Daratumumab

12.1 Mechanism of Action CD38 is a 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 IgG1κ 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). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T regs ) and B cells (CD38+B regs ) are decreased by daratumumab. Hyaluronan is a 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 a 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.

1 INDICATIONS AND USAGE DARZALEX FASPRO is a combination of daratumumab, a CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with: multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant 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 a 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 a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent high-risk smoldering multiple myeloma as monotherapy light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide and dexamethason

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. Pre-medicate with a corticosteroid, acetaminophen and a histamine-1 receptor antagonist. ( 2.6 ) The recommended dosage of DARZALEX FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to recommended schedule. ( 2.2 , 2.3 , 2.4 ) Administer post-medications as recommended. ( 2.6 ) 2.1 Important 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 (2.6) ] . Type and screen patients prior to starting DARZALEX FASPRO. 2.2 Recommended 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 to 5 minutes. Tables 1, 2, 3, 4, 5, and 6 provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of a 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 1 when DARZALEX FASPRO is administered: 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. Table 1: DARZALEX FASPRO dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) and for monotherapy Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) Use the dosing schedule provided in Table 2 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) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 54 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 16 doses) Week 55 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 55 every four weeks When DARZALEX FASPRO is administered as part of a 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 3 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 phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Eligible for Autologous Stem Cell Transplant (ASCT) Use the dosing schedule in Table 4 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT. Table 4: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and

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) ] . Infections [see Warnings and Precautions (5.3) ] . Neutropenia [see Warnings and Precautions (5.4) ] . Thrombocytopenia [see Warnings and Precautions (5.5) ] . The most common adverse reactions (≥20%) in patients with multiple myeloma eligible for autologous stem cell transplant who received DARZALEX FASPRO-VRd are peripheral neuropathy, fatigue, upper respiratory infection, constipation, musculoskeletal pain, insomnia, rash, diarrhea, edema, and pyrexia. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who were ineligible for autologous stem cell transplant who received DARZALEX FASPRO-VRd are upper respiratory tract infection, sensory neuropathy, musculoskeletal pain, diarrhea, fatigue, edema, rash, motor dysfunction, COVID-19, constipation, sleep disorder, cough, pneumonia, renal impairment, dizziness, nausea, urinary tract infection, pyrexia, abdominal pain, dyspnea, decreased appetite, and bruising. ( 6.1 ) 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 high-risk smoldering multiple myeloma who received DARZALEX FASPRO monotherapy are upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions. ( 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone (n=351) from the start of induction to the end of consolidation compared to bortezomib, lenalidomide and dexamethasone (VRd) (n=347) was evaluated in PERSEUS [see Clinical Studies (14.1) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8 and once every 2 weeks from weeks 9 to 16 during induction in combination with VRd or VRd alone. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT. Within 12 weeks of ASCT, and when engraftment was complete, patients received DARZALEX FASPRO once every 2 weeks from weeks 1 to 8 during consolidation in combination with VRd or VRd alone. The median duration of treatment for induction and consolidation was 9.9 months (0.5 to 18.5 months) for DARZALEX FASPRO-VRd. Serious adverse reactions occurred in 37% of patients who received DARZALEX FASPRO-VRd. The most frequent serious adverse reaction in >5% of patients who received DARZALEX FASPRO-VRd was pneumonia (6%). Fatal adverse reactions occurred in 1.7% of patients who received DARZALEX FASPRO-VRd. Permanent treatment discontinuation due to an adverse reaction o

7 DRUG INTERACTIONS 7.1 Effects 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 Tests Daratumumab 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 a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.