)Infections and infestations Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. 520 BronchitisBronchitis includes bronchitis, and bronchitis viral. 122Only Grade adverse reactions occurred. General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 392 Pyrexia212 Edema peripheralEdema peripheral includes generalized edema, edema peripheral, and peripheral swelling. 200Psychiatric disorders Insomnia336 Vascular disorders HypertensionHypertension includes blood pressure increased, and hypertension. 3221 Gastrointestinal disorders Diarrhea290 Nausea210 Vomiting150Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 240 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 232 Nervous system disorders Headache230 Peripheral sensory neuropathy110Musculoskeletal and connective tissue disorders Back pain172 Musculoskeletal chest pain110Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with carfilzomib and dexamethasone include:Gastrointestinal disorders: abdominal pain, constipation, pancreatitisInfection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsisMetabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, arthralgiaNervous system disorders: paresthesia, dizziness, syncopeGeneral disorders and administration site conditions: injection site reaction, infusion reactions, chillsSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: cardiac failureVascular disorders: hypotensionTable 13 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone in PLEIADES.Table 13:Select Laboratory Abnormalities (>=30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADESLaboratory AbnormalityDARZALEX FASPRO-KdDenominator is based on the safety population treated with DARZALEX FASPRO-Kd (N=66). All Grades (%)Grades 3-4 (%)Decreased platelets8818Decreased lymphocytes8350Decreased leukocytes6818Decreased neutrophils5515Decreased hemoglobin476Decreased corrected calcium452Increased alanine aminotransferase (ALT)355. Gastrointestinal disorders: abdominal pain, constipation, pancreatitis. Infection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsis. Metabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemia. Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia. Nervous system disorders: paresthesia, dizziness, syncope. General disorders and administration site conditions: injection site reaction, infusion reactions, chills. Skin and subcutaneous tissue disorders: rash, pruritus. Cardiac disorders: cardiac failure. Vascular disorders: hypotension. MonotherapyThe safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see Clinical Trials (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO, 37% were exposed for months or longer and 1% were exposed for greater than one year.Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than patient were general physical health deterioration, septic shock, and respiratory failure.Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than patients were thrombocytopenia and hypercalcemia.Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia.The most common adverse reaction (>=20%) was upper respiratory tract infection.Table 14 summarizes the adverse reactions in COLUMBA.Table 14: Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBAAdverse ReactionDARZALEX FASPRO(N=260)Intravenous Daratumumab(N=258)All Grades(%)Grade >=3(%)All Grades(%)Grade >=3(%)Infections Upper respiratory tract infectionUpper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection. 241Only grade adverse reactions occurred. 221 PneumoniaPneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. 85106Grade adverse reactions occurred. Gastrointestinal disorders Diarrhea151 110.4 Nausea80.4 110.4 General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 151 162 Infusion reactionsInfusion reactions includes terms determined by investigators to be related to infusion. 132 345 Pyrexia130131 Chills60.4 121 Musculoskeletal and connective tissue disorders Back pain102 123 Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 91 140 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 61 111 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included:General disorders and administration site conditions: injection site reaction, peripheral edemaMusculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasmsGastrointestinal disorders: constipation, vomiting, abdominal painMetabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydrationPsychiatric disorders: insomniaVascular disorders: hypertension, hypotensionNervous system disorders: dizziness, peripheral sensory neuropathy, paresthesiaInfections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis virus reactivationSkin and subcutaneous tissue disorders: pruritus, rashCardiac disorders: atrial fibrillationRespiratory, thoracic and mediastinal disorders: pulmonary edemaTable 15 summarizes the laboratory abnormalities in COLUMBA.Table 15: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBALaboratory AbnormalityDARZALEX FASPRODenominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258). Intravenous Daratumumab All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Decreased leukocytes65195714Decreased lymphocytes59365636Decreased neutrophils55194311Decreased platelets43164514Decreased hemoglobin42143916. General disorders and administration site conditions: injection site reaction, peripheral edema. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasms. Gastrointestinal disorders: constipation, vomiting, abdominal pain. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration. Psychiatric disorders: insomnia. Vascular disorders: hypertension, hypotension. Nervous system disorders: dizziness, peripheral sensory neuropathy, paresthesia. Infections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis virus reactivation. Skin and subcutaneous tissue disorders: pruritus, rash. Cardiac disorders: atrial fibrillation. Respiratory, thoracic and mediastinal disorders: pulmonary edema. Light Chain Amyloidosis. In Combination with Bortezomib, Cyclophosphamide and DexamethasoneThe safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (DARZALEX FASPRO-VCd) was evaluated in ANDROMEDA [see Clinical Studies (14.3)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity or maximum of years. Among patients who received DARZALEX FASPRO-VCd, 74% were exposed for months or longer and 32% were exposed for greater than one year.Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX FASPRO-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure.Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required dosage interruption in >=3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%).The most common adverse reactions (>=20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.Table 16 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA.Table 16: Adverse Reactions (>=10%) in Patients with AL Amyloidosis Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) with Difference Between Arms of >5% Compared to VCd in ANDROMEDAAdverse ReactionDARZALEX FASPRO-VCd(N=193)VCd(N=188)All Grades(%) Grades 3-4(%) All Grades(%) Grades 3-4(%) Infections Upper respiratory tract infectionUpper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. 401Only grade adverse reactions occurred. 211 PneumoniaPneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. 151095Gastrointestinal disorders Diarrhea366 304 Constipation342 290Nervous system disorders Peripheral sensory neuropathy313 202 Respiratory, thoracic and mediastinal disorders DyspneaDyspnea includes dyspnea, and dyspnea exertional. 264204 CoughCough includes cough, and productive cough. 201 110Musculoskeletal and connective tissue disorders Back pain122 60 Arthralgia10050 Muscle spasms101 50Cardiac disorders ArrhythmiaArrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia 11452General disorders and administration site conditions Injection site reactionsInjection site reactions includes terms determined by investigators to be related to daratumumab injection. 11000Clinically relevant adverse reactions not included in Table 16 and occurred in patients who received DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone included:Skin and subcutaneous tissue disorders: rash, pruritusNervous system disorders: paresthesiaGeneral disorders and administration site conditions: infusion reaction, chillsCardiac disorders: cardiac failureCardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients., cardiac arrestMetabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydrationInfections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenzaVascular disorders: hypertensionMusculoskeletal and connective tissue disorders: musculoskeletal chest painGastrointestinal disorders: pancreatitisRespiratory, thoracic and mediastinal disorders: pulmonary edemaTable 17 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in ANDROMEDA.Table 17: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) in ANDROMEDALaboratory AbnormalityDARZALEX FASPRO-VCdVCdAll Grades(%)Grades 3-4(%) All Grades(%)Grades 3-4(%)Denominator is based on the number of patients with baseline and post-baseline laboratory value for each laboratory test, N=188 for DARZALEX FASPRO-VCd and N=186 for VCd.Decreased lymphocytes81547146Decreased hemoglobin666706Decreased leukocytes607464Decreased platelets463404Decreased neutrophils306184. Skin and subcutaneous tissue disorders: rash, pruritus. Nervous system disorders: paresthesia. General disorders and administration site conditions: infusion reaction, chills. Cardiac disorders: cardiac failureCardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients., cardiac arrest. Metabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydration. Infections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenza. Vascular disorders: hypertension. Musculoskeletal and connective tissue disorders: musculoskeletal chest pain. Gastrointestinal disorders: pancreatitis. Respiratory, thoracic and mediastinal disorders: pulmonary edema. Cardiac Adverse Reactions in Light Chain (AL) AmyloidosisAmong patients who received DARZALEX FASPRO in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage (3%), Stage II (46%) and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage and II and 28% of patients with Stage III). Serious cardiac disorders in >2% of patients included cardiac failure (8%), cardiac arrest (4%) and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage and II and 19% of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the DARZALEX FASPRO-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).. 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 or other hyaluronidase products may be misleading.In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of combination therapy, less than 1% of 819 patients developed treatment-emergent anti-daratumumab antibodies.In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of combination therapy, 7% of 812 patients developed treatment-emergent anti-rHuPH20 antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.. 6.3 Postmarketing Experience. The following adverse reactions have been identified with 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: Anaphylactic reaction, Systemic administration reactions (including death)Gastrointestinal: PancreatitisInfections: Cytomegalovirus, Listeriosis.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical 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.. Newly Diagnosed Multiple Myeloma. In Combination with Bortezomib, Melphalan and PrednisoneThe safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in single-arm cohort of PLEIADES [see Clinical Studies (14.1)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 6, once every weeks from weeks to 54 and once every weeks starting with week 55 until disease progression or unacceptable toxicity (N=67) in combination with bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for months or longer and 19% were exposed for greater than one year.Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than patient was neutropenic sepsis.Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia.The most common adverse reactions (>=20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.Table summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.Table 6: Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADESAdverse ReactionDARZALEX FASPRO with Bortezomib, Melphalan and Prednisone(N=67) All Grades(%) Grades >=3(%) Infections Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. 390 Bronchitis160 PneumoniaPneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. 157Only grade adverse reactions occurred. Gastrointestinal disorders Constipation370 Nausea360 Diarrhea333 Vomiting210 Abdominal painAbdominal pain includes abdominal pain, and abdominal pain upper. 130General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 363 Pyrexia340 Edema peripheralEdema peripheral includes edema, edema peripheral, and peripheral swelling. 131 Nervous system disorders Peripheral sensory neuropathy341 Dizziness100Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 240Psychiatric disorders Insomnia223 Musculoskeletal and connective tissue disorders Back pain213 Musculoskeletal chest pain120Metabolism and nutrition disorders Decreased appetite151 Skin and subcutaneous tissue disorders Rash130 Pruritus120Vascular disorders Hypertension136 Hypotension103 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone included:General disorders and administration site conditions: infusion reaction, injection site reaction, chillsInfections: herpes zoster, urinary tract infection, influenza, sepsisMusculoskeletal and connective tissue disorders: arthralgia, muscle spasmsNervous system disorders: headache, paresthesiaMetabolism and nutrition disorders: hypocalcemia, hyperglycemiaRespiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edemaCardiac disorders: atrial fibrillationTable summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.Table 7: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADESLaboratory AbnormalityDARZALEX FASPRO with Bortezomib, Melphalan and PrednisoneDenominator is based on the safety population treated with DARZALEX FASPRO-VMP (N=67). All Grades(%) Grades 3-4(%) Decreased leukocytes9652Decreased lymphocytes9384Decreased platelets9342Decreased neutrophils8849Decreased hemoglobin4819. General disorders and administration site conditions: infusion reaction, injection site reaction, chills. Infections: herpes zoster, urinary tract infection, influenza, sepsis. Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms. Nervous system disorders: headache, paresthesia. Metabolism and nutrition disorders: hypocalcemia, hyperglycemia. Respiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edema. Cardiac disorders: atrial fibrillation. Relapsed/Refractory Multiple Myeloma. In Combination with Lenalidomide and DexamethasoneThe safety of DARZALEX FASPRO with lenalidomide and dexamethasone was evaluated in single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for months or longer and 20% were exposed for greater than one year.Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients.Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than patient were pneumonia and anemia.Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased.The most common adverse reactions (>=20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.Table summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.Table 8: Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADESAdverse ReactionDARZALEX FASPRO with Lenalidomide and Dexamethasone(N=65) All Grades(%)Grades >=3(%)General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 525Only grade adverse reactions occurred. Pyrexia232 Edema peripheral183 Gastrointestinal disorders Diarrhea455 Constipation262 Nausea120 Vomiting110Infections Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 433 PneumoniaPneumonia includes lower respiratory tract infection, lung infection, and pneumonia. 2317 BronchitisBronchitis includes bronchitis, and bronchitis viral. 142 Urinary tract infection110Musculoskeletal and connective tissue disorders Muscle spasms312 Back pain140Respiratory, thoracic and mediastinal disorders DyspneaDyspnea includes dyspnea, and dyspnea exertional. 223 CoughCough includes cough, and productive cough. 140Nervous system disorders Peripheral sensory neuropathy172 Psychiatric disorders Insomnia175 Metabolism and nutrition disorders Hyperglycemia129 Hypocalcemia110Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with lenalidomide and dexamethasone included:Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest painNervous system disorders: dizziness, headache, paresthesiaSkin and subcutaneous tissue disorders: rash, pruritusGastrointestinal disorders: abdominal painInfections: influenza, sepsis, herpes zosterMetabolism and nutrition disorders: decreased appetiteCardiac disorders: atrial fibrillationGeneral disorders and administration site conditions: chills, infusion reaction, injection site reactionVascular disorders: hypotension, hypertensionTable summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.Table 9: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADESLaboratory AbnormalityDARZALEX FASPRO with Lenalidomide and DexamethasoneDenominator is based on the safety population treated with DARZALEX FASPRO-Rd (N=65). All Grades(%)Grades 3-4(%)Decreased leukocytes9434Decreased lymphocytes8258Decreased platelets869Decreased neutrophils8952Decreased hemoglobin458. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain. Nervous system disorders: dizziness, headache, paresthesia. Skin and subcutaneous tissue disorders: rash, pruritus. Gastrointestinal disorders: abdominal pain. Infections: influenza, sepsis, herpes zoster. Metabolism and nutrition disorders: decreased appetite. Cardiac disorders: atrial fibrillation. General disorders and administration site conditions: chills, infusion reaction, injection site reaction. Vascular disorders: hypotension, hypertension. In Combination with Pomalidomide and DexamethasoneThe safety of DARZALEX FASPRO with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone (Pd) in patients who had received at least one prior line of therapy with lenalidomide and proteasome inhibitor (PI) was evaluated in APOLLO [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity in combination with pomalidomide and dexamethasone (n=149) or pomalidomide and dexamethasone (n=150). Among patients receiving DARZALEX FASPRO-Pd, 71% were exposed for months or longer and 50% were exposed for greater than one year.Serious adverse reactions occurred in 50% of patients who received DARZALEX FASPRO-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO-Pd were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients who received DARZALEX FASPRO-Pd.Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-Pd.The most common adverse reactions (>=20%) were fatigue, pneumonia, upper respiratory tract infection, and diarrhea.Table 10 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO.Table 10:Adverse Reactions Reported in >=10% of Patients and With at Least 5% Greater Frequency in the DARZALEX FASPRO-Pd Arm in APOLLOAdverse ReactionDARZALEX FASPRO-Pd (N=149) Pd (N=150)All Grades(%)Grades >=3(%)All Grades(%)Grades >=3(%)Key: Pd=pomalidomide-dexamethasoneGeneral disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 4613395Only grade adverse reactions occurred. Pyrexia190140 Edema peripheralEdema peripheral includes edema, edema peripheral and peripheral swelling. 15090Infections PneumoniaPneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. 3823Grade adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO-Pd arm and n=2 (1.3%) in the Pd arm. 2717 Upper respiratory infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection. 361 222 Gastrointestinal disorders Diarrhea225 141 Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 13080Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with pomalidomide and dexamethasone include:Metabolism and nutrition disorders: hypocalcemia, hypokalemia, decreased appetite, dehydrationNervous system disorders: peripheral sensory neuropathy, syncope, headache, paresthesia, dizzinessMusculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgiaPsychiatric disorders: insomniaGastrointestinal disorders: nausea, abdominal pain, vomitingSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: atrial fibrillationGeneral disorders and administration site conditions: infusion reactions, chills, injection site reactionInfections: urinary tract infection, influenza, hepatitis reactivation, herpes zoster, sepsisVascular disorders: hypertension, hypotensionTable 11 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in APOLLO.Table 11:Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Pd or Pd in APOLLOLaboratory AbnormalityDARZALEX FASPRO-PdDenominator is based on number of subjects with baseline and post-baseline laboratory value for each laboratory test: N=148 for DARZALEX FASPRO-Pd and N=149 for Pd. Pd All Grades(%) Grades 3-4(%) All Grades(%) Grades 3-4(%)Key: Pd=pomalidomide-dexamethasoneDecreased neutrophils97848463Decreased leukocytes95648240Decreased lymphocytes93597933Decreased platelets75196019Decreased hemoglobin51165715. Metabolism and nutrition disorders: hypocalcemia, hypokalemia, decreased appetite, dehydration. Nervous system disorders: peripheral sensory neuropathy, syncope, headache, paresthesia, dizziness. Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia. Psychiatric disorders: insomnia. Gastrointestinal disorders: nausea, abdominal pain, vomiting. Skin and subcutaneous tissue disorders: rash, pruritus. Cardiac disorders: atrial fibrillation. General disorders and administration site conditions: infusion reactions, chills, injection site reaction. Infections: urinary tract infection, influenza, hepatitis reactivation, herpes zoster, sepsis. Vascular disorders: hypertension, hypotension. In Combination with Carfilzomib and DexamethasoneThe safety of DARZALEX FASPRO with carfilzomib and dexamethasone was evaluated in single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from Weeks to 8, once every weeks from Weeks to 24 and once every weeks starting with Week 25 until disease progression or unacceptable toxicity (N=66) in combination with carfilzomib and dexamethasone. Among these patients, 77% were exposed for months or longer and 27% were exposed for greater than one year.Serious adverse reactions occurred in 27% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone.Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO.Dosage interruptions due to an adverse reaction occurred in 46% of patients who received DARZALEX FASPRO.The most common adverse reactions (>=20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.Table 12 summarizes the adverse reactions in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES.Table 12:Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO with Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) in PLEIADESAdverse ReactionDARZALEX FASPRO-Kd (N=66) All Grades (%)Grade >=3 (%)Infections and infestations Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. 520 BronchitisBronchitis includes bronchitis, and bronchitis viral. 122Only Grade adverse reactions occurred. General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 392 Pyrexia212 Edema peripheralEdema peripheral includes generalized edema, edema peripheral, and peripheral swelling. 200Psychiatric disorders Insomnia336 Vascular disorders HypertensionHypertension includes blood pressure increased, and hypertension. 3221 Gastrointestinal disorders Diarrhea290 Nausea210 Vomiting150Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 240 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 232 Nervous system disorders Headache230 Peripheral sensory neuropathy110Musculoskeletal and connective tissue disorders Back pain172 Musculoskeletal chest pain110Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with carfilzomib and dexamethasone include:Gastrointestinal disorders: abdominal pain, constipation, pancreatitisInfection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsisMetabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, arthralgiaNervous system disorders: paresthesia, dizziness, syncopeGeneral disorders and administration site conditions: injection site reaction, infusion reactions, chillsSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: cardiac failureVascular disorders: hypotensionTable 13 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone in PLEIADES.Table 13:Select Laboratory Abnormalities (>=30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADESLaboratory AbnormalityDARZALEX FASPRO-KdDenominator is based on the safety population treated with DARZALEX FASPRO-Kd (N=66). All Grades (%)Grades 3-4 (%)Decreased platelets8818Decreased lymphocytes8350Decreased leukocytes6818Decreased neutrophils5515Decreased hemoglobin476Decreased corrected calcium452Increased alanine aminotransferase (ALT)355. Gastrointestinal disorders: abdominal pain, constipation, pancreatitis. Infection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsis. Metabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemia. Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia. Nervous system disorders: paresthesia, dizziness, syncope. General disorders and administration site conditions: injection site reaction, infusion reactions, chills. Skin and subcutaneous tissue disorders: rash, pruritus. Cardiac disorders: cardiac failure. Vascular disorders: hypotension. MonotherapyThe safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see Clinical Trials (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO, 37% were exposed for months or longer and 1% were exposed for greater than one year.Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than patient were general physical health deterioration, septic shock, and respiratory failure.Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than patients were thrombocytopenia and hypercalcemia.Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia.The most common adverse reaction (>=20%) was upper respiratory tract infection.Table 14 summarizes the adverse reactions in COLUMBA.Table 14: Adverse Reactions (>=10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBAAdverse ReactionDARZALEX FASPRO(N=260)Intravenous Daratumumab(N=258)All Grades(%)Grade >=3(%)All Grades(%)Grade >=3(%)Infections Upper respiratory tract infectionUpper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection. 241Only grade adverse reactions occurred. 221 PneumoniaPneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. 85106Grade adverse reactions occurred. Gastrointestinal disorders Diarrhea151 110.4 Nausea80.4 110.4 General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 151 162 Infusion reactionsInfusion reactions includes terms determined by investigators to be related to infusion. 132 345 Pyrexia130131 Chills60.4 121 Musculoskeletal and connective tissue disorders Back pain102 123 Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 91 140 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 61 111 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included:General disorders and administration site conditions: injection site reaction, peripheral edemaMusculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasmsGastrointestinal disorders: constipation, vomiting, abdominal painMetabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydrationPsychiatric disorders: insomniaVascular disorders: hypertension, hypotensionNervous system disorders: dizziness, peripheral sensory neuropathy, paresthesiaInfections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis virus reactivationSkin and subcutaneous tissue disorders: pruritus, rashCardiac disorders: atrial fibrillationRespiratory, thoracic and mediastinal disorders: pulmonary edemaTable 15 summarizes the laboratory abnormalities in COLUMBA.Table 15: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBALaboratory AbnormalityDARZALEX FASPRODenominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258). Intravenous Daratumumab All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Decreased leukocytes65195714Decreased lymphocytes59365636Decreased neutrophils55194311Decreased platelets43164514Decreased hemoglobin42143916. General disorders and administration site conditions: injection site reaction, peripheral edema. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasms. Gastrointestinal disorders: constipation, vomiting, abdominal pain. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration. Psychiatric disorders: insomnia. Vascular disorders: hypertension, hypotension. Nervous system disorders: dizziness, peripheral sensory neuropathy, paresthesia. Infections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis virus reactivation. Skin and subcutaneous tissue disorders: pruritus, rash. Cardiac disorders: atrial fibrillation. Respiratory, thoracic and mediastinal disorders: pulmonary edema. Light Chain Amyloidosis. In Combination with Bortezomib, Cyclophosphamide and DexamethasoneThe safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (DARZALEX FASPRO-VCd) was evaluated in ANDROMEDA [see Clinical Studies (14.3)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity or maximum of years. Among patients who received DARZALEX FASPRO-VCd, 74% were exposed for months or longer and 32% were exposed for greater than one year.Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX FASPRO-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure.Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required dosage interruption in >=3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%).The most common adverse reactions (>=20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.Table 16 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA.Table 16: Adverse Reactions (>=10%) in Patients with AL Amyloidosis Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) with Difference Between Arms of >5% Compared to VCd in ANDROMEDAAdverse ReactionDARZALEX FASPRO-VCd(N=193)VCd(N=188)All Grades(%) Grades 3-4(%) All Grades(%) Grades 3-4(%) Infections Upper respiratory tract infectionUpper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. 401Only grade adverse reactions occurred. 211 PneumoniaPneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. 151095Gastrointestinal disorders Diarrhea366 304 Constipation342 290Nervous system disorders Peripheral sensory neuropathy313 202 Respiratory, thoracic and mediastinal disorders DyspneaDyspnea includes dyspnea, and dyspnea exertional. 264204 CoughCough includes cough, and productive cough. 201 110Musculoskeletal and connective tissue disorders Back pain122 60 Arthralgia10050 Muscle spasms101 50Cardiac disorders ArrhythmiaArrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia 11452General disorders and administration site conditions Injection site reactionsInjection site reactions includes terms determined by investigators to be related to daratumumab injection. 11000Clinically relevant adverse reactions not included in Table 16 and occurred in patients who received DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone included:Skin and subcutaneous tissue disorders: rash, pruritusNervous system disorders: paresthesiaGeneral disorders and administration site conditions: infusion reaction, chillsCardiac disorders: cardiac failureCardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients., cardiac arrestMetabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydrationInfections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenzaVascular disorders: hypertensionMusculoskeletal and connective tissue disorders: musculoskeletal chest painGastrointestinal disorders: pancreatitisRespiratory, thoracic and mediastinal disorders: pulmonary edemaTable 17 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in ANDROMEDA.Table 17: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) in ANDROMEDALaboratory AbnormalityDARZALEX FASPRO-VCdVCdAll Grades(%)Grades 3-4(%) All Grades(%)Grades 3-4(%)Denominator is based on the number of patients with baseline and post-baseline laboratory value for each laboratory test, N=188 for DARZALEX FASPRO-VCd and N=186 for VCd.Decreased lymphocytes81547146Decreased hemoglobin666706Decreased leukocytes607464Decreased platelets463404Decreased neutrophils306184. Skin and subcutaneous tissue disorders: rash, pruritus. Nervous system disorders: paresthesia. General disorders and administration site conditions: infusion reaction, chills. Cardiac disorders: cardiac failureCardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients., cardiac arrest. Metabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydration. Infections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenza. Vascular disorders: hypertension. Musculoskeletal and connective tissue disorders: musculoskeletal chest pain. Gastrointestinal disorders: pancreatitis. Respiratory, thoracic and mediastinal disorders: pulmonary edema. Cardiac Adverse Reactions in Light Chain (AL) AmyloidosisAmong patients who received DARZALEX FASPRO in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage (3%), Stage II (46%) and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage and II and 28% of patients with Stage III). Serious cardiac disorders in >2% of patients included cardiac failure (8%), cardiac arrest (4%) and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage and II and 19% of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the DARZALEX FASPRO-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, 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.No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant human hyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure of hyaluronidase in monkeys given 22,000 U/kg/week subcutaneously (12 times higher than the human dose) for 39 weeks. As hyaluronidase is recombinant form of the endogenous human hyaluronidase, no carcinogenicity, mutagenesis, or effects on fertility are expected.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. CD38 is transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including clonal plasma cells in multiple myeloma and light chain (AL) amyloidosis, as well as other cell types. Surface CD38 has multiple functions, including 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.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in DARZALEX FASPRO acts locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.. 12.2 Pharmacodynamics. 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 FASPRO treatment.. Cardiac ElectrophysiologyDARZALEX FASPRO 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 FASPRO has the potential to delay ventricular repolarization.. Exposure-Response RelationshipThe exposure-response relationship and time course of pharmacodynamics of DARZALEX FASPRO have not been fully characterized.. 12.3 Pharmacokinetics. Following the recommended dose of DARZALEX FASPRO 1,800 mg/30,000 units subcutaneously once weekly for weeks, daratumumab peak concentration (Cmax) increased 4.8-fold and area under the curve (AUC0-7 days) increased 5.4-fold from the 1st dose to the 8th dose as monotherapy. Maximum trough concentrations for DARZALEX FASPRO are typically observed at the end of the weekly dosing regimens for both monotherapy and combination therapies. The mean +- standard deviation (SD) maximum trough serum concentration (Ctrough) after the 8th dose was 593 +- 306 ug/mL when DARZALEX FASPRO was administered as monotherapy and 537 +- 277 ug/mL, 526 +- 226 ug/mL, and 756 +- 276 ug/mL when DARZALEX FASPRO was administered as combination with Pd, Rd, and Kd, respectively.Table 18 lists the observed mean (+-SD) maximum trough concentrations (Ctrough) after the 8th dose, simulated median (5th-95th percentiles) maximum Ctrough after the 8th dose, simulated median (5th-95th percentiles) Cmax after the 8th dose, and simulated median (5th-95th percentiles) area under the curve (AUC0-7day) after the 8th dose following DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously in patients with multiple myeloma or light chain (AL) amyloidosis.Table 18: Daratumumab Exposure for Patients with Multiple Myeloma or Light Chain (AL) AmyloidosisParameterIntravenous Daratumumab 16 mg/kg in Patients with Multiple MyelomaPatients with multiple myeloma who received daratumumab monotherapy DARZALEX FASPRO 1,800 mg/30,000 units in Patients with Multiple Myeloma DARZALEX FASPRO 1,800 mg/30,000 units in Patients with Light Chain (AL) AmyloidosisPatients with AL amyloidosis who received daratumumab in combination with VCd Observed mean+-SD max Ctrough after 8th dose (ug/mL)522+-226Geometric mean ratio between 1,800 mg SC and 16 mg/kg was 108% (90% CI: 96, 122) in patients with multiple myeloma Source: MMY3012 Primary Analysis Clinical Study Report 593+-306 597+-232Source: AMY3001 Primary Analysis Clinical Study Report Simulated median (5th-95th percentiles) max Ctrough after 8th dose (ug/mL)472 (144-809)Source: Population Pharmacokinetics and Exposure-response Analysis Report for Subcutaneously Administered Daratumumab in Multiple Myeloma Subjects 563 (177-1063) 662 (315-1037)Source: Population Pharmacokinetics and Exposure-response Analysis Report for Daratumumab Subcutaneous Administration for the Treatment of Subjects with AL Amyloidosis Simulated median (5th-95th percentiles) Cma after 8th dose (ug/mL)688 (369-1061) 592 (234-1114) 729 (390-1105) Simulated median (5th-95th percentiles) AUC0-7days after 8th dose (ug/mLday)4019 (1740-6370) 4017 (1515-7564) 4855 (2562-7522) AbsorptionAt the recommended dose of DARZALEX FASPRO 1,800 mg/30,000 units, the absolute bioavailability is 69%, with peak concentrations occurring around days (Tmax) in patients with multiple myeloma. Peak concentrations occurred around days in patients with light chain (AL) amyloidosis.. DistributionThe estimated mean (coefficient of variation, CV) volume of distribution for the central compartment is 5.2 (37%) and peripheral compartment was 3.8 in patients with multiple myeloma. The estimated mean volume of distribution was 10.8 (28%) in patients with light chain (AL) amyloidosis.. EliminationDaratumumab is cleared by parallel linear and nonlinear saturable target mediated clearances. The estimated mean (CV%) linear clearance of daratumumab is 119 mL/day (59%) in patients with multiple myeloma and is 210 mL/day (42%) in patients with light chain (AL) amyloidosis. The estimated mean (CV%) elimination half-life associated with linear clearance is 20 days (22%) in patients with multiple myeloma and 28 days (74%) in patients with light chain (AL) amyloidosis.. Specific PopulationsThe following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered DARZALEX FASPRO as monotherapy or as combination therapy: sex, age (33 to 92 years), renal impairment [Creatinine clearance (CLcr) 15 to 89 mL/min as determined by the Cockcroft-Gault formula], and mild hepatic impairment (total bilirubin to 1.5 times ULN and AST>ULN). The effect of moderate and severe hepatic impairment on daratumumab pharmacokinetics is unknown.. Racial or Ethnic GroupsOf 190 patients with light chain (AL) amyloidosis who received DARZALEX FASPRO and had maximum Ctrough after the 8th dose, African-Americans (4%) had 24% higher daratumumab mean maximum Ctrough after the 8th dose compared to that of Whites (83%) and Asians (10%) had 16% higher mean maximum Ctrough after the 8th dose compared to that of Whites. The difference in exposure between that of Asians and Whites could be explained in part by differences in body size. The effect of African-American race on exposure and related safety and efficacy of daratumumab is unknown.. Body WeightIn patients with multiple myeloma who received DARZALEX FASPRO 1,800 mg/30,000 units as monotherapy, the mean maximum Ctrough after the 8th dose was 12% lower in the higher body weight (BW) group (>85 kg), while the mean maximum Ctrough after the 8th dose was 81% higher in the lower BW group (<=50 kg) compared to the corresponding BW groups in the intravenous daratumumab arm.In patients with light chain (AL) amyloidosis who received DARZALEX FASPRO 1,800 mg/30,000 units in combination and had maximum Ctrough after the 8th dose, the mean maximum Ctrough after the 8th dose was 22% lower in the higher BW group (>85 kg), while the mean maximum Ctrough was 37% higher in the lower BW group (<=50 kg) compared to the patients with body weight of 51-85 kg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Newly Diagnosed Multiple Myeloma. In Combination with Bortezomib, Melphalan and PrednisoneThe efficacy of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in single-arm cohort of PLEIADES (NCT03412565), multi-cohort, open-label trial. Eligible patients were required to have newly diagnosed multiple myeloma who are ineligible for transplant. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 6, once every weeks from weeks to 54 and once every weeks starting with week 55 until disease progression or unacceptable toxicity; bortezomib 1.3 mg/m2 subcutaneously twice weekly on Weeks 1, 2, and for the first 6-week cycle (Cycle 1; doses), followed by once weekly on Weeks 1, 2, and for eight more 6-week cycles (Cycles 2-9; doses per cycle); and melphalan mg/m2 and prednisone 60 mg/m2 orally on Days to of the nine 6-week cycles (Cycles 1-9). The major efficacy outcome measure was overall response rate (ORR).A total of 67 patients received DARZALEX FASPRO with VMP. The median age was 75 years (range: 66 to 86 years); 46% were male; 69% were White, 8% Asian, and 2% Black or African American; and 33% had ISS Stage I, 45% had ISS Stage II, and 22% had ISS Stage III disease.Efficacy results are summarized in Table 19. The median duration of follow-up for patients was 6.9 months.Table 19: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-VMPDARZALEX FASPRO-VMP(N=67)CI=confidence intervalOverall response rate (sCR+CR+VGPR+PR), (%)Based on treated patients 59 (88%)95% CI (%)(78%, 95%) Stringent complete response (sCR)5 (8%) Complete response (CR)7 (10%) Very good partial response (VGPR)31 (46%) Partial response (PR)16 (24%). 14.2Relapsed/Refractory Multiple Myeloma. In Combination with Lenalidomide and DexamethasoneThe efficacy of DARZALEX FASPRO with lenalidomide and dexamethasone (DARZALEX FASPRO-Rd) was evaluated in single-arm cohort of PLEIADES (NCT03412565), multi-cohort, open-label trial. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity with lenalidomide 25 mg once daily orally on Days 1-21 of each 28-day cycle; and dexamethasone 40 mg per week (or reduced dose of 20 mg per week for patients >75 years or BMI <18.5). The major efficacy outcome measure was ORR.A total of 65 patients received DARZALEX FASPRO with Rd. The median age was 69 years (range: 33 to 82 years); 69% were male; 69% were White, and 3% Black or African American; and 42% had ISS Stage I, 30% had ISS Stage II, and 28% had ISS Stage III disease. Patients had received median of prior line of therapy. total of 52% of patients had prior ASCT; 95% of patients received prior PI; 59% received prior immunomodulatory agent, including 22% who received prior lenalidomide; and 54% of patients received both prior PI and immunomodulatory agent.Efficacy results are summarized in Table 20. The median duration of follow-up for patients was 7.1 months.Table 20: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-RdDARZALEX FASPRO-Rd(N=65)CI=confidence intervalOverall response rate (sCR+CR+VGPR+PR), (%)Based on treated patients 59 (91%)95% CI (%)(81%, 97%) Stringent complete response (sCR)4 (6%) Complete response (CR)8 (12%) Very good partial response (VGPR)30 (46%) Partial response (PR)17 (26%). In Combination with Pomalidomide and DexamethasoneThe efficacy of DARZALEX FASPRO with pomalidomide and dexamethasone (DARZALEX FASPRO-Pd) versus pomalidomide and dexamethasone (Pd) alone was evaluated in APOLLO (NCT03180736), an open-label, randomized, active-controlled trial. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or unacceptable toxicity with pomalidomide mg once daily orally on Days 1-21 of each 28-day cycle; and dexamethasone 40 mg per week (or reduced dose of 20 mg per week for patients >75 years). The major efficacy outcome measure was progression-free survival (PFS).A total of 304 patients were randomized: 151 to the DARZALEX FASPRO-Pd arm and 153 to the Pd arm. The median age was 67 years (range: 35 to 90); 53% were male and 89% were White, <1% were Black or African American, and <1% were Asian, and 45% had ISS Stage I, 33% had ISS Stage II, and 22% had ISS Stage III disease. Patients had received median of prior lines of therapy (range 1-5), with 11% of patients having received prior line of therapy and 75% of patients having received 2-3 prior lines of therapy. All patients received prior treatment with PI and lenalidomide, and 56% of patients received prior ASCT. The majority of patients were refractory to lenalidomide (80%), PI (48%), or both an immunomodulatory agent and PI (42%).APOLLO demonstrated an improvement in PFS in the DARZALEX FASPRO-Pd treatment group as compared to the Pd treatment group; the median PFS was 12.4 months in the DARZALEX FASPRO-Pd treatment group and 6.9 months in the Pd treatment group (HR [95% CI]: 0.63 [0.47, 0.85]; p-value 0.0018), representing 37% reduction in the risk of disease progression or death for patients treated with DARZALEX FASPRO-Pd versus Pd.Figure 1:Kaplan-Meier Curve of PFS in APOLLOAdditional efficacy results from APOLLO are presented in Table 21.Table 21:Efficacy results from APOLLOBased on intent-to-treat population DARZALEX FASPRO-Pd (n=151)Pd (n=153)Pd=pomalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence intervalOverall response (sCR+CR+VGPR+PR) (%) 104 (68.9%)71 (46.4%)P-valuep-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors <0.0001 Stringent complete response (sCR)14 (9.3%)2 (1.3%) Complete response (CR)23 (15.2%)4 (2.6%) Very good partial response (VGPR)40 (26.5%)24 (15.7%) Partial response (PR)27 (17.9%)41 (26.8%)MRD negativity rateBased on the intent-to-treat population Based on threshold of 10-5 using next-generation sequencing assay (clonoSEQ). (%)13 (8.6%)3 (2.0%) 95% CI (%)(4.7%, 14.3%)(0.4%, 5.6%)P-valuep-value from Fishers exact test. 0.0102MRD negativity rate in patients with CR or better Number of patients with CR or betterN=37N=6 MRD negativity rate (%)13 (35.1%)3 (50.0%) 95% CI (%)(20.2%, 52.5%)(11.8%, 88.2%)In responders, the median time to response was month (range: 0.9 to 9.1 months) in the DARZALEX FASPRO-Pd group and 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had not been reached in the DARZALEX FASPRO-Pd group (range: to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.With median follow-up of 16.9 months, 99 deaths were observed; 48 in the DARZALEX FASPRO-Pd group and 51 in the Pd group. Median OS was not reached for either treatment group.. Figure 1. In Combination with Carfilzomib and DexamethasoneThe efficacy of DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) was evaluated in single-arm cohort of PLEIADES (NCT03412565), multi-cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from Weeks to 8, once every weeks from Weeks to 24 and once every weeks starting with Week 25 until disease progression or unacceptable toxicity with carfilzomib administered by IV infusion at dose of 20 mg/m2 on Cycle Day and if dose of 20 mg/m2 was tolerated, carfilzomib was administered at dose of 70 mg/m2 as 30-minute IV infusion, on Cycle Day and Day 15, and then Day 1, and 15 of each cycle and dexamethasone 40 mg per week (or reduced dose of 20 mg per week for patients >=75 years or BMI <18.5). The major efficacy outcome measure was ORR.A total of 66 patients received DARZALEX FASPRO with Kd. The median age was 61 years (range: 42 to 84); 52% were male; 73% were White and 3% Black or African American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. total of 79% of patients had prior ASCT; 91% of patients received prior PI. All patients received prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.Efficacy results are summarized in Table 22. At median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least months.Table 22:Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-KdDARZALEX FASPRO-Kd (N=66)CI=confidence intervalOverall response rate (sCR+CR+VGPR+PR), (%)Based on treated patients 56 (84.8%)95% CI (%)(73.9%, 92.5%) Stringent complete response (sCR)11 (16.7%) Complete response (CR)14 (21.2%) Very good partial response (VGPR)26 (39.4%) Partial response (PR)5 (7.6%). MonotherapyThe efficacy of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA (NCT03277105), an open-label, randomized, non-inferiority study. Eligible patients were required to have 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. Patients were randomized to receive DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until unacceptable toxicity or disease progression. The major efficacy outcome measures were ORR by the IMWG response criteria and maximum Ctrough at pre-dose Cycle Day [see Clinical Pharmacology (12.3)]. Randomization was stratified by body weight, myeloma type, and number of prior lines of therapy.A total of 522 patients were randomized: 263 to the DARZALEX FASPRO arm and 259 to the intravenous daratumumab arm. The median age was 67 years (range: 33 to 92 years); 55% were male; and 78% were White, 14% Asian, and 3% Black or African American. The median weight was 73 kg (range: 29 to 138). Patients had received median of prior lines of therapy. total of 51% of patients had prior ASCT; 100% of patients received both PI and an immunomodulatory agent. Forty-nine percent of patients were refractory both PI and an immunomodulatory agent. Eighty-two percent of patients were refractory to their last line of prior systemic therapy.The results show that DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously is non-inferior to daratumumab 16 mg/kg administered intravenously in terms of ORR and maximum trough concentration [see Clinical Pharmacology (12.3)]. Median progression-free survival was 5.6 months in the DARZALEX FASPRO arm and 6.1 months in the intravenous daratumumab arm. ORR results are provided in Table 23.Table 23: Efficacy Results from COLUMBADARZALEX FASPRO (N=263)Intravenous Daratumumab(N=259) Overall response (sCR+CR+VGPR+PR), (%)Based on intent-to-treat population. 108 (41%)96 (37%)95% CI (%)(35%, 47%)(31%, 43%)Ratio of response rates (95% CI)1.11 (0.89, 1.37) CR or better, (%)5 (1.9%)7 (2.7%) Very good partial response (VGPR)45 (17%)37 (14%) Partial response (PR)58 (22%)52 (20%). 14.3Light Chain Amyloidosis. In Combination with Bortezomib, Cyclophosphamide and DexamethasoneThe efficacy of DARZALEX FASPRO with VCd was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial. Eligible patients were required to have newly diagnosed light chain (AL) amyloidosis with at least one affected organ, measurable hematologic disease, Cardiac Stage I-IIIA (based on European Modification of Mayo 2004 Cardiac Stage), and NYHA Class I-IIIA. Patients with NYHA Class IIIB and IV were excluded. Patients were randomized to receive bortezomib 1.3 mg/m2 administered subcutaneously, cyclophosphamide 300 mg/m2 (max dose 500 mg) administered orally or intravenously, and dexamethasone 40 mg (or reduced dose of 20 mg for patients >70 years or body mass index <18.5 or who have hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) administered orally or intravenously on Days 1, 8, 15, and 22 of each 28-day cycle with or without DARZALEX FASPRO 1,800 mg/30,000 units subcutaneously once weekly from weeks to 8, once every weeks from weeks to 24 and once every weeks starting with week 25 until disease progression or maximum of two years. When DARZALEX FASPRO and dexamethasone were administered on the same day, dexamethasone 20 mg was administered before DARZALEX FASPRO with the remaining dose of dexamethasone administered after DARZALEX FASPRO if applicable. The major efficacy outcome measure was confirmed hematologic complete response (HemCR) rate based on Consensus Criteria as determined by the Independent Review Committee (negative serum and urine immunofixation, involved free light chain level decrease to less than the upper limit of normal, and normal free light chain ratio). Randomization was stratified by Cardiac Stage (European Modification of Mayo 2004 Cardiac Stage) countries that typically offer autologous stem cell transplant (ASCT) for patients with light chain (AL) amyloidosis, and renal function.A total of 388 patients were randomized: 195 to DARZALEX FASPRO-VCd and 193 to VCd. The median patient age was 64 years (range: 34 to 87 years); 58% were male; 76% White, 17% Asian, and 3% Black or African American; 23% had light chain (AL) amyloidosis Cardiac Stage I, 40% had Stage II, and 37% had Stage IIIA. The median number of organs involved was (range: 1-6) and 66% of patients had or more organs involved. Vital organ involvement was: cardiac 71%, renal 59% and hepatic 8%. The majority (79%) of patients had lambda free light chain disease.Efficacy results are summarized in Table 24.Table 24: Efficacy results from ANDROMEDABased on intent-to-treat population DARZALEX FASPRO-VCd(n=195)VCd(n=193)VCd=bortezomib-cyclophosphamide-dexamethasoneHematologic complete response (HemCR), (%)82 (42%)26 (13%) p-valuep-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001Very good partial response (VGPR), (%)71 (36%)69 (36%)Partial response (PR), (%)26 (13%)53 (27%)Hematologic VGPR or better (HemCR VGPR), (%)153 (78%)95 (49%)Major organ deterioration progression-free survivalMajor organ deterioration-PFS defined as hematologic progression, major organ (cardiac or renal) deterioration or death, Hazard ratio with 95% CI0.58 (0.37, 0.92)The median time to HemCR was 59 days (range: to 299 days) in the DARZALEX FASPRO-VCd arm and 59 days (range: 16 to 340 days) in the VCd arm. The median time to VGPR or better was 17 days (range: to 336 days) in the DARZALEX FASPRO-VCd arm and 25 days (range: to 171 days) in the VCd arm. The median duration of HemCR had not been reached in either arm.The median follow-up for the study is 11.4 months. Overall survival (OS) data were not mature. total of 56 deaths were observed [N=27 (13.8%) DARZALEX FASPRO-VCd vs. N=29 (15%) VCd group].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. DARZALEX FASPRO is contraindicated in patients with history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. Patients with history of severe hypersensitivity to daratumumab, hyaluronidase 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 the CD38 antigen. Daratumumab is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.Hyaluronidase (recombinant human) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is glycosylated single-chain protein produced by Chinese Hamster Ovary cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). Hyaluronidase (recombinant human) has molecular weight of approximately 61 kDa.DARZALEX FASPRO(R) (daratumumab and hyaluronidase-fihj) injection is sterile, preservative-free, colorless to yellow, and clear to opalescent solution supplied in single-dose vial for subcutaneous administration.Each DARZALEX FASPRO 15 mL single-dose vial contains 1,800 mg of daratumumab and 30,000 units of hyaluronidase, L-histidine (4.9 mg), L-histidine hydrochloride monohydrate (18.4 mg), L-methionine (13.5 mg), polysorbate 20 (6 mg), sorbitol (735.1 mg), and Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For subcutaneous use only.Pre-medicate with corticosteroid, acetaminophen and histamine-1 receptor antagonist. (2.5)The recommended dosage of DARZALEX FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately to minutes according to recommended schedule. (2.2, 2.3)Administer post-medications as recommended. (2.5). Pre-medicate with corticosteroid, acetaminophen and histamine-1 receptor antagonist. (2.5). The recommended dosage of DARZALEX FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately to minutes according to recommended schedule. (2.2, 2.3). Administer post-medications as recommended. (2.5). 2.1Important Dosing Information. DARZALEX FASPRO is for subcutaneous use only.Administer medications before and after administration of DARZALEX FASPRO to minimize administration-related reactions [see Dosage and Administration (2.5)].Type and screen patients prior to starting DARZALEX FASPRO.. DARZALEX FASPRO is for subcutaneous use only.. Administer medications before and after administration of DARZALEX FASPRO to minimize administration-related reactions [see Dosage and Administration (2.5)].. Type and screen patients prior to starting DARZALEX FASPRO.. 2.2Recommended Dosage for Multiple Myeloma. The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3-5 minutes. Tables 1, 2, 3, and provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of combination therapy.. Monotherapy and In Combination with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd), Pomalidomide and Dexamethasone (DARZALEX FASPRO-Pd) or Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd)Use the dosing schedule provided in Table when DARZALEX FASPRO is administered:in combination with lenalidomide and dexamethasone (4-week cycle) ORin combination with pomalidomide and dexamethasone (4-week cycle) ORin combination with carfilzomib and dexamethasone (4-week cycle) ORas monotherapy.Table 1: DARZALEX FASPRO dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) 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 weeksWhen DARZALEX FASPRO is administered as part of combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs.. in combination with lenalidomide and dexamethasone (4-week cycle) OR. in combination with pomalidomide and dexamethasone (4-week cycle) OR. in combination with carfilzomib and dexamethasone (4-week cycle) OR. as monotherapy.. In Combination with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP)Use the dosing schedule provided in Table when DARZALEX FASPRO is administered in combination with bortezomib, melphalan and prednisone (6-week cycle).Table 2: DARZALEX FASPRO dosing schedule in combination with bortezomib, melphalan and prednisone (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 weeksWhen DARZALEX FASPRO is administered as part of combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs.. In Combination with Bortezomib, Thalidomide, and Dexamethasone (DARZALEX FASPRO-VTd)Use the dosing schedule in Table when DARZALEX FASPRO is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle).Table 3: DARZALEX FASPRO dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle)Treatment phaseWeeksScheduleInductionWeeks 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)When DARZALEX FASPRO is administered as part of combination therapy, see the prescribing information for dosage recommendations for the other drugs.. In Combination with Bortezomib and Dexamethasone (DARZALEX FASPRO-Vd)Use the dosing schedule in Table when DARZALEX FASPRO is administered in combination with bortezomib and dexamethasone (3-week cycle).Table 4: DARZALEX FASPRO dosing schedule in combination 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 weeksWhen DARZALEX FASPRO is administered as part of combination therapy, see the prescribing information for dosage recommendations for the other drugs.. 2.3Recommended Dosage for Light Chain Amyloidosis. In Combination with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd)Use the dosing schedule provided in Table when DARZALEX FASPRO is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).Table 5: DARZALEX FASPRO dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle)WeeksScheduleWeeks 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 progression or maximum of yearsFirst dose of the every-4-week dosing schedule is given at Week 25 every four weeksWhen DARZALEX FASPRO is administered as part of combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs.. 2.4Administration. If dose of DARZALEX FASPRO is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.. 2.5Recommended Concomitant Medications. Pre-medicationAdminister the following pre-medications 1-3 hours before each dose of DARZALEX FASPRO: Acetaminophen 650 to 1,000 mg orally Diphenhydramine 25 to 50 mg (or equivalent) orally or intravenously Corticosteroid (long- or intermediate-acting) Monotherapy Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO. In Combination Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO administration.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 FASPRO administration days [see Clinical Studies (14)].Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX FASPRO administration days when patients have received dexamethasone (or equivalent) as pre-medication.. Acetaminophen 650 to 1,000 mg orally. Diphenhydramine 25 to 50 mg (or equivalent) orally or intravenously. Corticosteroid (long- or intermediate-acting) Monotherapy Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO. In Combination Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO administration.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 FASPRO administration days [see Clinical Studies (14)].Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX FASPRO administration days when patients have received dexamethasone (or equivalent) as pre-medication.. Post-medicationAdminister the following post-medications: MonotherapyAdminister 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 FASPRO. In CombinationConsider 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 administration of DARZALEX FASPRO.If background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the administration of DARZALEX FASPRO, additional corticosteroids may not be needed [see Clinical Studies (14)].If the patient does not experience major systemic administration-related reaction after the first doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).For patients with history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first doses of DARZALEX FASPRO, consider discontinuing these additional post-medications, if the patient does not experience major systemic administration-related reaction.. MonotherapyAdminister 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 FASPRO.. In CombinationConsider 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 administration of DARZALEX FASPRO.If background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the administration of DARZALEX FASPRO, 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 FASPRO and continue for months following the end of treatment [see Adverse Reactions (6.1)]. 2.6Dosage Modifications for Adverse Reactions. No dose reductions of DARZALEX FASPRO are recommended. Consider withholding DARZALEX FASPRO to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.3, 5.4)].. 2.7Preparation and Administration. DARZALEX FASPRO should be administered by healthcare provider.To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DARZALEX FASPRO for subcutaneous use. Do not administer DARZALEX FASPRO intravenously.DARZALEX FASPRO is ready to use.. Preparation Remove the DARZALEX FASPRO vial from refrigerated storage [2C to 8C (36F to 46F)] and equilibrate to ambient temperature [15C to 30C (59F to 86F)]. Store the unpunctured vial at ambient temperature and ambient light for maximum of 24 hours. Keep out of direct sunlight. Do not shake. Withdraw 15 mL from the vial into syringe. DARZALEX FASPRO is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately. After the solution of DARZALEX FASPRO is withdrawn into the syringe, replace the transfer needle with syringe closing cap. Label the syringe appropriately to include the route of administration per institutional standards. Label the syringe with the peel-off label. To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present.. Remove the DARZALEX FASPRO vial from refrigerated storage [2C to 8C (36F to 46F)] and equilibrate to ambient temperature [15C to 30C (59F to 86F)]. Store the unpunctured vial at ambient temperature and ambient light for maximum of 24 hours. Keep out of direct sunlight. Do not shake.. Withdraw 15 mL from the vial into syringe.. DARZALEX FASPRO is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately.. After the solution of DARZALEX FASPRO is withdrawn into the syringe, replace the transfer needle with syringe closing cap. Label the syringe appropriately to include the route of administration per institutional standards. Label the syringe with the peel-off label.. To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present.. StorageIf the syringe containing DARZALEX FASPRO is not used immediately, store the DARZALEX FASPRO solution for up to hours at ambient temperature and ambient light. Discard after hours, if not used.. If the syringe containing DARZALEX FASPRO is not used immediately, store the DARZALEX FASPRO solution for up to hours at ambient temperature and ambient light. Discard after hours, if not used.. AdministrationInject 15 mL of DARZALEX FASPRO into the subcutaneous tissue of the abdomen approximately inches [7.5 cm] to the right or left of the navel over approximately 3-5 minutes. No data are available on performing the injection at other sites of the body. Rotate injection sites for successive injections. Never inject DARZALEX FASPRO into areas where the skin is red, bruised, tender, hard or areas where there are scars. Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose. During treatment with DARZALEX FASPRO, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO.. Inject 15 mL of DARZALEX FASPRO into the subcutaneous tissue of the abdomen approximately inches [7.5 cm] to the right or left of the navel over approximately 3-5 minutes. No data are available on performing the injection at other sites of the body.. Rotate injection sites for successive injections.. Never inject DARZALEX FASPRO into areas where the skin is red, bruised, tender, hard or areas where there are scars.. Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.. During treatment with DARZALEX FASPRO, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units/mL) colorless to yellow and clear to opalescent solution in single-dose vial.. Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units/mL) solution in single-dose vial (3). Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units/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 DARZALEX FASPRO-treated 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. DARZALEX FASPRO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingWith the combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide, refer to the lenalidomide, thalidomide or pomalidomide 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 FASPRO and for months after the last dose. Additionally, refer to the lenalidomide, thalidomide or pomalidomide labeling for additional recommendations for contraception.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 291 patients who received DARZALEX FASPRO as monotherapy for relapsed and refractory multiple myeloma, 37% were 65 to <75 years of age, and 19% were 75 years of age or older. No overall differences in effectiveness of DARZALEX FASPRO have been observed between patients >=65 years of age and younger patients. Adverse reactions that occurred at higher frequency (>=5% difference) in patients >=65 years of age included upper respiratory tract infection, urinary tract infection, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema. Serious adverse reactions that occurred at higher frequency (>=2% difference) in patients >=65 years of age included pneumonia.Of the 214 patients who received DARZALEX FASPRO as combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO as combination therapy with lenalidomide and low-dose dexamethasone for relapsed and refractory multiple myeloma, 43% were 65 to <75 years of age, and 18% were 75 years of age or older. No overall differences in effectiveness were observed between patients >=65 years (n=131) and <65 years (n=85). Adverse reactions occurring at higher frequency (>=5% difference) in patients >=65 years of age included fatigue, pyrexia, peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at higher frequency (>=2% difference) in patients >=65 years of age included neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary tract infection.Of the 193 patients who received DARZALEX FASPRO as part of combination therapy for light chain (AL) amyloidosis, 35% were 65 to <75 years of age, and 10% were 75 years of age or older. Clinical studies of DARZALEX FASPRO as part of combination therapy for patients with light chain (AL) amyloidosis did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs from that of younger patients. Adverse reactions that occurred at higher frequency in patients >=65 years of age were peripheral edema, asthenia, pneumonia and hypotension.No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. DARZALEX FASPRO(R) (daratumumab and hyaluronidase-fihj) injection is sterile, preservative-free, colorless to yellow, and clear to opalescent solution for subcutaneous use supplied as individually packaged single-dose vials providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase per 15 mL (NDC 57894-503-01).. Store DARZALEX FASPRO vials in refrigerator at 2oC to 8oC (36oF to 46oF) in the original carton to protect from light.Do not freeze or shake.

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 or other hyaluronidase products may be misleading.In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of combination therapy, less than 1% of 819 patients developed treatment-emergent anti-daratumumab antibodies.In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of combination therapy, 7% of 812 patients developed treatment-emergent anti-rHuPH20 antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DARZALEX FASPRO is combination of daratumumab, CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with:multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplantmultiple 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 therapymultiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplantmultiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapymultiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and proteasome inhibitormultiple myeloma in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapymultiple myeloma 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.light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone in newly diagnosed patients. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1.2)Limitations of Use:DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials (1.2). multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant. 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. multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and proteasome inhibitor. multiple myeloma in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. multiple myeloma 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.. light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone in newly diagnosed patients. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1.2). DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials (1.2). 1.1Multiple Myeloma. DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma:in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.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, 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 pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and proteasome inhibitor.in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.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 bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.. 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, 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 pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and proteasome inhibitor.. in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.. 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.. 1.2Light Chain Amyloidosis. DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis.This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).. Limitations of UseDARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials [see Warnings and Precautions (5.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Hypersensitivity and Other Administration ReactionsAdvise patients to seek immediate medical attention for any of the following signs and symptoms of systemic administration-related reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing, and blurred vision [see Warnings and Precautions (5.1)].. Cardiac Toxicity in Patients with Light Chain (AL) AmyloidosisAdvise patients to immediately contact their healthcare provider if they have signs or symptoms of cardiac adverse reactions [see Warnings and Precautions (5.2)].. 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 have bruising or bleeding [see Warnings and Precautions (5.4)].. 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 (5.5), Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to avoid becoming pregnant during treatment with DARZALEX FASPRO and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].Advise patients that lenalidomide, thalidomide and pomalidomide have the potential to cause fetal harm and have specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide, thalidomide and pomalidomide are only available through REMS program [see Use in Specific Populations (8.1, 8.3)].. Interference with Laboratory TestsAdvise patients to inform their healthcare provider, including personnel at blood transfusion centers, that they are taking DARZALEX FASPRO, in the event of planned transfusion [see Warnings and Precautions (5.6)].Advise patients that DARZALEX FASPRO 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 (5.7)].. Hepatitis Virus (HBV) ReactivationAdvise patients to inform healthcare providers if they have ever had or might have hepatitis infection and that DARZALEX FASPRO could cause hepatitis virus to become active again [see Adverse Reactions (6.1)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no data on the presence of daratumumab and hyaluronidase 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 FASPRO is administered with lenalidomide, thalidomide or pomalidomide, advise women not to breastfeed during treatment with DARZALEX FASPRO. Refer to lenalidomide, thalidomide or pomalidomide prescribing information for additional information.. Data. Animal DataNo systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on post-natal development through sexual maturity in offspring of mice treated daily during lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. CD38 is transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including clonal plasma cells in multiple myeloma and light chain (AL) amyloidosis, as well as other cell types. Surface CD38 has multiple functions, including 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.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in DARZALEX FASPRO acts locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, 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.No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant human hyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure of hyaluronidase in monkeys given 22,000 U/kg/week subcutaneously (12 times higher than the human dose) for 39 weeks. As hyaluronidase is recombinant form of the endogenous human hyaluronidase, no carcinogenicity, mutagenesis, or effects on fertility are expected.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 15 mL Vial Box. NDC 57894-503-01DARZALEX Faspro(R) (daratumumab andhyaluronidase-fihj)Injection1,800 mg and30,000 Units/15 mL(120 mg and 2,000 Units/mL)For Subcutaneous Use OnlyAdminister subcutaneousinjection over to minutes.Rx onlyOne 15 mL VialSingle-dose vial.Discard unused portion.janssen. PRINCIPAL DISPLAY PANEL 15 mL Vial Box.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. 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 FASPRO treatment.. Cardiac ElectrophysiologyDARZALEX FASPRO 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 FASPRO has the potential to delay ventricular repolarization.. Exposure-Response RelationshipThe exposure-response relationship and time course of pharmacodynamics of DARZALEX FASPRO have not been fully characterized.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following the recommended dose of DARZALEX FASPRO 1,800 mg/30,000 units subcutaneously once weekly for weeks, daratumumab peak concentration (Cmax) increased 4.8-fold and area under the curve (AUC0-7 days) increased 5.4-fold from the 1st dose to the 8th dose as monotherapy. Maximum trough concentrations for DARZALEX FASPRO are typically observed at the end of the weekly dosing regimens for both monotherapy and combination therapies. The mean +- standard deviation (SD) maximum trough serum concentration (Ctrough) after the 8th dose was 593 +- 306 ug/mL when DARZALEX FASPRO was administered as monotherapy and 537 +- 277 ug/mL, 526 +- 226 ug/mL, and 756 +- 276 ug/mL when DARZALEX FASPRO was administered as combination with Pd, Rd, and Kd, respectively.Table 18 lists the observed mean (+-SD) maximum trough concentrations (Ctrough) after the 8th dose, simulated median (5th-95th percentiles) maximum Ctrough after the 8th dose, simulated median (5th-95th percentiles) Cmax after the 8th dose, and simulated median (5th-95th percentiles) area under the curve (AUC0-7day) after the 8th dose following DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously in patients with multiple myeloma or light chain (AL) amyloidosis.Table 18: Daratumumab Exposure for Patients with Multiple Myeloma or Light Chain (AL) AmyloidosisParameterIntravenous Daratumumab 16 mg/kg in Patients with Multiple MyelomaPatients with multiple myeloma who received daratumumab monotherapy DARZALEX FASPRO 1,800 mg/30,000 units in Patients with Multiple Myeloma DARZALEX FASPRO 1,800 mg/30,000 units in Patients with Light Chain (AL) AmyloidosisPatients with AL amyloidosis who received daratumumab in combination with VCd Observed mean+-SD max Ctrough after 8th dose (ug/mL)522+-226Geometric mean ratio between 1,800 mg SC and 16 mg/kg was 108% (90% CI: 96, 122) in patients with multiple myeloma Source: MMY3012 Primary Analysis Clinical Study Report 593+-306 597+-232Source: AMY3001 Primary Analysis Clinical Study Report Simulated median (5th-95th percentiles) max Ctrough after 8th dose (ug/mL)472 (144-809)Source: Population Pharmacokinetics and Exposure-response Analysis Report for Subcutaneously Administered Daratumumab in Multiple Myeloma Subjects 563 (177-1063) 662 (315-1037)Source: Population Pharmacokinetics and Exposure-response Analysis Report for Daratumumab Subcutaneous Administration for the Treatment of Subjects with AL Amyloidosis Simulated median (5th-95th percentiles) Cma after 8th dose (ug/mL)688 (369-1061) 592 (234-1114) 729 (390-1105) Simulated median (5th-95th percentiles) AUC0-7days after 8th dose (ug/mLday)4019 (1740-6370) 4017 (1515-7564) 4855 (2562-7522) AbsorptionAt the recommended dose of DARZALEX FASPRO 1,800 mg/30,000 units, the absolute bioavailability is 69%, with peak concentrations occurring around days (Tmax) in patients with multiple myeloma. Peak concentrations occurred around days in patients with light chain (AL) amyloidosis.. DistributionThe estimated mean (coefficient of variation, CV) volume of distribution for the central compartment is 5.2 (37%) and peripheral compartment was 3.8 in patients with multiple myeloma. The estimated mean volume of distribution was 10.8 (28%) in patients with light chain (AL) amyloidosis.. EliminationDaratumumab is cleared by parallel linear and nonlinear saturable target mediated clearances. The estimated mean (CV%) linear clearance of daratumumab is 119 mL/day (59%) in patients with multiple myeloma and is 210 mL/day (42%) in patients with light chain (AL) amyloidosis. The estimated mean (CV%) elimination half-life associated with linear clearance is 20 days (22%) in patients with multiple myeloma and 28 days (74%) in patients with light chain (AL) amyloidosis.. Specific PopulationsThe following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered DARZALEX FASPRO as monotherapy or as combination therapy: sex, age (33 to 92 years), renal impairment [Creatinine clearance (CLcr) 15 to 89 mL/min as determined by the Cockcroft-Gault formula], and mild hepatic impairment (total bilirubin to 1.5 times ULN and AST>ULN). The effect of moderate and severe hepatic impairment on daratumumab pharmacokinetics is unknown.. Racial or Ethnic GroupsOf 190 patients with light chain (AL) amyloidosis who received DARZALEX FASPRO and had maximum Ctrough after the 8th dose, African-Americans (4%) had 24% higher daratumumab mean maximum Ctrough after the 8th dose compared to that of Whites (83%) and Asians (10%) had 16% higher mean maximum Ctrough after the 8th dose compared to that of Whites. The difference in exposure between that of Asians and Whites could be explained in part by differences in body size. The effect of African-American race on exposure and related safety and efficacy of daratumumab is unknown.. Body WeightIn patients with multiple myeloma who received DARZALEX FASPRO 1,800 mg/30,000 units as monotherapy, the mean maximum Ctrough after the 8th dose was 12% lower in the higher body weight (BW) group (>85 kg), while the mean maximum Ctrough after the 8th dose was 81% higher in the lower BW group (<=50 kg) compared to the corresponding BW groups in the intravenous daratumumab arm.In patients with light chain (AL) amyloidosis who received DARZALEX FASPRO 1,800 mg/30,000 units in combination and had maximum Ctrough after the 8th dose, the mean maximum Ctrough after the 8th dose was 22% lower in the higher BW group (>85 kg), while the mean maximum Ctrough was 37% higher in the lower BW group (<=50 kg) compared to the patients with body weight of 51-85 kg.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified with 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: Anaphylactic reaction, Systemic administration reactions (including death)Gastrointestinal: PancreatitisInfections: Cytomegalovirus, Listeriosis.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryDARZALEX FASPRO 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 FASPRO 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 FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available through REMS program. Refer to the lenalidomide, thalidomide or pomalidomide 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 FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until hematology evaluation is completed.. Data. Animal DataDARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase. Mice 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 the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose.There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1)11/2021Indications and Usage (1.2)1/2021Dosage and Administration (2.2)11/2021Dosage and Administration (2.3)1/2021Warnings and Precautions (5.1)1/2022Warnings and Precautions (5.2)1/2021.

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.

PATIENT INFORMATIONDARZALEX (Dar-zah-lex) FASPRO(R) (Fas-pro)(daratumumab and hyaluronidase-fihj)injection, for subcutaneous useThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 1/2022DARZALEX FASPRO may be used with other medicines called lenalidomide, thalidomide or pomalidomide. You should also read the Medication Guide that comes with lenalidomide, thalidomide or pomalidomide if you use DARZALEX FASPRO with these medicines. What is DARZALEX FASPRODARZALEX FASPRO is prescription medicine used to treat adult patients with 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 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, 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 pomalidomide and dexamethasone in people who have received at least one prior medicine including lenalidomide and proteasome inhibitor to treat multiple myeloma.in combination with the medicines carfilzomib and dexamethasone in people who have received one to three prior medicines to treat multiple myeloma.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.DARZALEX FASPRO is prescription medicine also used in combination with the medicines bortezomib, cyclophosphamide and dexamethasone in patients with newly diagnosed light chain (AL) amyloidosis.It is not known if DARZALEX FASPRO is safe and effective in children.Do not receive DARZALEX FASPRO if you have history of severe allergic reaction to daratumumab, hyaluronidase or any of the ingredients in DARZALEX FASPRO. See the end of this leaflet for complete list of ingredients in DARZALEX FASPRO.Before you receive DARZALEX FASPRO, 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 FASPRO 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 FASPRO. Tell your healthcare provider right away if you get worsening tiredness or yellowing of your skin or white part of your eyes.are pregnant or plan to become pregnant. DARZALEX FASPRO 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 FASPRO.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 FASPRO. Talk to your healthcare provider about birth control methods that you can use during this time.Before starting DARZALEX FASPRO in combination with lenalidomide, thalidomide or pomalidomide, females and males must agree to the instructions in the lenalidomide, thalidomide or pomalidomide REMS program.The lenalidomide, thalidomide and pomalidomide REMS have 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, thalidomide and pomalidomide REMS about sperm donation and how lenalidomide, thalidomide and pomalidomide can pass into human semen. are breastfeeding or plan to breastfeed. It is not known if DARZALEX FASPRO passes into your breast milk. You should not breastfeed during treatment with DARZALEX FASPRO. Talk to your healthcare provider about the best way to feed your baby during treatment with DARZALEX FASPRO.Before you receive DARZALEX FASPRO for light chain (AL) amyloidosis, tell your healthcare provider if you have history of heart problems. DARZALEX FASPRO should not be used in light chain (AL) amyloidosis patients with highly advanced heart disease outside of clinical trials. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive DARZALEX FASPRODARZALEX FASPRO may be given alone or together with other medicines used to treat multiple myeloma.DARZALEX FASPRO will be given to you by your healthcare provider as an injection under the skin, in the stomach area (abdomen).DARZALEX FASPRO is injected over to minutes.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 FASPRO and after each dose of DARZALEX FASPRO to help reduce the risk of serious allergic reactions and other reactions due to release of certain substances by your body (systemic).If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of DARZALEX FASPRODARZALEX FASPRO may cause serious reactions, including:Serious allergic reactions and other severe injection-related reactions. Serious allergic reactions and reactions due to release of certain substances by your body (systemic) that can lead to death, can happen with DARZALEX FASPRO. Tell your healthcare provider or get medical help right away if you get any of these symptoms during or after an injection of DARZALEX FASPRO.shortness of breath or trouble breathingdizziness or lightheadedness (hypotension)coughwheezingheart beating faster than usuallow oxygen in the blood (hypoxia)throat tightnessrunny or stuffy noseheadacheitchinghigh blood pressurenauseavomitingchillsfeverchest painblurred visionInjection site reactions. Skin reactions at or near the injection site (local), including injection site reactions, can happen with DARZALEX FASPRO. Symptoms at the site of injection may include itching, swelling, bruising, pain, rash, bleeding, or redness of the skin. These reactions sometimes happen more than 24 hours after an injection of DARZALEX FASPRO.Heart problems in people with light chain (AL) amyloidosis. Heart problems, in some cases fatal, have occurred. Your healthcare provider will monitor you closely during treatment with DARZALEX FASPRO. Call your healthcare provider right away if you get any of the following symptoms: chest pain, feeling faint, swollen legs, shortness of breath, or abnormal heart rhythm.Decreases in blood cell counts. DARZALEX FASPRO 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 FASPRO. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.Changes in blood tests. DARZALEX FASPRO 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 FASPRO. Your healthcare provider will do blood tests to match your blood type before you start treatment with DARZALEX FASPRO. Tell all of your healthcare providers that you are being treated with DARZALEX FASPRO before receiving blood transfusions. The most common side effects of DARZALEX FASPRO when used alone include: cold-like symptoms (upper respiratory infection) and decreased red blood cell counts. The most common side effects of DARZALEX FASPRO used in combination therapy include: tirednessnauseadiarrheashortness of breathtrouble sleepingheadachefevercoughmuscle spasmsback painvomitinghigh blood pressurecold-like symptoms (upper-respiratory infection)nerve damage causing tingling, numbness or painconstipationlung infection (pneumonia)swollen hands, ankles, or feetdecreased red blood cell countsThese are not all the possible side effects of DARZALEX FASPRO.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 DARZALEX FASPRO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about DARZALEX FASPRO that is written for health professionals.What are the ingredients in DARZALEX FASPROActive ingredient: daratumumab and hyaluronidase-fihj Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 20, sorbitol, and water for injection. Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044 U.S. License Number 1864 For more information, call 1-800-526-7736 or go to www.DARZALEXFASPRO.com.. 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 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, 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 pomalidomide and dexamethasone in people who have received at least one prior medicine including lenalidomide and proteasome inhibitor to treat multiple myeloma.. in combination with the medicines carfilzomib and dexamethasone in people who have received one to three prior medicines to treat multiple myeloma.. 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.. have history of breathing problems.. have had shingles (herpes zoster).. have ever had or might now have hepatitis infection as DARZALEX FASPRO 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 FASPRO. Tell your healthcare provider right away if you get worsening tiredness or yellowing of your skin or white part of your eyes.. are pregnant or plan to become pregnant. DARZALEX FASPRO 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 FASPRO.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 FASPRO. Talk to your healthcare provider about birth control methods that you can use during this time.Before starting DARZALEX FASPRO in combination with lenalidomide, thalidomide or pomalidomide, females and males must agree to the instructions in the lenalidomide, thalidomide or pomalidomide REMS program.The lenalidomide, thalidomide and pomalidomide REMS have 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, thalidomide and pomalidomide REMS about sperm donation and how lenalidomide, thalidomide and pomalidomide 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 FASPRO. Talk to your healthcare provider about birth control methods that you can use during this time.. Before starting DARZALEX FASPRO in combination with lenalidomide, thalidomide or pomalidomide, females and males must agree to the instructions in the lenalidomide, thalidomide or pomalidomide REMS program.The lenalidomide, thalidomide and pomalidomide REMS have 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, thalidomide and pomalidomide REMS about sperm donation and how lenalidomide, thalidomide and pomalidomide can pass into human semen. The lenalidomide, thalidomide and pomalidomide REMS have 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, thalidomide and pomalidomide REMS about sperm donation and how lenalidomide, thalidomide and pomalidomide can pass into human semen.. are breastfeeding or plan to breastfeed. It is not known if DARZALEX FASPRO passes into your breast milk. You should not breastfeed during treatment with DARZALEX FASPRO. Talk to your healthcare provider about the best way to feed your baby during treatment with DARZALEX FASPRO.. DARZALEX FASPRO may be given alone or together with other medicines used to treat multiple myeloma.. DARZALEX FASPRO will be given to you by your healthcare provider as an injection under the skin, in the stomach area (abdomen).. DARZALEX FASPRO is injected over to minutes.. 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 FASPRO and after each dose of DARZALEX FASPRO to help reduce the risk of serious allergic reactions and other reactions due to release of certain substances by your body (systemic).. Serious allergic reactions and other severe injection-related reactions. Serious allergic reactions and reactions due to release of certain substances by your body (systemic) that can lead to death, can happen with DARZALEX FASPRO. Tell your healthcare provider or get medical help right away if you get any of these symptoms during or after an injection of DARZALEX FASPRO.. 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. runny or stuffy nose. headache. itching. high blood pressure. nausea. vomiting. chills. fever. chest pain. blurred vision. Injection site reactions. Skin reactions at or near the injection site (local), including injection site reactions, can happen with DARZALEX FASPRO. Symptoms at the site of injection may include itching, swelling, bruising, pain, rash, bleeding, or redness of the skin. These reactions sometimes happen more than 24 hours after an injection of DARZALEX FASPRO.. Heart problems in people with light chain (AL) amyloidosis. Heart problems, in some cases fatal, have occurred. Your healthcare provider will monitor you closely during treatment with DARZALEX FASPRO. Call your healthcare provider right away if you get any of the following symptoms: chest pain, feeling faint, swollen legs, shortness of breath, or abnormal heart rhythm.. Decreases in blood cell counts. DARZALEX FASPRO 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 FASPRO. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.. Changes in blood tests. DARZALEX FASPRO 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 FASPRO. Your healthcare provider will do blood tests to match your blood type before you start treatment with DARZALEX FASPRO. Tell all of your healthcare providers that you are being treated with DARZALEX FASPRO before receiving blood transfusions. tiredness. nausea. diarrhea. shortness of breath. trouble sleeping. headache. fever. cough. muscle spasms. back pain. vomiting. high blood pressure. cold-like symptoms (upper-respiratory infection). nerve damage causing tingling, numbness or pain. constipation. lung infection (pneumonia). swollen hands, ankles, or feet. decreased red blood cell counts.

SPL UNCLASSIFIED SECTION.

1.1Multiple Myeloma. DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma:in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.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, 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 pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and proteasome inhibitor.in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.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 bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.. 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, 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 pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and proteasome inhibitor.. in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.. 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.

STORAGE AND HANDLING SECTION.

Store DARZALEX FASPRO vials in refrigerator at 2oC to 8oC (36oF to 46oF) in the original carton to protect from light.Do not freeze or shake.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryDARZALEX FASPRO 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 FASPRO 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 FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available through REMS program. Refer to the lenalidomide, thalidomide or pomalidomide 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 FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until hematology evaluation is completed.. Data. Animal DataDARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase. Mice 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 the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose.There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.. 8.2 Lactation. Risk SummaryThere is no data on the presence of daratumumab and hyaluronidase 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 FASPRO is administered with lenalidomide, thalidomide or pomalidomide, advise women not to breastfeed during treatment with DARZALEX FASPRO. Refer to lenalidomide, thalidomide or pomalidomide prescribing information for additional information.. Data. Animal DataNo systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on post-natal development through sexual maturity in offspring of mice treated daily during lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.. 8.3 Females and Males of Reproductive Potential. DARZALEX FASPRO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingWith the combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide, refer to the lenalidomide, thalidomide or pomalidomide 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 FASPRO and for months after the last dose. Additionally, refer to the lenalidomide, thalidomide or pomalidomide labeling for additional recommendations for contraception.. 8.4 Pediatric Use. Safety and effectiveness of DARZALEX FASPRO in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 291 patients who received DARZALEX FASPRO as monotherapy for relapsed and refractory multiple myeloma, 37% were 65 to <75 years of age, and 19% were 75 years of age or older. No overall differences in effectiveness of DARZALEX FASPRO have been observed between patients >=65 years of age and younger patients. Adverse reactions that occurred at higher frequency (>=5% difference) in patients >=65 years of age included upper respiratory tract infection, urinary tract infection, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema. Serious adverse reactions that occurred at higher frequency (>=2% difference) in patients >=65 years of age included pneumonia.Of the 214 patients who received DARZALEX FASPRO as combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO as combination therapy with lenalidomide and low-dose dexamethasone for relapsed and refractory multiple myeloma, 43% were 65 to <75 years of age, and 18% were 75 years of age or older. No overall differences in effectiveness were observed between patients >=65 years (n=131) and <65 years (n=85). Adverse reactions occurring at higher frequency (>=5% difference) in patients >=65 years of age included fatigue, pyrexia, peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at higher frequency (>=2% difference) in patients >=65 years of age included neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary tract infection.Of the 193 patients who received DARZALEX FASPRO as part of combination therapy for light chain (AL) amyloidosis, 35% were 65 to <75 years of age, and 10% were 75 years of age or older. Clinical studies of DARZALEX FASPRO as part of combination therapy for patients with light chain (AL) amyloidosis did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs from that of younger patients. Adverse reactions that occurred at higher frequency in patients >=65 years of age were peripheral edema, asthenia, pneumonia and hypotension.No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity and Other Administration Reactions: Permanently discontinue DARZALEX FASPRO for life-threatening reactions. (5.1)Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis: Monitor patients with cardiac involvement more frequently for cardiac adverse reactions and administer supportive care as appropriate. (5.2)Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO to allow recovery of neutrophils. (5.3)Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Consider withholding DARZALEX FASPRO 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 (5.5, 8.1, 8.3).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 FASPRO. (5.6, 7.1). Hypersensitivity and Other Administration Reactions: Permanently discontinue DARZALEX FASPRO for life-threatening reactions. (5.1). Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis: Monitor patients with cardiac involvement more frequently for cardiac adverse reactions and administer supportive care as appropriate. (5.2). Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO to allow recovery of neutrophils. (5.3). Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Consider withholding DARZALEX FASPRO 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 (5.5, 8.1, 8.3).. 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 FASPRO. (5.6, 7.1). 5.1Hypersensitivity and Other Administration Reactions. Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO [see Adverse Reactions (6.3)].. Systemic ReactionsIn pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of combination therapy, 9% of patients experienced systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.Severe reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.5)]. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.5)].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 daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO.. Local ReactionsIn this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred median of minutes (range: minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.. 5.2Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis. Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions (6.1)]. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied.Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.. 5.3Neutropenia. Daratumumab 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 FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed.. 5.4Thrombocytopenia. Daratumumab 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 FASPRO until recovery of platelets.. 5.5Embryo-Fetal Toxicity. Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to pregnant woman. DARZALEX FASPRO 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 FASPRO and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].The combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.. 5.6Interference 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 administration. 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 FASPRO. Type and screen patients prior to starting DARZALEX FASPRO [see Dosage and Administration (2.1)].. 5.7Interference 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 DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.